Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=CC=C[CH:28]=1.C(NCC)C.C#CC.C([O-])(O)=O.[Na+]>[Cl-].[Cl-].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.[Pd+2].[Cu]I.CN(C)C=O>[C:1]([SiH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:28]#[C:27][CH3:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccnc(Cl)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: C#CC
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC#Cc1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)ccn1
Temperature: 120 °C
Yield: 104.4 %

Procedure:
A reaction tube is charged under an atmosphere of argon with 4-(tert-butyl-diphenyl-silanyloxymethyl)-2-chloro-pyridine (9.47 g, 24.79 mmol), palladium(II)-bis(triphenylphosphine)-dichloride (1.78 g, 2.49 mmol, 0.1 equiv), copper(I) iodide (477 mg, 2.49 mmol, 0.1 equiv), and triphenylphosphine (3.94 g, 14.9 mmol, 0.6 equiv). The tube is degassed by alternating three times between vacuum and argon. Diethylamine (39 ml) and N,N-dimethylformamide (2.0 ml), and propyne (50% in THF, 10.1 g, 247 mmol, 10 equiv) are added under an argon atmosphere. The tube is sealed, and the reaction mixture is heated under microwave irradiation for 20 minutes at 120° C. After cooling, the reaction mixture is poured into a semi-concentrated aqueous solution of NaHCO3. After three extractions with EtOAc, the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient from hexane/EtOAc 100:0 to 50:50) affords the title compound (6.0 g, 63%). 1H NMR (400 MHz, d6-DMSO): δ=8.41 (d, J=5.0 Hz, 1H), 7.57-7.55 (m, 4H), 7.43-7.32 (m, 11H), 7.27 (d, J=5.0 Hz, 1H), 4.72 (s, 2H), 1.99 (s, 3H), 0.98 (s, 9H). MS (ES+): 386 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5([NH:34]C(=O)OC(C)(C)C)[CH2:31][O:30]C(C)(C)[O:28][CH2:27]5)=[CH:23][C:22]=4[CH:42]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12])#[N:2].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:34][C:26]([C:24]1[O:25][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)=[CH:42][C:22]=2[CH:23]=1)([CH2:27][OH:28])[CH2:31][OH:30]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1C#N
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1C#N
Yield: 29 %

Procedure:
When product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) in Example 36, Step E, the similar procedure afforded the title compound in 29% yield, as off white solid. 1H NMR (DMSO-d6) 8.49 (d, 1H, J=2.22 Hz); 8.39 (dd, 1H, J=8.91, 2.22 Hz); 8.28 (d, 1H, J=1.41 Hz); 7.93 (dd, 1H, J=8.55, 1.71 Hz); 7.68 (d, 1H, J=8.58 Hz); 7.48 (d, 1H, J=9.06 Hz); 6.89 (s, 1H); 4.78 (b, 2H); 4.22 (t, 2H, J=6.42 Hz); 3.68-3.52 (m, 4H); 1.84-1.73 (m, 2H); 1.0 (t, 3H, J=7.41 Hz).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH:44]=[CH2:45].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:45][CH2:44][C:43]([N:42]([CH3:47])[CH3:41])=[O:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=CC(=O)N(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy) -20(S)-hydroxypregna-5,7,16-triene (400 mg, 0.72 mmol) in tetrahydrofuran (7.2 ml), sodium hydride (60% in oil, 46 mg, 1.15 mmol) was added and stirred at room temperature for 30 minutes under a nitrogen stream. After addition of N,N-dimethylacrylamide (308 mg, 3.11 mmol), the reaction mixture was further stirred at the same temperature for 3 hours, poured into saturated aqueous ammonium chloride, extracted with ethyl acetate (3 times) and washed with saturated aqueous sodium chloride and water. The organic layer was dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (459 mg, 96.9%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][N:12](C)C=O>>[CH3:11][NH:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN(C)C=O
Product: CNc1ncccc1[N+](=O)[O-]
Yield: 80 %

Procedure:
25 g (0.16M) of 2-chloro-3-nitropyridine is dissolved in 200 ml dimethylformamide. For three hours monomethylamine is bubbled into the solution. The mixture is heated to reflux overnight. After the solvent is removed the oily residue is triturated with water and the solid is collected and air dried. The crude material is recrystallized from hexane to give 19.5 g (80% yield) of title compound, melting point 62°-3° C.
Reaction SMILES: NC1N(CCN2CCOCC2)C2C=CC=CC=2N=1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH3:25])=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Nc1nc2ccccc2n1CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(O)cc1

Procedure:
A mixture of 2-amino-1-(2-morpholinoethyl) benzimidazole (10 mmol, 2.46 g) and 4-hydroxyphenacyl bromide (10 mmol, 2.15 g) (obtained by bromination of para-hydroxyacetophenone with cupric bromide in a mixture of chloroform and ethyl acetate) is heated at reflux for 1 hour in 10 ml of dimethylformamide. After cooling, the mixture is poured into 50 ml of water and rendered alkaline with ammonium hydroxide. The resulting oil is removed and treated with water. The crystallised residue is filtered, dried, and recrystallised from ethanol.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(OCc4ccccc4)cc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 68.7 %

Procedure:
2-[2-(4-Benzyloxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (1.21 g, 2.6 mmol, 1.0 eq) was dissolved in ethyl acetate (12 ml), and 10% palladium-carbon catalyst (300 mg, water content 50%) was added. The mixture was stirred in a stream of hydrogen for 4 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1-ethyl acetate) to give 2-[2-(4-hydroxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (681.8 mg, 68.7%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(NC(N)=[S:25])(=O)C>C(O)C>[SH:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CS)cc2)cs1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a suspension of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (589.7 mg, 2.000 mmol) in ethanol (10 ml) was added 1-acetyl-2-thiourea (472.6 mg, 4.000 mmol), and the mixture was heated under reflux for 19 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 30 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(sulfanylmethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (507.7 mg, 1.736 mmol, yield 86.8%) as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][C:38]([F:42])=[CH:37][CH:36]=4)=[C:8]2[N:7]=1)[CH3:5])=[N+]=[N-].C1COCC1.CP(C)C.O>CCOC(C)=O>[NH2:1][CH:4]([C:6]1[CH:11]=[C:10]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[N:9]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][C:38]([F:42])=[CH:37][CH:36]=4)=[C:8]2[N:7]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 5-(1-azidoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (6.2 g, 10.3 mmol) and THF (90 mL) was added 1M trimethylphosphine in THF (30.8 mL, 30.8 mmol) dropwise. After 30 minutes the reaction was complete by HPLC. Water (30 mL) was therefore added and the reaction stirred an additional hour. The contents of the flask were transferred to a separatory funnel, diluted with 300 mL of EtOAc and washed three times with water and three times with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified the remaining crude material by flash chromatography (0-2% 0.7N NH3 in MeOH/CHCl3) to afford 5-(1-aminoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.9 g, 82% yield) as a yellow solid. HPLC: 6.62 min (Method C). LCMS: ESI+ m/z of 583 (M+H)
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[CH:8]([CH2:14][O:15][P:16]([O:22][CH2:23][CH:24]=[CH2:25])([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[O:7][C@H:6]1[N:26]1[CH:31]=[C:30]([F:32])[N:29]=[C:28]([C:33]([NH2:35])=[O:34])[C:27]1=[O:36])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[P:16]([O:22][CH2:23][CH:24]=[CH2:25])([O:18][CH2:19][CH:20]=[CH2:21])([O:15][CH2:14][C@@H:8]1[C@@H:9]([OH:10])[C@@H:5]([OH:4])[C@H:6]([N:26]2[CH:31]=[C:30]([F:32])[N:29]=[C:28]([C:33]([NH2:35])=[O:34])[C:27]2=[O:36])[O:7]1)=[O:17]
Reactant: C=CCOP(=O)(OCC=C)OCC1O[C@@H](n2cc(F)nc(C(N)=O)c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOP(=O)(OCC=C)OC[C@H]1O[C@@H](n2cc(F)nc(C(N)=O)c2=O)[C@H](O)[C@@H]1O
Reaction time: 0.08 h
Yield: 180.6 %

Procedure:
In 4.0 mL of methanol was dissolved 0.23 g of (2R,3R,4R,SR)-4-(acetyloxy)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-5-({[bis(allyloxy)-phosphoryl]oxy}methyl)tetrahydro-3-furanyl acetate. While cooling the solution with ice, 0.17 g of 28% methanol solution of sodium methoxide was added, and stirred for 5 minutes. Then, 0.15 mL of acetic acid was added, and the solvent was removed under reduced pressure. On the other hand, 1.0 g of (2R,3R,4R,5R)-4-(acetyloxy)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo1(2H)-pyrazinyl]-5-({[bis(allyloxy)phosphoryl]oxy}methyl)tetrahydro-3-furanyl acetate was reacted in the same manner as above. Both the reaction mixtures were united and purified by silica gel column chromatography [eluent: chloroform:methanol=40:1]. Thus, 0.35 g of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl diallyl phosphate was obtained as a yellow-colored solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[N:39]1([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][CH2:46][OH:47])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 662.2 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CC#N
Product: Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 70 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To 4-amino-5-fluoro-pyrimidin-2-ol* (1.0 g, 7.75 mmol) in acetonitrile (CH3CN; 40 mL) was added bis-N,O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 4-chlorobenzene sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered, and evaporated to yield the crude product as a white solid (1.3 g). Recrystallization from EtOAc and heptane furnished the title product as a white solid (0.96 g, 41%): mp 174-178° C.; 1H NMR (300 MHz, CDCl3) δ 8.5 (br s, 1H), 8.08 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.55-7.49 (m, 2H), 5.9 (br s, 1H); ESIMS m/z 304 ([M+H]+).
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]([NH-:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@H:30]1[CH2:32][C@@H:31]1[C:33](Cl)=[O:34]>ClCCl>[OH:2][CH2:3][C@H:4]([NH:17][C:33]([C@H:31]1[CH2:32][C@@H:30]1[C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Reactant: CC[C@H](C)COc1ccc([C@@H]([NH-])CO)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (1.08 g, 6.45 mmol) in dichloromethane (50 ml) in an ice-bath was added oxalyl chloride (6.50 ml, 64.4 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 250 ml round-bottom flask was charged with {(R)-2-hydroxy-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide HCl (6.47 mmol), dichloromethane (60 ml) and triethylamine (4.30 ml, 32.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×30 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (1.42 g, 58% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.6 Hz, 2H), 7.09 (m, 1H), 6.91 (m, 3H), 6.82 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.1 Hz, 1H), 5.06 (td, J=6.3, 4.3 Hz, 1H), 3.91 (m, 2H), 3.78 (m, 2H), 2.75 (m, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C21H28NO3S 374.5].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14](O)=[O:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:15])[CH:17]=[CH:18][N:19]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2ccccc21
Reaction time: 8 h

Procedure:
400 μL (3.53 mmol) 2,3-dihydro-1H-indole were added to 500 mg (3.17 mmol) 2-chloroisonicotinic acid, 600 μL (3.49 mmol) DIPEA and 1.10 g (3.43 mmol) TBTU in 20 mL THF. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with 15% potassium carbonate solution (1×), water (1×) and 1M hydrochloric acid (1×). The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with diisopropylether and suction filtered. The solid was dried at 40° C. in the circulating air dryer.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)CCO.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][OH:22])=[CH:18][CH:17]=1>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]=[O:22])=[CH:23][CH:24]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Agent: OCCc1cccc(C(F)(F)F)c1
Product: O=CCc1ccc(C(F)(F)F)cc1

Procedure:
Instead of 3-(trifluoromethyl)phenethyl alcohol, 4-(trifluoromethyl)phenethyl alcohol was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5](I)=[CH:4][N:3]=1.[CH2:14]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])[CH2:15][CH2:16][C:17]#[CH:18].O>CN(C)C=O.C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][N:19]2[C:20](=[O:29])[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:24])=[CH:4][N:3]=1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ncc(I)c(N2CCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Cl)nc1N1CCCC1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
To a suspension of bis(triphenylphosphine)palladium(II) dichloride (1.02 g) and copper(I) iodide (558 mg) in N,N-dimethylformamide (90 mL), triethylamine (10.2 mL), 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g), and N-(4-pentynyl)phthalimide (4.65 g) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, then dried under reduced pressure, and purified by silica gel column chromatography. The obtained solid matter was washed with ethyl acetate, and then dried under reduced pressure to obtain 2-(5-(2-chloro-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (H2, 3.66 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[CH:14]1[N:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:18](=[O:31])[CH2:17][CH2:16][CH2:15]1.O>C(Cl)Cl>[OH:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[CH:14]1[N:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:18](=[O:31])[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 6-(2,6-dimethoxy-3-nitrophenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (403 mg; 0.95 mmol) in anh. DCM (9 ml) was treated dropwise at rt with a solution of boron tribromide BBr3 (1 M in DCM; 4.4 ml; 4.4 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water and ice were added, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=30/1) afforded 6-(2-hydroxy-6-methoxy-3-nitrophenyl)-1-(quinolin-2-ylmethyl)-piperidin-2-one as a yellow solid (340 mg; 87%). LC-MS (conditions A): tR=0.60 min.; [M+H]+: 407.82 g/mol.