Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.ClC(Cl)C(OC(=O)C(Cl)Cl)=O.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][CH:25]=1>ClC(Cl)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([C:25]1[O:26][C:27]([CH3:29])=[CH:28][C:24]=1[CH3:23])=[O:11]
Reactant: Cc1coc(C)c1
Reactant: O=C(O)CCCc1cccs1
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(C(=O)CCCc2cccs2)o1
Temperature: 50 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
In 50 ml of dichloroethane were dissolved 8.51 g (0.05 mole) of 4-(2-thienyl)butyric acid and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.065 mole of 3,5-dimethylfuran and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 7 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure to obtain 2-[4-(2-thienyl)butyryl]3,5-dimethylfuran.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH:2]=[CH2:3].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.O>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (1.27 g) and 4-allyloxyquinaldic acid (1.2 g) in dimethylformamide (30 ml) were heated at 100° for 4 hours. 5-Aminotetrazole (1.33 g) was added and the mixture was stirred at 100° for 1 hour and cooled. Water (30 ml) was added and the solid was collected and dissolved in hot aqueous dimethylaminoethanol (15 ml, 5%). The solution was filtered and the filtrate was acidified with glacial acetic acid. 4-Allyloxy-N(1H-tetrazol- 5-yl)quinaldamide was collected and dried, m.p. 260° (d).
Reaction SMILES: [C:1]([C:3]1[CH2:8][N:7]2[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:12])[CH:11]=[C:6]2[N:5]([CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)#[N:2].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br.O>CN(C=O)C.[Ag-]=O>[C:1]([C:3]1[CH:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:5]([CH3:18])[C:6]2[N:7]([CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:12])[CH:11]=2)[C:8]=1[CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[F:27])#[N:2]
Reactant: CCOC(=O)C1C(=O)C=C2N(C)C(c3ccc(OC)cc3)=C(C#N)CN21
Reactant: Fc1ccccc1CBr
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C(=O)C=C2N(C)C(c3ccc(OC)cc3)C(C#N)=C(Cc3ccccc3F)N21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 3-cyano-6-ethoxycarbonyl-2-(4-methoxyphenyl)- 1-methyl-4H -pyrrolo[1,2-a]pyrimid-7-one (351 mg, 1.0 mmol.) in dry DMF (5 mL) under N2, 2-fluorobenzyl bromide (473 mg, 2.5 mmol) and silver(I) oxide (924 mg, 4 mmol) were added. The slurry was stirred for 2 days at room temperature and poured into water (10 mL). Crude product was extracted out from water by ethyl acetate (50 mL). The organic layer was then concentrated and purified by silica gel chromatography (ethyl acetate/hexane) to give a pure product. It was crystallized in ether/ethyl acetate to give the titled compound as off white crystals (310 mg, 52%); proton NMR (DMSO-d6): 8.67 (1H, s), 7.45-7.80 (6H, m), 7.00 (2H, d, J=7.8 Hz), 5.70 (2H, s), 4.18 (2H, q, J=6.6 Hz), 3.74 (3H, s), 2.56 (3H, s), 1.23 (3H, t, J=6.6 Hz); MS: 460 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCn1nc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Temperature: 100 °C
Yield: 32.1 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 252a (200 mg, 0.64 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (309 mg, 0.64 mmol), PdCl2(dppf) (52.5 mg, 0.060 mmol), K3PO4 (333 mg, 1.29 mmol), sodium acetate (105 mg, 1.29 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 252b as a yellow solid (120 mg, 27.6%). MS-ESI: [M+H]+ 584.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.Cl>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:18]2[CH2:19][CH2:20][CH2:21][CH:17]2[CH2:16][C:15]([O:14][CH3:13])=[O:22])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65 mmol) in DCM (15 ml) was added dropwise at 0° C. to a solution, cooled to 0° C., of pyrrolidin-2-ylacetic acid methyl ester (1.5 g, 8.4 mmol) in DCM (33 ml) and triethylamine was (2.66 ml, 21 mmol), and stirring was then carried out for 90 minutes at room temperature. 0.5 M HCl (20 ml) was then added, and stirring was carried out for a further 15 minutes. The organic phase was separated, washed with water and dried over sodium sulfate. The solvent was removed using a rotary evaporator and the product was used in the next stage without being purified further. Yield: 2.1 g (77%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][OH:36])=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:58][C:59]1[CH:68]=[C:67](O)[CH:66]=[CH:65][C:60]=1[C:61]([O:63][CH3:64])=[O:62].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:64][O:63][C:61](=[O:62])[C:60]1[CH:65]=[CH:66][C:67]([O:36][CH2:35][CH2:34][O:33][C:20]2[C:19]([Br:37])=[CH:18][C:17]([C:16](=[O:38])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:22][C:21]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:68][C:59]=1[OH:58]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.687 g, 1.16 mmol, 1 eq) in THF (10 mL) was added triphenylphosphine (0.680 g, 2.59 mmol, 2.23 eq) and methyl 2,4 dihydroxybenzoate (0.388 g, 2.30 mmol, 2.0 eq). The reaction was cooled to 0° C. and diethyl azodicarboxylate (0.220 mL, 1.40 mmol, 1.2 eq) was added. The cold bath was removed and the reaction was stirred overnight at rt. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc:hexane) to afford 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester 1H NMR (CDCl3) δ 11.90 (s, 1H); 7.97 (d, 1H); 7.84-7.50 (m, 6H); 7.28-7.12 (m, 5H); 6.40 (m, 1H); 6.24 (m, 1H); 6.10 (bt, 1H); 4.12 (dd, 2H); 4.00 (m, 2H); 3.92 (s, 3H); 3.45 (dd, 2H); 2.59 (t, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7](=[O:20])[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[C@H:1]([NH:5][C:6]1[C:7]([O:20][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (R)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol) and then Tf2O (615 mg, 2.18 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (400 mg, crude).
Reaction SMILES: CS(N)(=O)=O.C=[C:7]1[C:12]2=[N:13][C:14]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[CH:15][CH:16]=[C:11]2[O:10][CH2:9][CH2:8]1.S([O-])([O-])=[O:29].[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O1CCOCC1.O.C(Cl)Cl.CC(O)(C)C.O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N:20]2[CH:21]=[C:17]([C:14]3[N:13]=[C:12]4[C:7](=[O:29])[CH2:8][CH2:9][O:10][C:11]4=[CH:16][CH:15]=3)[CH:18]=[N:19]2)[CH:23]=1
Reactant: O=S([O-])[O-]
Reactant: C=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Agent: CS(N)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
AD-mix-a (13.9 g, 1.44 g/mmol) was added to t-BuOH/H2O (45 ml/45 ml), stirred at rt for 5 min. MeSO2NH2 (936 mg, 9.85 mmol) and K2OsO4.2H2O (21 mg, 0.058 mmol) was added to the reaction mixture. The mixture was then cooled with ice, 4-methylene-6-[1-(3-pyridyl) pyrazol-4-yl]-2,3-dihydropyrano[3,2-b]pyridine (2.8 g, 9.66 mmol) in THF (25 ml) was added slowly to the above solution. Sodium sulfite (22 g, 2.25 g/mmol) was then added. After stirring for 15 min at 0° C., the ice bath was removed and the reaction mixture was stirred at rt for 45 min. The mixture was diluted with DCM (100 ml) and H2O (100 ml) and the two layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, which was used directly for the next step. The crude product was dissolved in a 1:1 mixture of dioxane (30 ml) and H2O (30 ml), and sodium periodate (1.9 g, 9.26 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (50 ml) and H2O (50 ml) and the two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (EtOAc/MeOH, 50/1) to afford the title compound as red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[F:31][C:32]([F:52])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[CH:37][C:36]=1[S:47](Cl)(=[O:49])=[O:48]>>[F:52][C:32]([F:31])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:44])([F:45])[F:46])=[CH:37][C:36]=1[S:47]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:6]1=[O:11])(=[O:49])=[O:48]
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Yield: 66.6 %

Procedure:
With 200 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of the brochure No. WO01/98295, and 183 mg of 2,5-bis(2,2,2-trifluoroethoxy)benzene sulfonyl chloride as starting materials, 238 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Br.[NH2:51][CH:52]1[CH2:57][CH2:56][O:55][C:53]1=[O:54]>C(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[NH2:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:51][CH:52]4[CH2:57][CH2:56][O:55][C:53]4=[O:54])=[CH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NC1CCOC1=O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CCOC3=O)cn2)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
6-[1-(3-amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid (1 g) was added to a co-solvent of tetrahydrofuran (25 ml) and methylene chloride (15 ml) and with the successive addition of 1.3-dicyclohexylcarbodimide (1.3 g) and 1-hydroxybenzotriazole (0.46 g) at 15° C.˜20° C., the mixture was stirred for 2 hours. A mixture of α-amino-γ-butyrolactone hydrobromide (1.1 g) and triethylamine (0.9 ml) was added again to the mixture at 20° C. and stirred at 20° C.˜25° C. for 3 hours. With the addition of methylene chloride (50 ml), the mixture was washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with chloroform and tetrahydrofuran to give a desired compound of 1.07 g (yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[CH:5]=[C:4]([CH2:16]Cl)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][NH:25][CH3:26]>CN(C=O)C>[CH:13]12[N:8]([C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH2:16][N:25]([CH3:26])[CH3:24])[CH:5]=3)[CH:9]([CH2:15][CH2:14]1)[CH2:10][O:11][CH2:12]2
Reactant: ClCc1cc(N2C3CCC2COC3)nc(Cl)n1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
A flask was charged with 8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.30 g, 8.39 mmol) and DMF (40 ml) was added to give a yellow solution. Potassium carbonate (2.90 g, 20.97 mmol) and dimethylamine (2.0M in THF, 4.6 ml, 9.23 mmol) were added and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was filtered through a Buchner funnel and washed with methylene chloride and ethyl acetate. The filtrate was concentrated to provide crude product as a brown oil, which solidified upon standing (2.61 g). The crude product was added to a silica gel column and was eluted with 0-10% methanol in methylene chloride to provide 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (2.01 g, 85%) as an off-white solid. HRMS; [M+H]+ Obs'd=283.1320, [M+H]+ Calc'd=283.1319.
Reaction SMILES: [CH3:1][C:2]1[N:40]=[C:5]2[N:6]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[Si:56]([O:39][C:37](=[CH2:38])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:40]=[C:5]23)[CH2:34][CH2:33]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2nc(C)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3nc(C)nc32)CC1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution (10 mL) of 4′-({2-methyl-5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.56 g) and diisopropylethylamine (0.36 mL) in methylene chloride was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.36 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.5 g, 72%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([N:40](C(OC(C)(C)C)=O)[C@H:41]([C:47](O)=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=O)(C)(C)C>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:47](=[O:48])[C@@H:41]([NH2:40])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Agent: Cl
Product: NCCCC[C@H](N)C(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and di-tert-butoxycarbonyl-L-lysine by using the same method as in Example 96.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>[Ag-]=O.C(O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:10]1[C:9](=[O:12])[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2](=[O:1])[CH:11]=1
Reactant: Nc1cccc(F)c1
Reactant: Oc1ccc(O)c2nccnc12
Agent: O=[Ag-]
Solvent: CCO
Product: O=C1C=C(Nc2cccc(F)c2)C(=O)c2nccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Approximately one gram of 5,8-dihydroxyquinoxaline was dissolved in 100 ml. of 2B ethanol. To the solution were added about 5 g. of freshly prepared silver (I) oxide and about 3 g. of 3-fluoroaniline. The reaction was stirred overnight at room temperature and worked up in the same manner as described in Example 3. Crystallization from ethyl acetate gave about 500 mg. of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
2-Acetylamino-4-chloromethylthiazole (480 mg), 3-(4-piperidyl)indole (500 mg) and sodium hydrogen carbonate (310 mg) was refluxed in a mixture of N,N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) for 1 hour and 40 minutes. After the reaction mixture cooled to ambient temperature, it was concentrated under reduced pressure. After addition of water (50 ml), the residue was extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (30:1 V/V). The eluate gave 2-acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (270 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15](=O)[CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.C(OC(=O)C)(=O)C>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH:14]([O:9][C:1](=[O:8])[CH3:2])[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1OCCS1=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1COC(COC(=O)c2ccccc2)S1
Temperature: 25 °C
Yield: 120 %

Procedure:
A mixture of 2-benzoyloxymethyl-3-oxo-1,3-oxathiolane (example 3) (10.5 g), tetra-n-butylammonium acetate (17 g) in acetic anhydride (250 ml) was heated at 110° to 120° C. under argon for 14 hours and cooled to room temperature. Excess acetic anhydride was removed under reduced pressure. The residue was dissolved in methylene chloride (500 ml), washed first with saturated aqueous NaHCO3 (2×200 ml), then with brine solution (200 ml), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (8:1) as eluant to give 7.4 g (60% yield) of the desired product as a mixture of cis- and trans- isomers. A small quantity of each isomer was also isolated and characterized by 1H- and 13C-NMR.
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1OCC([O:15][CH2:16][CH:17]1[CH:22]2[O:23][CH:21]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)=O)(C)C.[OH-:31].[K+]>>[OH:15][CH2:16][CH:17]1[CH2:18][NH:19][CH2:20][CH:21]([OH:23])[CH:22]1[OH:31]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(=O)OCC1CN(C(=O)OC(C)(C)C)CC2OC12
Reactant: [OH-]
Agent: [K+]
Product: OCC1CNCC(O)C1O
Yield: 65 %

Procedure:
tert-Butyl 3-((1R,2S,5R)-2-isopropyl-5-methyl-1-cyclohexyloxy)acetoxymethyl-4,5-epoxypiperidine-1-carboxylate (0.25 g, 0.59 mmol) and 10% aqueous potassium hydroxide were refluxed for 3h. The reaction mixture was evaporated to dryness in vacuo and purified on a silica gel column (Eluent: isopropyl alkohol /26% ammonium hydroxide (3/1)) to give 5-hydroxymethyl-3,4-piperidinediol as an oil (Yield: 56 mg, 65%).