Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[NH:16])OCC)[CH:10]=2)[NH:5][N:4]=1.[NH:17]([C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=O)[NH2:18]>CO>[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]=[C:19]([C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[NH:17][N:18]=3)[CH:10]=2)[NH:5][N:4]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NN)C1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4[nH]nc(Br)c4c3)n[nH]2)C1
Temperature: 85 °C
Yield: 99.4 %

Procedure:
Mixture of ethyl 3-bromo-1H-indazole-5-carbimidate hydrochloride (4.1 g, 13.5 mmol) and (R)-tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (5.1 g, 20 mmol) in MeOH (25 ml) was heated in a sealed tube at 85° C. overnight. After solvent was evaporated, the residue was diluted with DCM (200 ml) and washed with H2O (50 ml), Dried over Na2SO4; filtered and evaporated solvent. Chromatographed residue eluting with 5% MeOH/DCM to yield (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16](C(O)=O)[CH2:15][CH2:14][N:13]2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([O-])=[O:43])[CH3:38].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.C(Cl)Cl>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([CH:16]1[CH2:15][CH2:14][N:13]([C:21]([O:23][CH3:24])=[O:22])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[CH2:17]1)=[O:43])[CH3:38]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)c(F)c1
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
2-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.07 g, 8.8 mmol) (reference compound 33) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.140 g, 13.20 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (2.70 g, 15.84 mmol) suspended in methyl THF (30 mL) and magnesium chloride (1.508 g, 15.84 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 22 h using an oversized stirring bar (flask 2). The contents of flask 1 was transferred into flask 2 and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.348 g, 7.92 mmol) suspended in methyl THF (30 mL) and magnesium chloride (0.754 g, 7.92 mmol) was added. The suspension was stirred at 50° C. for 5 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (5:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). The product methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.190 g, 59.3%) was isolated as a colorless oil. MS m/z 420 (M+H)+
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4])[CH3:2].[OH:17][S:18]([Cl:21])(=O)=[O:19]>C(Cl)Cl>[C:14]([NH:13][C:9]1[CH:10]=[CH:11][C:12]([S:18]([Cl:21])(=[O:19])=[O:17])=[C:7]([CH2:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CCS(=O)(=O)Cc1cccc(NC(C)=O)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Cc1cc(NC(C)=O)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
To N-(3-(ethylsulfonylmethyl)phenyl)acetamide (1 g, 4 mmol) was added HOSO2Cl (4.8 g) dropwise at 0° C. The mixture was stirred at r.t. for 3 hrs. The reaction mixture was diluted with DCM and washed with water, the organics was dried over Na2SO4, concentrated under reduced pressure to give 4-acetamido-2-(ethylsulfonylmethyl)benzene-1-sulfonyl chloride (0.8 g, yield 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[C:34]1[C:38]([C:39](Cl)=[O:40])=[C:37]([CH3:42])[O:36][N:35]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[C:34]1[C:38]([C:39]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=3)[CH2:10][CH2:9]2)=[O:40])=[C:37]([CH3:42])[O:36][N:35]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OCCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(6-hydroxyhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 600.0 (M+H)+.
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ccncc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1ccncc21
Yield: 71.3 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,8-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (145 mg, 0.33 mmol) with benzoic acid (44 mg, 0.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol), 1-hydroxy-7-azabenzo-triazole (49 mg, 0.36 mmol), and N,N-diisopropylethyl amine (0.20 mL, 1.15 mmol), in N,N-dimethylformamide (4 mL) and stir over the weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanol/dichloromethane to give 98 mg (71%) of the desired product as a white solid. MS(ES): (M+1)+ 417.0, 418.1 m/z.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].CS(C)=O.CCOC(C)=O.CCCCCCC>[Cl-].[Na+].O.O>[Cl:21][C:16]1[CH:15]=[C:14]([C:3]2([C:1]#[N:2])[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCC(=O)CC1
Temperature: 135 °C
Reaction time: 12 h
Yield: 109.1 %

Procedure:
To 12-L, four-neck flask equipped with a temperature probe, reflux condenser and overhead stirrer was charged with methyl 5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate (424 g, crude, 350 g theoretical, 1.07 mol), brine (500 mL) and DMSO (3.4 L). The mixture was heated to 135° C. and stirred for 12 h. The progress of the reaction was monitored by TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). The reaction mixture was cooled to room temperature and combined with the crude mixture from a previous 145 g batch reaction, diluted with water (6 L), extracted with MTBE (6 L), and then EtOAc/MTBE (3:5, 8 L). The organics were combined and washed with brine (4×2.5 L), dried over MgSO4, filtered and concentrated under reduced pressure at 40-45° C. to afford a residue which was triturated with heptane/MTBE (1:1, 1.2 L). The resulting slurry was stirred for 0.5 h, filtered and dried under high vacuum for 2 h to afford the title compound [313 g, 77% over 2 steps, 100% (AUC) by GC] as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.9 (d, 1H), 7.75 (dd, 1H), 7.6 (dd, 1H), 2.8-2.5 (m, 2H), 2.48-2.3 (m, 6H).
Reaction SMILES: [ClH:1].Cl.Cl.[O:4]([C:11]1[C:12]([NH:27][C:28]2[S:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:29]=2)=[N:13][CH:14]=[C:15]([S:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[CH:25][S:26][C:19]=23)[CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[ClH:1].[ClH:1].[O:4]([C:11]1[C:12]([NH:27][C:28]2[S:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]3)[N:29]=2)=[N:13][CH:14]=[C:15]([S:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[CH:25][S:26][C:19]=23)[CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 147.2 %

Procedure:
A 250 mL flask was charged with 3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (5.6 g, 8.92 mmol), triethylamine (9.94 mL, 71.3 mmol), and CH2Cl2 (100 mL). Acetic anhydride (1.26 mL, 13.4 mmol) was added and the reaction was stirred at ambient temperature for 10 minutes. The reaction was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (5 to 10% methanol in EtOAc) to afford 1-(4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride (4.16 g, 73.6% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 12.48 (bs, 1H), 8.56 (d, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.40 (m, 2H), 7.18 (m, 1H), 7.14 (m, 2H), 7.07 (d, 1H), 4.32 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.01 (m, 5H), 1.73 (m, 1H), 1.59 (m, 1H). Mass spectrum (apci) m/z=561.3 (M+H-2HCl).
Reaction SMILES: [Na].[C:2](#[N:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18]>>[CH3:8][O:7][C:6]1[CH:5]=[C:4]([CH:3]([C:2]#[N:14])[C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH:13]=[CH:12][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1

Procedure:
25.7 g (1.1 mol eq.) of sodium in small pieces were added gradually to a solution of 198 g (1.1 mol) of homoveratronitrile in 500 ml of diethyl carbonate in such a manner that the temperature remained at approximately 100°. Thereafter, the reaction mixture was heated to reflux for 1 hour, evaporated under reduced pressure, treated with cooled water, acidified with 70 ml of glacial acetic acid and extracted with ether. The combined organic extracts were dried and evaporated. The residual oil Was distilled in a high vacuum, whereby ethyl 3,4-dimethoxyphenylcyanoacetate was obtained, b.p. 170°-172°/70 Pa. HPLC purity >99%.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)SC)#[N:5]>CN(C=O)C>[NH2:5][C:4]1[N:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[C:20]3[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CSC(=NCCCOc1cccc2c(N3CCOCC3)nccc12)NC#N
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc2c(N3CCOCC3)nccc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Methyl hydrazine (7.3 g) is added to a stirred suspension of 1-cyano-2-methyl-3-[3-(1-morpholino-5-isoquinolyloxy)propyl]pseudothiourea (11.56 g) in DMF (91.5 ml). The reaction mixture is stirred at 40° C. under nitrogen for 24 hrs and evaporated in vacuo resulting in a red oil which partially crystallizes on standing. The residue is dissolved in boiling acetonitrile (150 ml) and the hot solution treated with Darco G-60, filtered through Celite, concentrated and cooled. The precipitate is collected, washed with acetonitrile and dried in vacuo at elevated temperature. The dried precipitate is recrystallized from absolute ethanol, dried in vacuo at 75° C. affording the desired product as a powder, M.P. 178°-180° C. Elemental analysis indicates the product as a 1/4 hydrate.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[NH2:11]>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:10]([C:12]2[CH:17]=[N:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cn1
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Temperature: 80 °C
Yield: 6.6 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4,4-dimethyl-3-oxopentanenitrile (782 mg, 6.25 mmol) in anhydrous EtOH (30 ml) was added 5-hydrazinyl-2-methylpyridine (1 g, 8.12 mmol) and the reaction mixture was heated at 80° C. overnight. The residue was purified by silica gel chromatography (DCM/EtOAc 10-50%) to afford 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (95 mg, 7%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 2.59 (s, 3H), 3.67 (brs, 2H), 5.56 (s, 1H), 7.25 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 1H), 8.74 (s, 1H); LC-MS (ESI) m/z 231 (M+H)+.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.[F:33]C1C=CC2SC(I)=NC=2C=1C(F)(F)F>>[F:33][C:4]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Fc1ccc2sc(I)nc2c1C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)c(F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 5-fluoro-2-iodo-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 80° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.02-8.92 (brm, 1H), 8.80-8.70 (brm, 1H), 8.58 (dd, J=4.8, 9.2 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (brs, 1H), 8.05 (s, 1H), 7.64 (dd, J=9.2, 11.2 Hz, 1H), 4.56-4.47 (mc, 1H), 3.40 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.4 Hz, 2H), 2.30-2.11 (m, 4H). MS(ES+): m/z=463.07 (95) [MH+], 380.02 (100) [MH+-piperidine]. HPLC: tR=2.28 min (polar—5 min, ZQ2).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cnc(NC(C)=O)s2)cc1
Temperature: 120 °C
Yield: 78.7 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 4-methoxythiophenol (1.5 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (30 ml) was heated at 120° C. for 3.5 hours with stirring. The reaction mixture was poured into ice water and the precipitates were collected by filtration to give solid. The solid was recrystallized from ethanol to give 2-acetylamino-5-(4-methoxyphenylthio)thiazole (2.2 g, Yield: 78.6%). mp: 190°-191° C. IR (Nujol): 3175, 1695, 1565, 1490, 1295, 1250 cm-1
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:23])[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:21]([CH3:23])[CH3:22])[CH2:31][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: CC(C)c1ccccc1N1CCNCC1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2C(C)C)CC1
Yield: 73 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.[NH:12]1[CH:16]=[N:15][C:14]([C:17]([O:19]C)=[O:18])=[N:13]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:12]1[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[N:13]1
Reactant: COC(=O)c1nc[nH]n1
Reactant: OB(O)c1cc(F)ccc1F
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1ncn(-c2cc(F)ccc2F)n1

Procedure:
This intermediate was prepared from 2,5-difluorophenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C[N:16]([CH:18]=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:16][CH2:18][CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 25.0 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 100 ml of abs. DMF was added 26.0 g of potassium carbonate, followed by 14.2 g of (cycloheylmethyl)amine. After 16 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 36.7 g (100%) of 4-(Cyclohexylmethyl-amino)-3-nitro-benzoic acid methyl ester as an orange solid.
Reaction SMILES: S([CH2:11][N:12]=C=O)(C1C=CC(C)=CC=1)(=O)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH:24]=O)=[CH:19][CH:18]=1.CO>COCCOC.O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH2:24][C:11]#[N:12])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(C)(C)C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(C)(C)CC#N)cc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a mixture of KOBu-t (450 mg, 4.2 mmol) and TosCH2NCO (410 mg, 2.1 mmol) in DME (8 ml) was added a solution of Compound 45 (350 mg, 2.0 mmol) in DME (2 ml) with cooling (-40° C.). The mixture was stirred at same temperature for 10 min. and then at room temperature for 1 h and to this was added MeOH (6 ml) dropwise. The mixture was stirred at same temperature for 1 hr. and then at room temperature for 15 h. The mixture was concentrated to give a solid, which was dissolved in water (10 ml). The aqueous layer was extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give crude product (480 mg) as a yellow oil. The crude product was purified by a column chromatography to give Compound 46 (230 mg, 1.2 mmol,. 60%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](I)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[N:20]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:30]([F:38])[CH:31]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cccnc3n2-c2ccc(OCc3ccccc3)c(F)c2)c1
Yield: 46.2 %

Procedure:
0.38 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (example 7) and 0.37 g of 4-benzyloxy-3-fluorophenylboronic acid are dissolved in 16 ml of degassed dioxane. Then a solution of 0.276 g of potassium carbonate and 0.85 g of lithium chloride in 13 ml of degassed water and 0.115 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 18 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 28:1). Concentration of the chromatographically pure fractions and crystallisation from ethyl acetate gives 0.21 g of the title compound as a yellowish solid of m.p. 168–170° C. The mass spectrum shows the molecular peak MH+ at 455.3 Da.
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]([O:25][CH:26]([CH3:28])[CH3:27])([CH2:22][CH2:23][CH3:24])[CH2:20]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>O1CCCC1>[N:48]1([CH2:20][C:19]([O:25][CH:26]([CH3:28])[CH3:27])([C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])[CH2:22][CH2:23][CH3:24])[CH:52]=[N:51][CH:50]=[N:49]1
Reactant: CCCC(CO)(OC(C)C)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Cn1cncn1)(OC(C)C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.5 g (30 mmoles) of dimethyl azodicarboxylate is added dropwise, at room temperature, to a solution of 5.8 g (20 mmoles) of 2-(2,4-dichlorophenyl)-2-isopropoxypentan-1-ol, 7.9 g (30 mmoles) of triphenylphosphine and 1.66 g (24 mmoles) of 1,2,4-triazole in 100 ml of absolute tetrahydrofuran, and the reaction mixture is then stirred for 3 hours at room temperature and then for a further 16 hours at 50° C. and is evaporated; the residue is digested with 100 ml of diethyl ether, the insoluble residue is filtered off, and the ether phase is concentrated again and purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether). This gives a colourless oil having physical data which agree entirely with those in Example 3b).