Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15](C3C=CC(CNC)=CC=3)[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:4]3[CH:3]=[CH:2][C:28]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:5]=3[CH2:6][NH:8][CH3:9])[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-propargyl-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.53 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>O1CCOCC1>[Cl:12][CH2:13][C:14]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: O=C(CCl)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of p-chlorobenzoic hydrazide (11.2 g) in dioxane (100 ml) was added chloroacetyl chloride (6 ml). The resulting mixture was refluxed for three hours cooled to room temperature and filtered. The resulting solid was washed with ethyl ether and dried to yield N'-chloroacetyl-4-chlorobenzoic hydrazide as white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl.O>[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14]
Reactant: NCCc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1Br
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NCCc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-phenethylamine (0.28 mL, 2.195 mmol) in DCM (2.0 mL) was added 2-bromo-3-methylbenzoyl chloride (0.15 mL, 0.998 mmol) dropwise via syringe at ambient temperature. Mixture was allowed to stir overnight, then diluted with water (30 mL) and extracted with DCM (30 mL). The organic extract was washed with 1N HCl (2×25 mL) and 1N NaOH (2×25 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 2-bromo-3-methyl-N-phenethylbenzamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:23][O:24][C:25](=[O:29])[CH2:26][NH:27][CH3:28].CCN(CC)CC>CN(C=O)C>[CH3:23][O:24][C:25](=[O:29])[CH2:26][N:27]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:28]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), sarcosine methyl ester hydrochloride 0.139 g (1.0 mmol) with Et3N 1.0 mL (10.0 mmol) in DMF 2 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. 1H NMR (CD3OD, 400 MHz) δ 7.63-7.70 (m, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.07-7.11 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.62 (s, 3H), 3.45 (s, 3H); HRMS (ES) m/z calcd for C20H22N4O3 (M+H) 367.1764, found 367.1772.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:26])[NH:11][C:12]2[C:13]([CH2:24][CH3:25])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH2:24][CH3:25])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:26])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:13]([CH3:18])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCl
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 4-(adamantan-1-yl)-2-methylphenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (3.63 g, 23.29 mmol) and ethyl chloroacetate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate as a white solid (2.6 g, 95.9% yield).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>>[Cl:8][C:7]1[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1

Procedure:
2,3,5-Trichloro-pyridine (910 mg, 5.0 mmol, Aldrich) and (R)-(−)-2-methyl-piperazine (700 mg, 7.0 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 247 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:25]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32]O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[I:42]I>ClCCl>[I:42][CH2:32][CH:31]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: II
Reactant: CCCCCCCCC(CO)CCCCCC
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC(CI)CCCCCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Under air, triphenylphosphine (107.44 g, 410 mmol, 1.19 equiv.) and imidazole (28.9 g, 424 mmol, 1.23 equiv.) were dissolved in dichloromethane (800 mL). 2-Hexyl-1-decanol (100 mL, 345 mmol., 1.00 equiv.) was added to the solution, and the reaction mixture was cooled to 0° C. Iodine (103.6 g, 408 mmol., 1.18 equiv.) was added portion-wise over 1 hour, after which the suspension was stirred at 0° C. for an additional hour, and then at ambient temperature for 18 hours. The mixture was quenched with saturated aqueous Na2SO3 (150 mL), and DCM was removed in vacuo. Hexane (200 mL) was added to the residue, and the mixture was filtered to remove salts that had precipitated. The organic material was extracted with hexanes (3×300 mL), dried over Na2SO4, filtered through a pad of silica gel, and then concentrated in vacuo to give a clear, colorless oil (97.8 g, 82% yield). 1H NMR (500 MHz, CDCl3) δ 3.28 (d, J=4.6 Hz, 2H), 1.34-1.19 (m, 24H), 1.12 (b, 1H), 0.91-0.87 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N:24]=[C:25]=[S:26])[O:5][CH2:6][C:7]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].I.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.[OH-].[Na+].O1CCCC1>O>[N:28]1([C:25]([NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][C:7]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=3[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=2[F:1])=[S:26])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(N=C=S)c(F)c1
Reactant: C1CCNNC1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Yield: 81.2 %

Procedure:
By the method of Example 1, Step C, of U.S. Pat. No. 4,906,281, 1.50 g (0.004 mole) of methyl 2-[2-(3-fluoro-4-isothiocyanatophenoxymethyl)-5-methyl-phenoxy]propionate and 1.07 g (0.005 mole) of perhydropyridazine monohydroiodide (prepared by the method of Example 1, Step B, of U.S. Pat. No. 4,906,281) were reacted in the presence of 0.20 g (0.0050 mole of sodium hydroxide in 40 mL of water and 10 ML of tetrahydrofuran, yielding 1.50 g of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxy-methyl]-5-methylphenoxy]propionate as a syrup. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:27](=[O:28])[CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.6 M of n-Butyllithium in hexanes (35 mL) was added to a solution of (S)-4-benzyloxazolidin-2-one (10 g, 56.4 mmol) in THF (150 mL) at −78° C. After 15 minutes, intermediate (7a) (9.5 g, 56.4 mmol) in THF (20 mL) was added dropwise at −78° C. After 30 minutes, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo and the crude material was extracted with EtOAc (3×200 mL) and water (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7b), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.Cl>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (1.00 g) and DMF (66 μL) in ethyl acetate (11 mL) was added oxalyl dichloride (1.11 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A small amount of 1N hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (929 mg) as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH:24]=[C:25]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:26][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of benzothiophene (3 g, 22.4 mmol) in anhydrous tetrahydrofuran (50 ml) at -10° C. under nitrogen was added n-butyllithium (9.83 ml of a 2.5M solution in toluene), the mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was cooled to -40° C. and 1-benzyl-4-piperidone (4.23 g, 22.4 mmol) added, allowed to warm to room temperature and stirred for 14 hr. The reaction mixture was concentrated in vacuo and trifluoroacetic acid (10 ml) added. This mixture was stirred at room temperature for 14 hr and then concentrated in vacuo. The product was extracted into dichloromethane (3×100 ml) from aqueous potassium carbonate. The organic layer was washed with water (1×50 ml), brine (1×50 ml) and dried (MgSO4). After concentration of the extracts the crude product was purified using silica gel column chromatography to yield the title compound (4.2 g, 68%) as a colourless oil; δH (CDCl3) 2.64 (2H, m, tetrahydropyridinyl CH2), 2.74 (2H, m, tetrahydropyridinyl CH2), 3.18 (2H, m, tetrahydropyridinyl CH2), 3.65 (2H, s, PhCH2N), 6.18 (1H, m, CH=CR), 7.11 (1H, s, 3'-H), and 7.24-7.73 (9H, m, Ar--H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1N(COCC[Si](C)(C)C)C=C([Sn](C)(C)C)N=1.C[Sn](C)(C)C1NC=NC=1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][CH:2]=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: C[Sn](C)(C)c1cnc[nH]1
Agent: Cc1nc([Sn](C)(C)C)cn1COCC[Si](C)(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccccc1OCC2

Procedure:
Following the procedure for 265, a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and a mixture of regioisomers 2-methyl-1((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethyl stannyl)-1H-imidazole and 2-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-5-(trimethyl stannyl)-1H-imidazole were reacted to give 9-(1-(2-(tert-butyldimethylsilyl)ethoxy)methyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrob enzo[f]imidazo[1,2-d][1,4]oxazepine which was dissolved (360 mg, 0.71 mmol) in ethanol (3 mL). To the mixture was added HCl-methanol (3 mL, 4 mol/L) dropwise at 0° C. After 30 minutes, the temperature was allowed to warm up to 70° C. and stirred for over night. Concentrated, the residue was basified with TEA, then purified by per-TLC to give 240 mg of 271. Yield=91%. 1H NMR (MeOD, 400 MHz): δ 8.72 (s, 1 H), 8.60 (d, J=4.4 Hz, 1 H), 8.19 (s, 1 H), 7.87 (s, 1 H), 7.51 (d, J=2.0 Hz, 1 H), 7.46 (s, 1 H), 5.72-5.72 (m, 1 H), 4.65-4.64 (m, 2 H), 4.60-4.59 (m, 2 H), 2.68 (s, 3 H), 1.63-1.62 (d, J=6.8 Hz, 6 H). LC-MS: m/z=376 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][N:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:27]3[CH:26]=[N:25][C:24]([F:23])=[CH:29][CH:28]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Fc1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(F)nc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-fluoro-5-iodopyridine (0.106 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.30 (d, J=7.5 Hz, 1H), 7.51 (t, J=8.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.1 Hz, 3H), 8.03 (d, J=8.4 Hz, 2H), 8.20 (t, J=7.2 Hz, 1H), 8.49 (s, 1H), 12.73 (br s, 1H). MS (m/z): 407.33 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(Cc2ccncc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Under ice-cooling, to a mixture of 18.0 g of cyanoacetic acid and 25 mL of oxalyl chloride were added 0.07 mL of DMF and 10 mL of dichloromethane, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added toluene, followed by further concentrating under reduced pressure. This procedure was repeated and excess hydrogen chloride and oxalyl chloride were removed. A mixture of the obtained crude product and 50 mL of dichloromethane was added to a mixture of 80 mL of a 1 M aqueous sodium hydroxide solution, 300 mL of dichloromethane, and 14.3 g of 4-(pyridin-4-ylmethyl)aniline under ice-cooling. During mixing the reagent, a 1 M aqueous sodium hydroxide solution was added on time to adjust the reaction solution to be kept alkaline. After stirring at room temperature for 30 minutes, the organic layer was collected by separation and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 10.2 g of 2-cyano-N-[4-(pyridin-4-ylmethyl)phenyl]acetamide as a pale yellow solid.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O>[I:10][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[NH:12][N:13]=[CH:8][C:7]=12
Reactant: NN
Reactant: O=Cc1c(I)ccnc1F
Solvent: O
Product: Ic1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Fluoro-4-iodo-3-pyridinecarbaldehyde (from Asymchem) (0.97 g) was added portionwise over 5 min to hydrazine hydrate (5 ml). The resulting suspension was stirred at room temperature for 5 h. Water (10 ml) was added and the solid was filtered and washed with further water to give title compound, 664 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22][OH:23].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1C[O:38][CH2:37]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:21](=[O:24])[CH2:22][O:23][C:37]1=[O:38]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2NC(=O)CO)C1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COC2=O)C1
Reaction time: 8 h

Procedure:
N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-2-hydroxy-acetamide (20 mg) was dissolved in absolute THF (2 ml), and reacted at room temperature with sodium hexamethyldisilazide solution (0.5 ml; 2 M in THF) with stirring. Afterward, 1,1-carbonyldiimidazole (13 mg) was added and the mixture was stirred at room temperature for 2 h. After standing overnight, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in water/acetonitrile and the clear solution was freeze-dried overnight. 10 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCN(CC)CC.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
TBSCl (18.7 g, 124.3 mmol), Et3N (14.08 g, 139.2 mmol) and DMAP (194.3 mg, 8.9 mmol) were dissolved in CH2Cl2 (120 mL) and the solution was cooled to 0-5° C. (3-Bromophenyl)methanol (18.5 g, 99.4 mmol) was added dropwise to the solution. After the addition of the (3-bromophenyl)methanol, the mixture was warmed to room temperature and stirred for 2 h. 5% HCl was added to the reaction mixture to adjust the pH=4-5. Then the organic phase was separated and the aqueous layer was extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with water and dried over Na2SO4. After removing the solvent, 28.5 g of {[(3-bromophenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane was obtained (Yield: 95.1%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][C:9](Cl)=[CH:10][C:5]=2[NH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18].CC([O-])(C)C.[K+].C1COCC1>>[Cl:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:19][C:17]([NH:16][CH2:15][CH2:14][O:13][CH3:12])=[O:18])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: Clc1cc2[nH]nc(Cl)c2cn1
Reactant: COCCNC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCNC(=O)Nc1cc2[nH]nc(Cl)c2cn1
Temperature: 60 °C
Yield: 25.6 %

Procedure:
A mixture of 3,6-dichloro-1H-pyrazolo[4,3-c]pyridine (583.6 mg, 3.10 mmol), 1-(2-methoxyethyl)urea (550 mg, 4.66 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (248 mg, 0.310 mmol) and 1.78 M KOtBu in THF (5231 μl, 9.31 mmol) was degassed and then THF (0.5 mL) was added. The reaction mixture was heated to 60° C. overnight. The reaction was diluted with ethyl acetate and washed with water. The combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC (0-30% MeOH-DCM) gave 1-(3-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(2-methoxyethyl)urea (214 mg, 0.794 mmol, 25.6% yield). MS ESI calc'd. for C10H13ClN5O2 [M+H]+ 270, found 270.