Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=[O:15])[N:2]=1.[OH-].[Na+].C(O)C>O>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Yield: 90.5 %

Procedure:
Compound 10 (1.2 g, 5 mmol), NaOH (0.8 g, 20 mmol), ethanol (20 ml) and H2O (40 ml) were added into a 50 ml round-bottom flask. The mixture was refluxed for 2 h. Ethanol was then evaporated in reduced pressure. The mixture was adjusted to pH with 5M HCl. After cooling with cold water, filtration, wash well with water and recrystallization with ethanol, white solids (0.96 g, 90%) were obtained. and mp 307-309° C. (reference[1]: 310° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>N1C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)[CH:8]=2)[N:3]=1)=[O:37]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2nc3ccc(N4CCN(C(C)=O)CC4)cc3c(NCc3ccccc3)c2C#N)c1
Temperature: 0 °C

Procedure:
To the solution of 1.2 g 2-amino-3-cyano-4-benzylamino-6-(4-acetylpiperazin-1-yl)quinoline in 20 ml pyridine, 1.5 g 3-methoxybenzoyl chloride is added and the mixture is heated at reflux temperature for 5 hours. The reaction mixture is poured onto 30 g ice-water and the precipitated solid material is filtered off. After drying 0.45 g of the title compound is obtained (MH+: 535).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][N:17]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 76 %

Procedure:
As described for Example 53, 3-(3,4-difluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (78 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (89 mg, 76%) which was obtained as a light yellow solid. MS: m/e=383.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32].[OH-].[Na+]>CS(C)=O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH:22]=[CH:21]2
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNCC1C=Cc2cc(F)cc(-c3ccccc3Cl)c2O1
Temperature: 60 °C
Yield: 44.5 %

Procedure:
To a solution of [8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.33 g, 0.748 mmol) in anhydrous dimethyl sulfoxide (1.2 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 3.74 mL, 7.48 mmol) and the mixture heated to 60° C. in a sealed vial for 2 days. The cooled reaction mixture was then poured into 2.0 M aqueous sodium hydroxide solution (40 mL) and the product extracted with ethyl acetate (50 mL). The separated organic extract was washed with water (50 mL), and saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 101 mg (45%) of {[8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}methylamine as a yellow syrup. The product was dissolved 2-propanol (1 mL) and diethyl ether (2 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.33 mL, 0.33 mmol) was added followed by hexane (3 mL). The resulting precipitate was filtered to afford 100 mg (39%) of {[8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a tan crystalline solid. HRMS: calcd for C17H15ClFNO+H+, 304.08990. found (ESI, [M+H]+), 304.0891.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1)[CH3:4].S(Cl)([Cl:15])=O.CS(O)(=O)=O>C(#N)C>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10][Cl:1])=[CH:8][CH:7]=1)[CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CN(C)Cc1ccc(CCl)o1

Procedure:
Combine 5-[(dimethylamino)methyl]-furfuryl alcohol hydrochloride (201 g, 1.05 mol) and acetonitrile (500 mL). Add dropwise, thionyl chloride (119 g, 1.0 mol) at such a rate that the temperature of the reaction is maintained at about 30° C. to 35° C. After the addition of thionyl chloride is complete, add methanesulfonic acid (144 g, 1.5 mol) while removing sulfur dioxide and acetonitrile by distillation. Stop the distillation when about 250 mL of distillate has been collected to give the title compound as a solution.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 82 %

Procedure:
As described for example 176, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (69 mg, 82%) which was obtained as a white foam. MS: m/e=411.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][NH:52]/[C:51]/1=[N:60]\[C:61]([C:63]1[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=1)=[O:62].CN1CCOCC1>CN(C=O)C>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([N:57]2[CH2:58][CH2:59][C:54]3([NH:50]/[C:51](=[N:60]/[C:61]([C:63]4[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=4)=[O:62])/[NH:52][CH2:53]3)[CH2:55][CH2:56]2)=[O:20])(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid (0.03 mmol, 10.2 mg) is treated with a solution of HATU (11.4 mg, 0.03 mmol) in DMF (1 ml) followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (11.9 mg, 0.03 mmol) and N-methyl morpholine (0.010 ml, 0.03 mmol) in DMF (1 ml) and shaken at room temperature overnight. The solution is evaporated under vacuum, redissolved in DMSO (0.5 ml) and purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 648.4
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>C(#N)C.O.CN(C)C=O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:31]=[N+:32]=[N-:33])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1-(diphenylmethyl)-3-hydroxyazetidine (5.5 g, 22.98 mmol) was dissolved in acetonitrile (16.5 mL), triethylamine (3.48 g, 34.45 mmol) was added. The reaction mixture was cooled to −10° C., methylsulfonyl chloride (3.16 g, 27.59 mmol) was added dropwise slowly. After completion of dropwise addition, the reaction was performed at 0° C. for 1 h, The resultant reaction liquid was poured into water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a white solid. The resultant white solid was added to N,N-dimethyl formamide (25 mL), sodium azide (5.38 g, 82.73 mmol) was added. The reaction mixture was warmed to 100° C. and the reaction was performed overnight. The resultant reaction liquid was cooled to room temperature, poured into water, extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered; the filtrate was rotatedly concentrated to dryness to yield 1-(diphenylmethyl)-3-azidoazetidine.
Reaction SMILES: [NH2:1][C:2](=[O:33])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:9]=[C:8]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:7]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2](=[O:33])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:9]=[C:8]([C:26]([OH:28])=[O:27])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a suspension of the (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)-amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylate (0.426 g, 0.941 mmol) in DCM (10 mL) was added TFA (5 mL, 67 mmol). After stirring overnight, the reaction was evaporated in vacuo and the residue triturated with 3 mL acetonitrile, filtered, rinsed once with 1 mL acetonitrile and dried under vacuum at 40° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid as an off-white powder (0.343 g, 0.865 mmol, 92% yield). 1H NMR (400 MHz, DMSO-d6): 8.40 (2H, d, J=8.8 Hz), 8.05 (1H, d, J=6.6 Hz), 7.56 (1H, s), 7.32-7.24 (2H, m), 7.19-7.14 (2H, m), 7.11 (1H, s), 7.07-7.01 (3H, m), 4.61-4.52 (1H, m), 1.37 (3H, d, J=7.0 Hz). LC/MS: m/z=397.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4]>CO.[Pd]>[NH2:10][C:9]1[CH:8]=[C:7]([CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CCC2CC2)sc1C(=O)O
Reaction time: 5 h

Procedure:
A suspension of 5-cyclopropylethynyl-3-nitrothiophene-2-carboxylic acid methyl ester (104 mg) and palladium (10% on carbon, 10 mg) in methanol (10 mL) was vigorously stirred under an atmosphere of hydrogen at atmospheric pressure for 5 hours. The catalyst was then filtered off with suction, and the filtrate was concentrated. The product with the molecular weight of 225.31 (C11H15NO2S); MS (ESI): 226 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1.CN1CCCC1=O.[N-:35]=[N+:36]=[N-:37].[Na+].Cl.O1CCOCC1>C1COCC1.O>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]4[NH:37][N:36]=[N:35][N:26]=4)[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1
Reactant: N#CCC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Fc1cc(-c2nc(N3CCC(Cc4nnn[nH]4)CC3)c3sccc3n2)c(F)cc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 175.9 %

Procedure:
A mixture of 825 mg of {1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}acetonitrile, 15 ml of N-methylpyrrolidinone, 1.32 g of sodium azide and 2.81 g of triethylamide hydrochloride was stirred for 8 hours at 150° C. After the reaction mixture was allowed to cool to room temperature, 50 ml of water was added and the resultant was extracted with EtOAc. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give an oily substance. After the obtained oily substance was dissolved in 10 ml of THF and 4 ml of 4M HCl-dioxane solution was added, the resultant was concentrated under reduced pressure to give a solid. The obtained solid was recrystallized from iPrOH-EtOAc-ether to give 868 mg of 2-(4-chloro-2,5-difluorophenyl)-4-[4-(1H-tetrazole-5-ylmethyl)piperidine-1-yl]thieno[3,2-d]pyrimidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:40](=[O:41])[C:39]6[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=6[F:47])[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine (80 mg, 0.17 mmol) in THF (3 mL) was added TEA (25 μL, 0.25 mmol) and 2,6-difluorobenzoyl chloride (22 μL, 0.18 mmol). The reaction was stirred at rt for 2 h, and the reaction was diluted with 30 mL DCM and adsorbed onto silica. The crude product was purified by flash chromatography and reversed-phase HPLC to generate, after lyophilization, the title compound as a TFA salt (38 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.84 (s, 1H), 9.59 (s, 1H), 8.88 (d, J=6.7 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.58-7.62 (m, 1H), 7.41-7.52 (m, 4H), 7.24 (t, J=8.0 Hz, 2H), 7.13-7.16 (m, 2H), 6.61 (d, J=5.3 Hz, 1H), 4.04-4.12 (m, 1H), 3.22-3.28 (m, 2H), 3.06-3.12 (m, 2H), 2.82 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]ccc3c2)cc(OC)c1OC
Yield: 83.6 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.54 g, 7.83 mmol), 3,4,5-trimethoxyphenylboronic acid (1.83 g, 8.61 mmol) and dichlorobis(triphenylphosphine)palladium (II) (275 mg, 0.39 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and reacted in a microwave reactor for 5 min at 150° C. EtOAc was added and the mixture was washed with water, brine, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 1.86 g (84%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 9.9 (bs, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.11 (d. J=2.1 Hz, 1H), 7.41 (t, J=2.1 Hz, 1H), 6.82 (s, 2H), 6.58 (t, J=1.5 Hz, 1H), 3.96 (s, 6H), 3.92 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.I[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC>[Cu]I.O.C(OCC)(=O)C.O1CCOCC1>[N:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)=[CH:16][CH:17]=1
Reactant: Ic1ccncc1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccncc2)c2ncccc12
Yield: 67.1 %

Procedure:
1.76 g (10 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate, 2.66 g (13 mmol) of 4-iodopyridine, 0.19 g (1 mmol) of copper(1) iodide, 4.46 g (21 mmol) of tripotassium phosphate, 1.2 cm3 of a trans-1,2-cyclohexanediamine (10 mmol) and 0.5 cm3 of n-dodecane were added to 100 cm3 of dioxane under an argon atmosphere at a temperature in the region of 20° C. The mixture was heated at reflux of the solvent for 20 h and then it was rapidly added to a mixture of 300 cm3 of ethyl acetate and 300 cm3 of water. The organic phase was separated by settling, washed 3 times with 300 cm3 of water and then 300 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa) and the residue was triturated in 30 cm3 of diisopropyl ether, filtered off and then dried under a hood. 1.7 g of methyl 1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were thus obtained in the form of a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:16])[C:12]#[C:13][CH2:14][CH3:15].[Cl-]>C(N(CC)CC)C.[Cu]I>[CH3:9][O:10][C:11](=[O:16])[CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCC#CC(=O)OC
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1cccc(Br)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of 4.73 g of 2,6-dibromopyridine in 150 ml of triethylamine is mixed under ice cooling with 2.69 g of pentynoic acid methyl ester, 350 mg of bis-triphenylphosphinepalladium(II) chloride and 48 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 3 hours at room temperature. The precipitate--consisting of 2,6-bis-(4-methoxycarbonyl-1-butinyl)-pyridine and triethylammonium bromide--is suctioned off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 2.32 g of 5-(6-bromo-2-pyridyl)-4-pentynoic acid methyl ester of melting point 59°-61° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:36][CH2:35]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(C)cc1N1CCNCC1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1ccc(C)cc1N1CCN(C(=O)Nc2cc3ccccc3nc2C)CC1
Yield: 80 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].C([Li])CCC.CN([CH:16]=[O:17])C.[Cl-].[NH4+]>C1COCC1.C(O)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH:16]=[O:17])[S:5][C:6]=1[CH3:7]
Reactant: CN(C)C=O
Reactant: Cc1ncsc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, to a solution of 4,5-dimethylthiazole (0.62 g, 5.5 mmol) in anhydrous THF (40 mL) at −78° C., n-butyllithium (2.3 M in hexanes, 3.6 mL, 8.28 mmol) was slowly added and the reaction mixture was stirred at −78° C. for 1 h. Then a solution of anhydrous DMF (1.1 mL, 14.2 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred for 2.5 hours, allowing the temperature to raise to −60° C. Acetic acid (0.5 mL) and an aqueous solution of ammonium chloride were added, and warmed to room temperature. The resulting solution was extracted with diethyl ether and ethyl acetate. The combined organic phase were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, PE/EA, 1/0 to 7/3) to afford 4,5-dimethyl-1,3-thiazole-2-carbaldehyde, as a yellow oil which turns into a white solid after storage at −18° C. LCMS m/z (M+H) 142.1 found, 142.1 required.
Reaction SMILES: C(O)=O.C(O[CH:7](OCC)[CH2:8][CH:9]([O:14][CH3:15])[CH2:10][CH2:11][CH:12]=[CH2:13])C.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH3:15][O:14][CH:9]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:8][CH:7]=[N:25][OH:26]
Reactant: NO
Reactant: C=CCCC(CC(OCC)OCC)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: C=CCCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 80% formic acid solution (30 mL) was added to 7,7-diethoxy-5-methoxyhept-1-ene obtained in Preparation Example 57-(2) (2.98 g), and the mixture was stirred at room temperature for 10 minutes. After further adding a 75% ethanol solution (64 mL), sodium acetate (3.75 g) and hydroxylamine hydrochloride (1.92 g) were added, followed by further stirring for one hour and 20 minutes. The solvent was concentrated to about 40 mL under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution (three times), water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.95 g).