Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19].C(P(CCCC)CCCC)CCC>O>[CH2:16]([O:20][C:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:1]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCO
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Product: CCCCOC1=NC=CC(c2ccccc2)=CC1
Temperature: -40 °C
Yield: 44.1 %

Procedure:
A 22 Liter reaction flask is equipped with a heating mantle, overhead stirring apparatus, condenser, addition funnel, thermometer probe, and nitrogen inlet/outlet. The flask is purged thoroughly with nitrogen and maintained under nitrogen throughout the reaction. The flask is charged with 4-nitrobiphenyl (1700 g, 8.53 moles) and 1-butanol (3793 g, 51.2 moles). The resulting mixture is heated to reflux to form a clear solution. Tributylphosphine (3500 g, 17.3 moles) is charged to the addition funnel and added dropwise to the hot 4-nitrobiphenyl solution. The temperature is gradually increased as needed to maintain reflux. The reaction is monitored by gas chromatography analysis for completion. The reaction is cooled and water is added (500 mL). The reaction is concentrated to an oil, followed by the addition of petroleum ether (8.0 L). The resulting mixture is cooled to −40° C. and filtered to remove undesired tributylphosphine oxide. The filtrate is concentrated again and petroleum ether (8.0 L) is added. The mixture is cooled and filtered. The resulting filtrate is concentrated to an oil and purified by silica gel chromatography to give the title compound (908 g, 44%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])C.[OH-].[Na+]>CO.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:22])=[O:3])=[C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:9]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOc1cc(C(C)(C)C)ccc1C=CC(=O)O
Yield: 99.3 %

Procedure:
3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylic acid ethyl ester (40.4 mg, 0.132 mmol, 1 eq) and sodium hydroxide (52.8 mg, 1.32 mmole, 10 eq) were added in methanol and H2O. The reaction mixture was purified according to step 2 of Example 22 to give 3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylic acid (36.5 mg, 77.3%). 3-[4-tert-Butyl-2-(2-methoxyethoxy)-phenyl]acrylic acid (26.4 mg, 0.095 mmol, 1 eq.), Diethylcyanophosphine (17.3 μl, 0.114 mmol, 1.2 eq), N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (40.8 mg, 0.1114 mol, 1.2 eq.), and Triethylamine (39.7 μl, 0.285 mmol, 3 eq) were added in DMF. The mixture was stirred for overnight at room temperature. The reaction mixture was purified according to Example 17 to give a whitish solid (28.4 mg, 59.2%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (442 mg) and 37% formalin (0.29 mL) in the same manner as in Example 1 was dissolved in chloroform (8 mL), and triethylamine (0.49 mL) and 3-chloro-4-methoxy-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (f).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH:23]1([S:28]([Cl:31])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:31].[NH:19]=[C:17]([NH:18][S:28]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)(=[O:30])=[O:29])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:22])[NH2:11]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)C1CCCC1
Product: Cl
Product: N=C(NCCC[C@H](N)C(=O)N1CCCC1)NS(=O)(=O)C1CCCC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, cyclopentanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)CCl>[C:15]1([S:21]([N:24]2[CH:25]=[CH:26][C:27]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH3:14])=[CH:6][CH:7]=3)=[O:12])=[CH:28]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of aluminum chloride (4.62 g, 34.7 mmol) in ethylene chloride (50 mL) was added a solution of p-toluoyl chloride (4.91 g, 31.8 mmol) in ethylene chloride (5 mL) at room temperature over a period of 10 minutes. The mixture was stirred for 30 minutes, and thereto was added a solution of 1-benzenesulfonyl-1H-pyrrole (6.00 g, 28.9 mmol) in ethylene chloride (10 mL) over a period of 10 minutes. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water, and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (9.9 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[S:18][C:11]=12)[NH2:5].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:40]([C:37]2[C:38](=[O:39])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:34]=[CH:35][CH:36]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[S:18][C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CN1CCN(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-(4-methylpiperazin-1-yl)thieno[3,2-b]pyridin-7-yloxy)aniline (40.0 mg, 0.112 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (39.2 mg, 0.167 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (64.2 mg, 0.335 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (45.2 mg, 0.335 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0996 ml, 0.558 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (48.3 mg, 75.3%). LRMS (APCI pos): >99% purity, 254 nm, m/e 575 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.80 (s, 1H), 8.40 (d, 1H), 8.28 (d, 1H), 8.23 (d, 1H), 7.92 (dd, 1H), 7.61 (m, 2H), 7.36 (m, 1H), 7.17-7.24 (m, 3H), 6.36 (s, 1H), 6.29 (d, 1H), 3.37 (m, 4H), 2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)C#N.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13].[OH-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][N:24]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Agent: N#C[Cu]C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(C(C)(C)C)cn2)c1C
Reaction time: 0.33 h

Procedure:
tert-Butyl magnesium bromide (2M tetrahydrofuran solution; 35 ml) was added to a suspension of copper cyanide (3.1 g) in tetrahydrofuran (35 ml) at −78° C., stirred for 20 minutes, and then 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.1 g) described in Reference example 24(2) was added and the mixture was stirred at −78° C. for two hours. It was further stirred at room temperature for 16 hours. Ammonium hydroxide was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-tert-butylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (320 mg) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7](SC)[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=1.[OH-:14].[K+].CS.Cl>CO.O>[Cl:2][C:3]1[NH:8][C:7](=[O:14])[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=1
Reactant: CSc1nc(Cl)cc2nccn12
Reactant: [OH-]
Agent: CS
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(Cl)cc2nccn12
Yield: 87.5 %

Procedure:
7-Chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (10.5 g, 44.5 mmol) was partially dissolved in MeOH (40 mL) and then a solution of potassium hydroxide (11.2 g, 200 mmol) in water (100 mL) was slowly added and the reaction was heated to reflux. The reaction generates methane thiol, so caution was taken to contain this noxious gas in the hood. After 2 hours the reaction was cooled and then neutralized with a solution of 1N HCl to reach a pH of between 6 and 7. The reaction was filtered and the solid was washed with MeOH. The solids were dried on the filter cake and then dried on a high vacuum pump to provide 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (6.6 g, 87% yield) as a white solid. MS (apci) m/z=170.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[N:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1cccnc1
Temperature: 75 °C
Yield: 75.7 %

Procedure:
Pd(PPh3)4 (1.05 g, 0.91 mmol) was added to a to a solution of 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (2.0 g, 6.8 mmol), 4-carboxyphenylboronic acid (1.12 g, 6.7 mmol), and sodium carbonate (2.88 g, 27.2 mmol) in tetrahydrofuran/water, (1:1, 240 mL), and the resulting mixture was heated at 75° C. for 16 days. The solvent was evaporated and the residue dissolved in water. The aqueous phase was washed with ethyl acetate and then neutralized (pH 7) using HCl (10% aq.). The formed crystals were filtered off and dried in vacuo to give 1.7 g (77% yield) of the title compound: MS (ES) m/z 336 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CSc1ccccc1F
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 1.5 ml 2-fluorothioanisole in 50 ml dichloromethane, were added at 0° C. 1.2 g of aluminum chloride and 1 ml of phenylacetyl chloride. The reaction mixture was stirred for 12 hours at the room temperature. Then the reaction was quenched by adding appropriate amount of ice and aqueous HCl in one portion. The quenched mixture was extracted with dichloromethane (50 ml×3) and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, which was followed by removal of the magnesium sulfate by filtration. Then the filtrate was concentrated in vacuo and was purified by recrystallization from methanol to yield 1.8 g of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one. mp: 71-72° C. NMR: δ2.50 (s, 3H), 4.22 (s, 2H), 7.20-7.33 (m, 6H), 7.64 (m, 1H), 7.77 (m, 1H). Step 2: Preparation of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].[BrH:20]>C(O)(=O)C>[C:13]([OH:16])(=[O:15])[CH3:14].[C:13]([OH:16])(=[O:15])[CH3:14].[C:13]([OH:16])(=[O:15])[CH3:14].[C:13]([OH:16])(=[O:15])[CH3:14].[Br:20][C@:2]1([O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4])[OH:1]
Reactant: Br
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: OC[C@@H]1O[C@](O)(Br)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 78 %

Procedure:
L-glucose (−)-IV-12 (4.95 g, 27.4 mmol) was added acetic anhydride (25 mL) and HBr in acetic acid (5 mL, 33%) and stirred for 1 h until the solid dissolved. Another 25 mL of HBr in acetic acid was added and the reaction mixture stirred for 6 h. Concentration in vacuo with toluene and filtration through a silica gel plug (75% ether/hexanes) furnished pure bromo-α-L-glucopyranoside tetraacetate. The bromide was dissolved in ethyl acetate (140 mL), zinc (10.9 g, 166 mmol) added, and the mixture heated at reflux. N-methyl imidazole (2.21 mL, 27.7 mmol) was added in one portion and heating continued for 1 h. The mixture was concentrated in vacuo and purified by flash chromatography (33% ethyl acetate/hexane) to furnish (+)-IV-13 (5.89 g, 78% yield) as a clear oil: [α]D25 −24.04° (c 1.4, CHCl3); IR (CHCl3) 3010 (m), 1745 (s), 1655 (s), 1375 (s), 1230 (s), 1050 (s) cm−1; 1H NMR (500 MHz, CDCl3) s 6.48 (dd, J=6.2, 1.3 Hz, 1H), 5.36 (m, 1H), 5.24 (dd, J=7.6, 5.9 Hz, 1H), 4.86 (dd, J=6.2, 3.3 Hz, 1H), 4.41 (dd, J=12.1, 5.7 Hz, 1H), 4.27 (m, 1H), 4.21 (dd, J=12.1, 3.2 Hz, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3) s 170.5, 170.4, 169.5, 145.6, 99.0, 74.0, 67.4, 67.2, 61.4, 21.0, 20.8, 20.7; high resolution mass spectrum (Cl, NH3) m/z 290.1243 [(M+NH4)+; calcd for C12H16O7: 290.1239].
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[CH2:24][CH3:25].CNCCN.ClC1C=CC=C(Cl)C=1[C:34]([NH:36][C:37]1C=CC=C2[C:46]=1[N:45]=[CH:44]C(CC)=C2CNCCNC)=[O:35].C(N1C=CN=C1)(N1C=CN=C1)=O>COCCOC.CN1CCN(C)C1=O.O>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([CH2:24][CH3:25])=[C:3]2[CH2:2][N:36]1[CH2:37][CH2:46][N:45]([CH3:44])[C:34]1=[O:35])=[O:23]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CNCCNC
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Agent: CNCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: COCCOC
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CN1CCN(C)C1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (150 mg) and N-methylethylenediamine (141 mg) in 1,2-dimethoxyethane was stirred for 2 hours at 70° C. The mixture was partitioned between dichloroethane and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give a residue containing 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-[(2-methylaminoethyl-amino)methyl]quinoline. To the solution of the obtained residue in 1,3-dimethyl-2-imidazolidinone was added 1,1'-carbonyldiimidazole (309 mg), and the mixture was stirred for 30 minutes at 70° C., for 1 hour at 100° C. and for 1 hour at 150° C. Water was added to the mixture, and the resulting precipitates were collected by filtration. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) and crystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(3-methyl-2-oxoimidazolidin-1-ylmethyl)quinoline (28.6 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]4[N:23]([N:25]=[CH:26][C:27]=4[CH2:28][CH3:29])[CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]4[N:23]([N:25]=[CH:26][C:27]=4[CH2:28][CH3:29])[CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(CC)cnn4c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1cnn2cc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)cnc12
Temperature: 170 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-ethylpyrazolo[1,5-a]pyrimidin-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (24.9 mg, 0.044 mmol) and lithium iodide (200 mg) in pyridine (0.5 mL) was heated in microwave at 170° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with 5% acetic acid solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 30% MeOH/CH2Cl2). Lyophilization gave desired product. LCMS-ESI+: calc'd for C28H28ClN4O3S: 535.2. (M+H+); Found: 535.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 9.22 (dd, J=2.8, 1.6 Hz, 1H), 8.95 (dd, J=2.8, 1.6 Hz, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.58-7.37 (m, 3H), 5.31 (s, 1H), 2.86 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 1.34 (dd, J=7.8, 7.3 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[C:7]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)=[O:21])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9]2)=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of 1-[5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (2.5 g, 5.3 mmol) in anhydrous EtOH (40 mL) was added to a round bottle (100 mL) flask containing 10% Pd/C (30 mg). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction mixture was stirred at room temperature for 18 h, and then filtered through a pad of celite. The celite was washed with EtOH (200 mL) and the filtrate was concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 1.8 g (77%) of the desired product. 1H-NMR (DMSO-d6) δ 9.16 (s, 1H), 8.42 (d, J=5.4 Hz, 2H), 8.17 (s, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.09 to 7.04 (m, 4H), 6.86 (d, J=5.7 Hz, 2H), 6.64 (d, J=6.6 Hz, 2H), 6.28 (s, 1H), 6.38 (s, 2H), 1.18 (s, 9H); MS LC-MS [M+H]+=443, RT=1.95 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25](Br)[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(#N)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 138 (69.3 mg, 0.16 mmol) and bis(triphenylphosphine) palladium(II) acetate (11.68 mg, 0.015 mmol) was dissolved in a mixed solvent system of acetonitrile (120 mL) and TEA (80 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (0.044 mL, 0.31 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 138 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). The conditions for TLC were EtOAc on silica gel. A white solid 139 (58.8 mg, 80%) was obtained. mp 186-187° C.; IR (KBr, cm−1) 2410, 2358, 1716, 1497, 1253; 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1H), 4.41 (m, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.29 (d, J=7.2, 3H), 0.24 (s, 9H). MS (EI) m/e (relative intensity) 459 (M+, 28), 445 (32), 399 (51), 371 (100), 235 (71), 178 (75); [α]26D=28.2 (c 0.48, EtOAc).