Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53].[Cl-].[NH4+]>>[CH2:52]([NH:54][C:55]([N:31]1[C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([C:16]3[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=4)[CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:18][CH:17]=3)[C:20]=2[CH2:33][CH2:32]1)=[O:56])[CH3:53]
Reactant: CCN=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), triethylamine (780 μl, 5.56 mmol) and ethylisocyanate (780 μl, 5.56 mmol) were added, followed by refluxing for 6 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic layer was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid ethylamide (110.1 mg, Yield 97%). To this, trifluoroacetic acid (1 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 3 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. The solid was filtered, followed by purification by silica gel column chromatography (dichloromethane/2M ammonia methanol=50/1), to obtain the desired compound as a yellow solid (20.9 mg, Yield 31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br.CO.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:31])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])([CH3:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: BrBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.283 g, 0.683 mmol) in AcOH (1 mL) was added a solution of bromine (0.070 mL, 1.366 mmol) in AcOH (1 mL) drop-wise and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8. MeOH (5 mL), TEA (0.146 g, 1.439 mmol) and di-tert-butyl dicarbonate (0.188 g, 0.864 mmol) were added in sequence to the above mixture and the reaction mixture was stirred at ambient temperature for 1.5 h. The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 36%) as a solid. LC/MS (Table 1, Method 25) Rt=0.913 min.; MS m/z: 437 [M+H−56]+ and 439 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.26 (brs, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.75-4.70 (m, 1H), 4.60 (d, J=12.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.55 (m, 2H), 3.44 (d, J=8.4 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.32-1.27 (m, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]=2C(OCC)=O)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC(N1CCN(C2[C:55]3[C:50](=[CH:51][C:52](F)=[C:53](F)[CH:54]=3)N=CN=2)CC1)=O)(C)(C)C.[N-:58]=[C:59]=S>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[N:11]1[CH2:10][CH2:9][N:8]([C:6]([NH:58][C:59]2[CH:23]=[CH:22][C:21]([O:24][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[CH:20][CH:19]=2)=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: [N-]=C=S
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1N1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cc2nccc(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1OC

Procedure:
In the following Examples 408-410, substantially the same procedure as in Example 329 was repeated, except that 4-(6,7-dimethoxy-3-ethoxycarbonyl-4-quinolyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 18 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, and the corresponding isothiocyanate was used in place of 4-phenoxyphenyl isocyanate (used in Example 408), to give the desired compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:42]3[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=3)(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)cc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3,5-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (78 mg, 42%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 26.7 %

Procedure:
To a slurry of 66.4 g (0.50 mol) of isonipecotic acid, and 145 mL (0.50 mol) of triethylamine in 600 mL of methylene chloride was added a solution of 72 mL (0.50 mol) of benzyl chloroformate in 200 mL of toluene at 10° C. The slurry was allowed to warm to room temperature and after stirring for 17 h was treated with 1 L of a 10% aqueous sodium carbonate solution. The layers were separated, and the aqueous portion was extracted once with ether and then acidified to pH 3. The aqueous portion was then extracted with methylene chloride. The organic extract was washed with brine, dried over MgSO4 and concentrated to give 35.2 g of the title compound as an oil which was used without further purification.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[S:24][C:25]([CH:28]=O)=[CH:26][N:27]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.O1CCCC1.CO>C(Cl)Cl>[CH:1]1([NH:7][CH2:28][C:25]2[S:24][C:23]([NH:22][C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:10]([O:9][CH3:8])[CH:11]=3)=[N:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2ncc(CNC3CCCCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 19 mg (0.19 mmol) cyclohexylamine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (1 ml), methanol (1 ml) and methylene chloride (1 ml). The reaction was not complete and the same amount of reagent was added like in example 57. Only the imine was formed. Therefore the crude product was dissolved in methanol (1 ml) and 8.6 mg sodium borohydride was added and the reaction stirred for 4 hours at room temperature. After workup the crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 16 mg (21%) of (5-cyclohexylaminomethyl-thiazol-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow oil. MS ISP (m/e): 398.3 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.62 (s, 1H), 7.25 (s, 1H), 7.16 (d, 1H), 7.10 (s, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 3.94 (s, 2H), 3.85 (s, 3H), 2.54 (m, 1H), 2.30 (s, 3H), 1.93 (m, 2H), 1.72 (m, 2H), 1.64 (m, 1H), 1.28-1.09 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl.[OH-].[NH4+]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(SCC(F)(F)C(F)F)cc1N

Procedure:
4 G. of 2-nitro-4-(2,2,3,3-tetrafluoropropylthio) aniline is treated with 24 g. of stannous chloride in 25 ml. on concentrated hydrochloric acid. The mixture is stirred for one-half hour, basified with ammonium hydroxide and extracted with chloroform. The chloroform solution is filtered, dried over sodium sulfate, and evaporated to give 1,2-diamino-4-(2,2,3,3-tetrafluoropropylthio) benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].[CH2:12](N)[CH2:13][NH2:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]1[NH:14][CH2:13][CH2:12][N:11]=1.[ClH:1]
Reactant: NCCN
Reactant: N#CCc1c(F)cccc1Cl
Product: Cl
Product: Fc1cccc(Cl)c1CC1=NCCN1

Procedure:
2-(2-Chloro-6-fluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-chloro-6-fluoro-phenyl)-acetonitrile and ethylene diamine in analogy to Example 22; isolated as hydrochloride: colourless powder; MS (ISP): 212.9 ((M+H)+.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNC>CN(C=O)C.O>[CH3:17][N:18]([CH3:19])[C:10]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
2-(tert-butoxycarbonylamino)-2-ethylbutanoic acid ((200 mg, 0.87 mmol), HATU (CAN 148893-10-1, 660 mg, 1.74 mmol) and triethylamine (CAN 121-44-8, 260 mg, 2.61 mmol) was added to a solution of dimethylamine hydrochloride (CAN 506-59-2, 117 mg, 1.74 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The mixture was added to water (20 mL) and extracted with ethyl acetate (30 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (eluting with 30% ethyl acetate in petroleum ether) to give the product (120 mg, 53.7%); MS (EI): m/e=259.2 [M+H]+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[O:19])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([N:2]2[C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)=[O:19])=[CH:14][CH:13]=1
Reactant: O=c1[nH]sc2ccccc12
Reactant: Cc1ccc(CN=C=O)cc1
Product: Cc1ccc(CNC(=O)n2sc3ccccc3c2=O)cc1

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 61 (54% yield) was synthesized from benzo[d]isothiazol-3-one and 4-methylbenzyl isocyanate as a white solid. mp 171-173° C.; IR(KBr) 3281, 1711, 1650, 1538 cm−1; 1H-NMR (DMSO-d6) δ2.27 (s, 3H), 4.48 (d, J=5.8 Hz, 2H), 7.14 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 9.22 (br t, J=5.8 Hz, 1H); ESIMS m/e 299 (M++1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si](Cl)(C)C.C(=[N:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]([NH2:33])=[O:32])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[NH2:25][C:26]1[N:27]=[CH:28][N:29]([CH2:1][C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)[C:30]=1[C:31]([NH2:33])=[O:32]
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: COc1ccc(CO)cc1OC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cnc(N)c2C(N)=O)cc1OC
Yield: 62.6 %

Procedure:
A dimethyl sulfoxide solution of 4.29 ml (30 mmol) veratryl alcohol (3,4-dimethoxybenzyl alcohol) was treated in 22.86 ml (180 mmol) trimethylsilyl chloride at room temperature for 1 hour. The resulting product was dissolved in ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under vacuum, the resulting residue was reacted with 2.14 g (10 mmol) of 4-benzylideneamino-5-imidazole carboxamide and 5.52 (40 mmol) of potassium carbonate in the same manner as in Reference Example 2 to obtain 1.73 g of 4-amino-1-(3,4-dimethoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[CH:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]3[O:3][C:2]([NH:17][C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Reactant: Clc1ncc(-c2ccc3cnccc3c2)o1
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3ccc4cnccc4c3)o2)c1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A mixture of 2-chloro-5-(isoquinolin-6-yl)oxazole 14 (0.069 g, 0.30 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (0.157 g, 0.599 mmol) in 2-propanol (20 mL) was heated to 80° C. for 24 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(isoquinolin-6-yl)oxazol-2-yl)amino)phenyl)-1-phenylmethanesulfonamide 27 (0.099 g, 72% yield) as pale yellow solid. MS (ES) m/z 457 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[H][H].[CH3:10][C:11]([CH3:21])([CH2:15]OS(C)(=O)=O)[C:12](=[O:14])[CH3:13]>CN(C)C=O.O>[CH3:10][C:11]([CH3:21])([CH2:15][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)C(C)(C)COS(C)(=O)=O
Reactant: [H][H]
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(C)(C)Cn1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
In the course of 3 hours, 60 g (2 mols of sodium hydride (80% strength in paraffin oil) are added to a solution of 138 g (2 mols of 1,2,4-triazole in 1,600 ml of absolute dimethylformamide, with vigorous evolution hydrogen. The mixture is stirred for a further 30 minutes at room temperature. 388 g (2 mols of 3,3-dimethyl -4-[(methylsulphonyl)oxy]-2-butanone are then added dropwise in the course of 15 minutes. The reaction mixture is then stirred for 16 hours at 95° C. 100 ml of water are firstly added carefully to the reaction mixture, and the mixture is then poured into 4 1 of water. The mixture is extracted six times with dichloromethane. The combined organic phases are washed once with plenty of water, dried over sodium sulphate and concentrated under a high vacuum. After column chromatography (silica gel; dichloromethane/ethyl acetate=1:1), 290 g (86.8% of 3,3-dimethyl -4-(1,2,4-triazol-1-yl)-2-butanone are obtained as an oil with a content of 97% after GC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:22].[Na+].CO>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH2:18][CH3:19])=[O:22])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)c1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.20 g), sodium periodate (0.18 g), methanol (3 ml), water (1 ml), and THF (0.4 ml) was stirred at room temperature for 3.5 hours. Water was poured thereinto under ice-cooling, and then the precipitated solid was collected by filtration. The obtained solid was washed with water and hexane, and dried to give 0.19 g of 6-bromo-2-(2-ethylsulfinylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 43).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]1[O:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][C:12]([C:18](Cl)=[O:19])=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[OH:25]CCN1CCOCC1.N1C=CC=CC=1>C1C=CC=CC=1>[C:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:6]1[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]2=[O:17])([OH:25])=[O:19]
Reactant: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)Cl)ccc2o1
Reactant: OCCN1CCOCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 88.5 %

Procedure:
2'-isopropoxy-flavone-6-carbonyl-chloride (4.3 g) prepared according to Example 18, dissolved in anhydrous benzene (40 ml) was treated with N-hydroxyethyl-morpholine (3.2 g) and pyridine (1 ml) at room temperature for 24 hours. The benzene solution was washed with aqueous citric acid 40% with sodium bicarbonate and water, then evaporated to dryness. The residue, crystallized from acetone, gave morpholinoethyl-ester of 6-carboxy-2'-isopropoxy-flavone (3.6 g; m.p. 133°-135° C). By using the same method, the morpholinoethyl-esters of the 6-carboxy-flavones specified at the end of Example 20 were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=[CH:27][CH:28]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=5:5:1) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][CH3:11].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:9]([CH3:8])[CH2:10][CH3:11])=[N:5][N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: CCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (5 g) and butan-2-one (5.5 g) in acetic acid was added sodium cyanoborohydride (16 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.8 g, 61%).
Reaction SMILES: [C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[CH:2].[ClH:17].O1CCOCC1>ClCCl>[ClH:17].[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#CC1(C)CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-ethynyl-3-methylpiperidine-1-carboxylate (0.50 g, 2.24 mmol) in dichloromethane (10 mL) was added a solution of hydrogen chloride in 1,4-dioxane (3.0M, 5.0 mL, 15.00 mmol). The resulting solution was allowed to stir at room temperature. After 2 h, the mixture was concentrated to provide 0.34 g (95%) of 3-ethynyl-3-methylpiperidine hydrochloride (340 mg, 95%) as a white solid.