Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: Sc1ccc(Br)cc1Cl
Reactant: C=C(C)CCOP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCSc1ccc(Br)cc1Cl
Temperature: 85 °C

Procedure:
To a mixture of 4-bromo-2-chlorobenzenethiol (1.68 g, 7.54 mmol) and Cs2CO3 (4.09 g, 12.6 mmol) in DMF (8.98 mL) at room temperature was added 3-methylbut-3-en-1-yl diphenyl phosphate (2.00 g, 6.28 mmol, synthesized according to a procedure in U.S. Pat. No. 5,006,550, 9 Apr. 1991) dropwise via a syringe. The reaction mixture was heated to 85° C. for 1 hour. It was then allowed to cool to room temperature and diluted with water (20.0 mL). The resulting mixture was extracted with EtOAc:hexanes mixture (1:1, 75.0 mL, 2×) and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to give the desired product as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[CH:36]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[CH2:37].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH:36]=[CH2:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH2:31][C:30]2=[O:35])[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:19][CH2:20]1)=[O:13])[CH3:10]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(C)c4)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
Triethylamine (260 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (263 mg) in dichloromethane (20 ml), 4-vinylbenzenesulfonyl chloride (194 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the material was extracted with dichloromethane, dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from diisopropyl ether to obtain the colorless crystalline title compound (157 mg).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>CN(C=O)C.O>[CH:1]1[CH:10]=[C:9]([O:11][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OC1c3ccc(OCCN4CCCCC4)cc3OCC21
Yield: 69.1 %

Procedure:
Compound 6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by 1-(2-chloroethyl)piperidine hydrochloride (366 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 1-(2-(6a,11a-dihydro-6H-benzofuro[3,2-c]chromen-3-yloxy)ethyl)piperidine (102 mg, 70%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1([F:26])[CH2:22][CH:21]1[C:23](O)=[O:24]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([CH:21]3[CH2:22][C:20]3([F:26])[F:19])=[O:24])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)C3CC3(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and (RS)-2,2-difluoro-cyclopropanecarboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=364.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[N:6][CH:7]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1)=[O:19])#[CH:14]>>[CH3:42][C:41]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:36])([F:38])[F:37])[CH:22]=2)=[O:19])=[CH:16][C:15]=1[C:13]#[C:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2ncc[nH]2)nc1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2ncc[nH]2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(1H-imidazol-2-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:29]3[C:28]([CH3:27])=[N:32][N:31]=[N:30]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3nnnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[N:6][C:7]=1Cl.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[C:7]([NH:20][C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)=[N:6][CH:5]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cnc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cnc(Nc3cccc(O)c3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 22, Step 2 using 1-((5,6-dichloropyridin-3-yl)methyl)-4-(methylsulfonyl)piperazine and 3-aminophenol under microwave irradiation conditions (150° C., 30 min), and isolated as a pale yellow solid (70%). LCMS (API-ES) m/z 398 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:62]=[N+:63]=[N-:64])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[N:62]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[C:2]([CH3:16])([CH3:15])[CH3:1])=[N+:63]=[N-:64]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCSc1ccc(C(O)C(C)(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCSc1ccc(C(N=[N+]=[N-])C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2,2-dimethyl-1-[4-(propylthio)phenyl)propan-1-ol (466 mg, 1.95 mmol) in THF (10 ml) were added triphenylphosphine (666 mg, 2.54 mmol), diethyl azodicarboxylate (0.40 ml, 2.54 mmol), and finally diphenylphosphoryl azide (0.55 ml, 2.54 mmol). The mixture was stirred at room temperature over for 3 days. Water (1 ml) was added and the mixture was evaporated. The residue was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic phase was separated, washed with brine (30 ml), dried over MgSO4, filtered and evaporated to give an oil. The crude product was chromatographed on silica eluting with 4% EtOAc in hexanes to give the title product as a pale yellow oil (284 mg). 1H NMR δ (CDCl3) 7.29-7.27 (2H, m), 7.17-7.15 (2H, m), 4.23 (1H, s), 2.92 (2H, t, J=7.3 Hz), 1.73-1.67 (2H, m), 1.04 (3H, t, J=7.4 Hz), 0.90 (9H, s).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([NH:48][C:49](=[O:51])[CH3:50])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[C:45]([O:46][CH3:47])=[CH:40][CH:41]=[C:42]([NH:48][C:49](=[O:51])[CH3:50])[CH:43]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(NC(C)=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(NC(C)=O)cc1-c1ccc(C(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(C)C)cc1
Yield: 42.6 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.21 g), N-(3-bromo-4-methoxyphenyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.16 g), the title compound (1.14 g) was obtained as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To the suspension of 4-(3-fluoro-phenyl)-1H-indole (1.40 g, 6.63 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.07 g, 19.88 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.34 g, 89%) as a tan solid.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2.C(N(CC)CC)C.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30]([O:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2)=[O:31])[CH3:28]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1cc2c(C)nc(O)c([N+](=O)[O-])c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a slurry of 3-hydroxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (1.90 g, 7.19 mmol) in methylene chloride (100 mL) were added triethylamine (1.5 mL, 10.78 mmol), 4-dimethylaminopyridine (176 mg, 1.44 mmol) followed by diethylcarbamoyl chloride (0.81 mL, 8.62 mmol) in 5 mL of methylene chloride), added over a 10 minute period. The addition of each of the last three reagents was repeated twice two hours apart and then the mixture was stirred at room temperature overnight. The clear dark red-brown solution was washed with water (3×150 mL), saturated sodium bicarbonate solution and again with water. The organic phase was dried (Na2SO4), filtered and evaporated to dryness in vacuo. The tan residue was recrystallized from methylene chloride/ether to yield the title compound (2.04 g, 92.1%), mp 220°-221° C. (d). IR (KBr): 1738, 1520, 1260 cm-1. NMR (CDCl3): δ 1.24 and 1.28 [two t, J=7 Hz, total 6H, N(CH2CH3)2 ], 2.90 (s, 3H, 1-CH3), 3.20-3.80 (m, 4H, N(CH2CH3)2), 4.03 (s, 6H, 5,6-OCH3), 7.24 (s, 1H, 5- or 8-H), 7.28 (s, 1H, 5- or 8-H); MS (DCI): 364 (MH)+
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:26]=2[O:25][CH2:24]1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH:20][C:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:23][CH2:24][O:25][C:26]=4[CH:31]=3)=[O:33])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc5c(c4)OCO5)c(C)c(C)c3OC2(C)C)cc1
Yield: 65 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 65%. Melting point: 164-165° C. (Ethyl acetate-hexane).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2OC(=O)N[C@@H:10]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)[CH:6]=[CH:7][CH:8]=1.Br[C:30]1[CH:31]=[C:32]([C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=3[F:49])[O:40][C:39](=[O:50])[NH:38]2)[C:33]([F:36])=[N:34][CH:35]=1.C1(C#C)C=CC=CC=1>>[F:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[C@H:41]1[O:40][C:39](=[O:50])[NH:38][C@@H:37]1[C:32]1[C:33]([F:36])=[N:34][CH:35]=[C:30]([C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:31]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cc(F)ccc2F)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one and phenylacetylene. 1H NMR (CDCl3) δ: 8.37 (d, J=1.2 Hz, 1H), 8.11 (dd, J=8.9, 2.1 Hz, 1H), 7.56 (dd, J=7.6, 1.8 Hz, 2H), 7.35-7.42 (m, 3H), 7.21-7.26 (m, 1H), 7.07-7.14 (m, 2H), 6.99 (s, 1H), 5.57 (d, J=5.8 Hz, 1H), 5.07 (d, J=5.8 Hz, 1H). 19F NMR (CDCl3) δ: −71.32 (br. s., 1F), −117.12 (br. s., 1F), −123.54 (d, J=8.7 Hz, 1F). Mass spec.: 395.1 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH:26]([O:29][C:30]1[C:31](=O)[C:32](=[O:38])[C:33]=1[O:34]C(C)C)([CH3:28])[CH3:27].C(N(CC)CC)C>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:31]4[C:32](=[O:38])[C:33](=[O:34])[C:30]=4[O:29][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Oc1c(N2CCN(C(=O)c3ccc(/C=C/c4n[nH]c5ccccc45)cc3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 79.9 %

Procedure:
(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (1.0 g, 2.5 mmol) obtained in Example 18 was dissolved in methanol (9.9 mL), and the solution was added with 3,4-diisopropoxy-3-cyclobutene-1,2-dione (0.69 g, 3.5 mmol) and triethylamine (0.69 mL, 4.9 mmol), followed by stirring at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was added with ethanol, followed by stirring. The deposited crystal was collected by filtration to obtain (E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione (0.94 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH2:32][CH2:33]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccnc2ccccc12
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(4-quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 3 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate-methanol; 20: 1) and crystallized from dichloromethane-hexane to provide 1.2 g of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 135°-136° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:10][N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([NH2:21])=[N:15][C:16]=2[Cl:20])[CH2:5][C:6](OC)=[O:7].[BH4-].[Li+].O>C(O)(C)(C)C>[NH2:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH:4]([CH2:5][CH2:6][OH:7])[CH2:3][OH:2])=[C:16]([Cl:20])[N:15]=1
Reactant: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (-)-dimethyl-2-(2-amino-6-chloropurin-9-ylmethyl)succinate (enantiomeric excess 85%; 19.9 mg, 0.0607 mmol), dissolved in tert. butanol (2.0 ml) at 40° C., was added lithiumborohydride (30 mg, 1.38 mmol) in portions with stirring. After 1 hr at ambient temperature, water (0.3 ml) was added slowly and stirring continued over night. Inorganic salts were filtered, washed carefully with tert. butanol and the solution was evaporated to dryness. Preparative thin-layer chromatography (PSC-Fertigplatten, Merck) with chloroform+methanol (5+1) as mobile phase afforded 16.5 mg (theoretical yield) of (-)-2-(2-amino-6-chloropurin-9-ylmethyl)-1,4-butanediol. [α]D20 °-5.20°, [α]54620 -5.92° (c 0.625, ethanol). TLC on silica (chloroform+methanol 5+1): Rf 0.40, identical to that of the racemate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Ic1ccc(N2CCNCC2)nc1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a stirred solution of 2-chloro-5-iodo-pyridine (CAS number 69045-79-0, 10.52 g, 43.9 mmol) and diisopropylethylamine (11.5 mL, 65.9 mmol) in DMA (200 mL) was added piperazine (15.14 g, 0.176 mol). The mixture was then heated to 120° C. for 20 hours. The solid precipitate was then filtered off, and the filtrate evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo, to give 1-(5-iodopyridin-2-yl)piperazine as a yellow solid (10.42 g, 36 mmol, 82%).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([OH:28])[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)=[O:22].N1C=CN=C1.O>CN(C=O)C>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=1)=[O:22]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
TBDPSCl (1.73 g, 6.3 mmol) was dropped into a solution of (2S,4R)-4-Hydroxy-1-(4-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 2.9 mmol) and imidazole (0.98 g, 14.4 mmol) in DMF (20 mL), the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (50 mL), extracted with ethyl acetate (3×30 mL). The organic layers was combined, washed with water (2×30 mL), brine (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give compound 1.48 g (88%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.67-7.62 (m, 4H), 7.47-7.37 (m, 8H), 7.13 (d, 2H, J=8.7 Hz), 6.37 (s, 1H), 4.68-4.55 (m, 2H), 3.71 (s, 3H), 3.54-3.42 (m, 2H), 2.33-2.25 (m, 1H), 2.05-1.97 (m, 1H), 1.06 (s, 9H); LC-MS: 587.2 [M+1]+.