Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][Br:4].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[Br-:4].[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(C)CBr
Solvent: c1ccccc1
Product: CCC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 18.6 %

Procedure:
30.9 gm of 2-methylbromobutane and 53.7 gm of triphenylphosphine were dissolved into 50 ml of benzene and the mixture was refluxed for 88 hours. Crystals deposited were collected by filtration, washed with benzene, and dried to produce 15.7 gm of 2-methylbutyltriphenylphosphonium bromide (yield: 42%). The product was submitted to the next step without purification.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CC=O)CC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(CC=CCc1ccccc1)CC(C)(C)C
Yield: 65.2 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.80 g, 6.26 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.26 mmol, 1.0 equiv.) and 3,5,5-trimethylhexanal (1.33 g, 9.39 mmol, 1.5 equiv.), 0.94 g (65%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH3:1][N:2]([CH:29]1[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]1)[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[CH:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)=[CH:11][C:10]=2[OH:28])=[CH:5][CH:4]=1.C(Cl)Cl.Cl.B(Br)(Br)Br>CCO>[NH:18]1[CH:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[N:7]=[N:8][C:3]([N:2]([CH3:1])[CH:29]4[CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]4)=[CH:4][CH:5]=3)=[C:10]([OH:28])[CH:11]=2)[N:16]=[CH:17]1
Reactant: CN(c1ccc(-c2ccc(-c3cn(COCC[Si](C)(C)C)cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CN(c1ccc(-c2ccc(-c3c[nH]cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 110 °C
Yield: 5.5 %

Procedure:
To a microwave vial containing 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenol (mixture from previous step, 50 mg, 0.09 mmol) in EtOH (1.0 mL)/DCM (1.0 mL) and conc. HCl (8.5 μL) was added BBr3 (0.46 mL, 0.46 mmol). The vial was purged with N2 (2×) and the reaction mixture was heated at 110° C. in a microwave reactor for 30 min. The reaction mixture was filtered through celite (pre-packed filter funnel) with a MeOH wash. The filtrate was acidified to pH 3 using 1N HCl and purified by catch and release using SiliaBond Propylsulfonic Acid® (1 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). After evaporation, the material was purified via reverse phase HPLC to afford 5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (2 mg). MS: 407.4 [M+H+]. LCMS Rt=0.40 min [Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.60 Hz, 1H), 7.57-7.74 (m, 2H), 7.39 (s, 1H), 7.14-7.30 (m, 3H), 4.98 (br. s., 1H), 2.92 (s, 3H), 1.62 (d, J=13.14 Hz, 2H), 1.52 (t, J=12.38 Hz, 2H), 1.32 (s, 6H), 1.16 (s, 6H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.O=S(Cl)Cl.O>C(Cl)Cl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:7]([C:8]2[CH:16]=[CH:15][C:11]([CH3:12])=[CH:10][CH:9]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-2-methyl-propanol (14.5 ml, 151 mmol) was stirred in 30 ml CH2Cl2 at 0° C. 4-Methylbenzoyl chloride (p-toluoyl chloride) (4c) (11.69 g, 75.6 mmol) was added dropwise. 4-Methylbenzoyl chloride may be prepared by conventional processes. The mixture was stirred for 4 hrs, at which time 11 ml of SOCl2 (151 mmol) was added slowly. The mixture was warmed to room temperature overnight. Water (30 ml) was added, the layers separated, and the organic layer washed with water (5×20 ml). The combined water layer was rinsed once with 15 ml CH2Cl2, and then basified with aqueous ammonia. The cloudy mixture was extracted with CH2Cl2 (3×30 ml), dried over MgSO4, filtered and the solvent evaporated to yield 10.7 g as a white crystalline solid (75% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Li]CCCC.CCCCCC.[CH3:22][Sn:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH3:22][Sn:23]([CH3:25])([CH3:24])[C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a 3-necked flask equipped with a glass stopper, rubber septum and a nitrogen inlet was added 2,2′-bithiophene (10 g, 60.1 mmol) and anhydrous THF (100 mL). The dark (green) solution was cooled to 0° C. A 2.5 M solution of n-BuLi in hexane (26.4 mL, 66 mmol) was added via syringe. The reaction mixture was then stirred at 25° C. for 1.5 hours. The mixture was cooled to −78° C. and a 1.0 M solution of trimethylstannyl chloride in THF (66 mL, 66 mmol) was added slowly via syringe. The reaction mixture was allowed to warm to 25° C. and was stirred overnight. THF was removed in vacuo and the residue was dissolved in pentane (200 mL). The pentane layer was washed with water (3×200 mL), dried over MgSO4, and the pentane was removed in vacuo to yield a green oil. The oil was purified by vacuum distillation (118-120° C., 0.6 mmHg) to yield 12.5 g (64%) of product MS=330.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][O:17][CH3:18].O=P(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: COCCOc1cc2c(=O)[nH]cnc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 125 °C
Yield: 69 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one (0.6 g, 2.4 mmol) and POCl3 (1 mL) in toluene (10 mL) was heated at 125° C. for 2 hours, to afford 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline as solid (0.445 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 4.33 (t, 2H), 4.03 (s, 3H), 3.77 (t, 2H), 3.33 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10](O)[C:11]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][C:17]([CH3:24])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:43](C1C=CC2N=C(C(O)C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#[N:44].CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:23][CH:21]([F:22])[O:20][C:19]1[C:11]([CH:10]([NH:44][CH3:43])[C:8]2[NH:7][C:6]3[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[C:12]2[C:16](=[C:17]([CH3:24])[CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: Cc1cc(OC(F)F)c(C(O)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Reactant: Cc1cc(OC(F)F)c(C(O)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC(F)F)cc(C)c2[nH]ccc12
Temperature: 55 °C

Procedure:
To a solution of a mixture of tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (20 mg, 0.033 mmol) and methylamine (2.0M in THF, 0.17 mL, 0.33 mmol) in THF (0.33 mL) at room temperature, TBAF (1M in THF, 0.33 mL, 0.33 mmol) was added and the mixture was stirred at 55° C. After stirring overnight the reaction was cooled to room temperature, quenched with sat. aq. NH4Cl, extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (br. s., 1H) 7.94 (br. s., 1H) 7.60 (d, J=8.34 Hz, 1H) 7.49 (dd, J=8.34, 1.52 Hz, 1H) 7.29 (t, J=2.78 Hz, 1H) 7.06 (t, J=75.5 Hz, 1H) 6.81 (s, 1H) 6.49 (dd, J=3.03, 2.02 Hz, 1H) 5.55 (s, 1H) 2.46 (d, J=0.76 Hz, 3H) 2.36 (s, 3H). HRMS calcd. for C20H17F2N5O (M+H)+ 382.1474. found 382.1489.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1(C(OC(C)(C)C)=O)[CH2:20][S:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.[CH3:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:15]([C@@H:14]1[CH2:18][S:19][CH2:20][NH:13]1)=[O:17]
Reactant: Cc1ccccc1CN
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccccc1CNC(=O)[C@@H]1CSCN1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
EDC.HCl (6.30 g, 33.0 mmol) was added to a solution of Boc-Thz-OH (6.99 g, 30 mmol), 2-methylbenzylamine (4.46 ml, 36.0 mmol), and HOBt (4.05 g, 30 mmol) in CH2Cl2 (100 ml) while cooling with ice, and the mixture was stirred overnight. The reaction mixture was washed with 3% Na2CO3 (twice), 1NHCl (once), and 5% NaCl (once) and dried over MgSO4. After filtration and concentration, the residue was dissolved in CH2Cl2 (100 ml). After the addition of methanesulfonic acid MSA (5.86ml, 90mmol), the mixture was stirred for two hours. H2O (150 ml) was added to the reaction mixture and the aqueous layer adjusted to pH 8 with Na2CO3 was extracted with CH2Cl2 (100 ml). The extract was washed with 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from AcOEt/n-hexane to obtain the title compound (6.04 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: Nc1ccc(C(=O)N[C@@H]2CN(C3CCCCC3)C[C@@H]2O)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N[C@@H]2CN(C3CCCCC3)C[C@@H]2O)cc1
Reaction time: 18 h

Procedure:
A solution of 6.0 g (0.02 mole) of cis-4-amino-N-(1-cyclohexyl-4-hydroxy-3-pyrrolidinyl)benzamide in 250 ml of tetrahydrofuran was mixed with 8 g of powdered anhydrous potassium carbonate and stirred while 1.6 g (0.02 mole) of acetyl chloride was added dropwise. The mixture was stirred for 18 hr. The tetrahydrofuran was removed and the residue was partitioned between water and chloroform. The chloroform was separated and in a short time the product precipitated. The precipitate was filtered and then triturated with boiling acetone, filtered and dried. The yield of product melting at 200.0°-203.0° C. was 5.1 g (74%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)Cc2ccc(F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL), at 0° C. under nitrogen atmosphere, was slowly added 2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The red solution was stirred at 0° C. for 1.5 h. The reaction mixture was treated with 1 N HCl (13 mL) and diluted with methylene chloride (200 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione. The crude intermediate was suspended in absolute ethanol (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (SiO2, 230-400 mesh, 8:1 hexane-ethyl acetate gradient elution) to afford the desired product (4.6 g, 37%). 1H NMR (CDCl3) δ 7.23-7.15 (m, 2H), 7.05-6.98 (m, 2H), 4.18 (q, 2H, J=7.0 Hz), 3.81 (s, 2H), 3.46 (s, 2H), 1.26 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of 4-chloroaniline (98%, 500 g (3.84 mol) in pyridine (338 ml) and acetonitrile (800 ml), p-toluenesulfonyl chloride (807.8 g (4.11 mol)) was added with stirring at temperature below 15° C. After stirring for 16 hours at room temperature, water (4000 ml) was added to the reaction mixture and stirring was continued for 3 hours to have crystals separated. The crystals were then filtered and washed with water to give 1100 g (102%) of 4′-chloro-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[C:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[N:33]([CH2:34]C(O)=O)[N:32]=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=1>>[CH3:28][C:29]1[N:33]([CH2:34][C:21]([N:18]2[CH2:17][CH2:16][CH:15]([C:12]3[S:13][CH:14]=[C:10]([C:9]#[C:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:20][CH2:19]2)=[O:23])[N:32]=[C:31]([C:38]([F:41])([F:39])[F:40])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C#CCc3ccccc3)cs2)CC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C#CCc3ccccc3)cs2)CC1

Procedure:
tert-Butyl 4-[4-(3-phenylprop-1-yn-1-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (IV-5, 320 mg) is then deprotected dann analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (174 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(3-phenylprop-1-yn-1-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (33 mg).
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]([O-])=[CH:16][C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:54][NH2:55])[CH:49]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]2[N:54]([C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[N:55]=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(OC)cc(OC(F)(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1

Procedure:
500 mg (1.29 mmol) of the compound of Example 10A is reacted analogously to the synthesis of the compound of Example 20A with 207 mg (1.42 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 248 mg (51% of theory) of the title compound is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH:8]=[O:9]
Reactant: OCCC1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCC1CCCCO1
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a solution of 2-(tetrahydro-pyran-2-yl)-ethanol (53.5 g, 0.41 mol) in dichloromethane (1 L) was added pyridinium chlorochromate (176.8 g, 0.82 mol) in small portions at room temperature. The dark suspension was stirred for 3 h. The mixture was filtered through a short pad of silica gel. The filtrate was concentrated in vacuo and the residue was diluted with n-hexane (400 mL). The mixture was filtered through a short pad of silica gel and the filtrate was concentrated in vacuo to afford (tetrahydro-pyran-2-yl)-acetaldehyde (38 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Br)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH2:24]([O:27][CH3:28])[C:25]#[CH:26]>C(NC(C)C)(C)C.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.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([C:26]#[C:25][CH2:24][O:27][CH3:28])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: C#CCOC
Reactant: CCOC(=O)c1c(Br)cc(-c2c(CC)cccc2CC)nc1C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#CCOC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 105 °C

Procedure:
A mixture of 4-bromo-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic ethyl ester (308 mg, 0.82 mmol), methyl propargyl ether (0.69 mL, 8.2 mmol), Pd(PPh3)4 (95 mg, 0.082 mmol), and copper iodide (8 mg, 0.041 mmol) in diisopropylamine (8 mL) is heated at 105° C. in a sealed tube. After filtration through celite, the filtrate is concentrated in vacuo and the residue purified by flash chromatography to give 6-(2,6-diethyl-phenyl)-4-(3-methoxy-propyn-1-yl)-2-methyl-nicotinic acid ethyl ester as a yellow oil. 1H NMR (CDCl3) 7.36-7.29 (m, 2H), 7.20-7.15 (m, 2H), 4.47 (q, 2H), 4.32 (s, 2H), 3.41 (s, 3H), 2.62 (s, 3H), 2.38-2.27 (m, 4H), 1.41 (t, 3H), 1.06 (t, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([I:15])=[CH:10][N:9]=1.BrCC(C)=C>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:1][C:2]([CH3:5])=[CH2:3])[C:11]([I:15])=[CH:10][N:9]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CNc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Potassium tert-butoxide (4.56 g, 40.73 mmol) was added to a stirred solution of 2-chloro-5-iodo-pyridin-4-ylamine (8.62 g, 33.94 mmol) in anhydrous THF (140 mL) and the mixture was stirred at room temperature for 0.25 h. 3-Bromo-2-methyl-propene (5.51 g, 40.73 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residues partitioned between DCM (100 mL) and water (100 mL). The organic layer was separated, the solvent removed in vacuo and the residues subjected to column chromatography on silica. Gradient elution with 5-20% EtOAc in petrol afforded the title compound (7.93 g, 76%) as a pale yellow oil. 1H NMR (DMSO-d6) 8.24 (1H, s), 6.50 (1H, br t), 6.39 (1H, s), 4.84 (1H, d), 4.73 (1H, d), 3.83 (2H, d), 1.70 (3H, s). MS: [M+H]+ 309.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16]>C(Cl)(Cl)(Cl)Cl>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:20][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Reactant: CCOC(CN)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=S)NCC(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20 g of 4-carboethoxyphenyl isothiocyanate was dissolved in 50 ml of carbon tetrachloride, and 13 g of aminoacetaldehyde diethylacetal was dropwise added thereto in 5 minutes. Then, the resulting solution was stirred at room temperature for 1 hour. 50 ml of carbon tetrachloride was added to the reaction mixture, and crystals precipitated were collected by filtration, washed with 50 ml of carbon tetrachloride, then dried. Yield: 27.5 g (80.9 mol%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3nc(C4CCNCC4)c4ccccc43)nc12
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-3-yl)piperidine-1-carboxylate (22 mg, 33.1 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). After 15 h then mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-piperidin-4-yl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (14 mg, 98%). MS (M+H)+=434; 1H NMR (DMSO-d6) δ: 8.98 (s, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.30-7.41 (m, 1H), 3.61 (s, 4H), 3.20 (br. s., 3H), 2.80-2.93 (m, 2H), 1.88-2.12 (m, 2H), 1.43 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130°-135° for 7 hours. The cool mixture was triturated with hot water to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this product was treated with dilute ethanolic HCl to give the title compound m.p. 237°-241° (ethanol-water)