Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.C1C2C(=CC=CC=2)CCC1.[BH4-].[Na+].[H][H]>[Pd].[Pt].Cl.[Cl-].[Zn+2].[Cl-].C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C1=NCCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: c1ccc2c(c1)CCCC2
Product: c1ccc2c(c1)CCNC2

Procedure:
The 1,2,3,4-tetrahydroisoquinolines, of the general formula: ##STR10## may be prepared by the cyclodehydration of the appropriately substituted β-phenethylamide to the corresponding 3,4-dihydroisoquinoline by heating the aforesaid amide in the presence of such dehydrating agents as phosphorus pentoxide, anhydrous zinc chloride, phosphorus oxychloride or phosphorus pentachloride, usually in an inert organic solvent like toluene, xylene or tetralin, followed by reduction in the usual manner, e.g., with sodium borohydride or with hydrogen and palladium-on-charcoal catalyst (the Bischler-Napieralski route); by condensation between the appropriately substituted benzaldehyde and 2-aminoacetaldehyde dialkyl acetal, followed by reduction of the Schiff base product, e.g., with hydrogen and platinum catalyst, and then hydrolysis/ring closure of the resulting N-benzylamino acetaldehyde dialkyl acetal in 6N hydrochloric acid solution, followed by selective reduction of the ring, e.g., wth hydrogen and palladium-on-charcoal catalyst, to give the appropriate 1,2,3,4-tetrahydroisoquinoline [Bobbitt et al., Journal of Organic Chemistry, Vol. 30, p. 2247 (1965), and Bobbitt and Sih, ibid., Vol. 33, p. 856 (1968)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1ccc(SCc2ccccc2)cc1

Procedure:
Methyl(4-mercaptophenyl)acetate (0.2 mol) is heated at reflux with benzyl chloride (25 g, 0.2 mol) and K2CO3 (25 g, 0.2 mol) in 100 mL ethanol. The product is added to aqueous NaOH, extracted with ether, and purified by silica gel chromatography to yield methyl(4-benzylthiophenyl)acetate (3). (Scheme III, Step 1.)
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Br:37]NC(=O)CCC(N)=O.C(=O)(O)[O-].[Na+].O>C(Cl)(Cl)Cl.ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[C:27]([Br:37])=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3c2cc2c(c3Br)COC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (2.64 mmol) in chloroform (20 mL), add N-bromosuccinamide (2.9 mmol) along with sodium bicarbonate (5.28 mmol). After stirring the mixture at room temperature for 20 minutes, add water (20 mL) and dilute the mixture with dichloromethane (20 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude intermediate over silica gel eluting with ethyl acetate/hexane to obtain the title compound as an off white solid. MS (ES+): 593 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]([O-:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:24][N:25]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.CCOCC>[S:8]([OH:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH2:26][NH2:27])=[N:24][N:25]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])s1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)s1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81.8 %

Procedure:
TFA (0.30 mL) was added to a mixture of sodium (2S,5R)-2-(5-(((tert-butoxycarbonyl)amino)methyl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate (50 mg) in dry DCM (0.80 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2-3 hrs and then diluted with ether (−15 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-2-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (30 mg) as TFA salt. ESI-MS (EI+, m/z): 336.1. 1H NMR (300 MHz, D2O) δ 4.97 (br d, J=6.2 Hz, 1H), 4.68 (s, 2H), 4.19 (br s, 1H), 3.21 (br d, J=13.5 Hz, 1H), 2.94 (d, J=12.2 Hz, 1H), 2.54-2.49 (m, 1H), 2.30-2.07 (m, 2H), 1.98-1.87 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[CH3:20])=[O:8].[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[CH3:20])=[O:8])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34]
Reactant: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)c2cc(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 98.7 %

Procedure:
A mixture of 2.50 g (7.29 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone, 1.53 g (7.29 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 3.30 g (24 mmol) of potassium carbonate in 50 mL of acetone and 5 mL of DMF was stirred and heated at reflux for 26 hours. After workup as in Example 16 the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 3.40 g (98% yield) of 4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl benzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[S:38]1[CH:42]=[C:41]([CH2:43][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:43]/[C:41]4[N:40]=[CH:39][S:38][CH:42]=4)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc(/C=C/c3cscn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (1.00 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.27 g), potassium carbonate (0.44 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-5-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.77 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC(Cl)=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:46][C:47]([F:57])([F:56])[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C1COCC1.CN1C(=O)CCC1>[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([NH:53][C:52]1[CH:54]=[CH:55][C:49]([O:48][C:47]([F:46])([F:56])[F:57])=[CH:50][CH:51]=1)=[O:16]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIPEA (4.00 mL, 22.90 mmol) was added to a solution of 3-iodo-4-methylbenzoic acid (2 g, 7.63 mmol) and 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU, 3.47 g, 8.40 mmol) in THF (18 mL) and NMP (2 mL) and the RM was stirred at RT for 30 min. 4-(Trifluoromethoxy)aniline (1.536 mL, 11.45 mmol) was then added and the RM was stirred at RT for 14 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. 1M HCl (50 mL) and extracted with TBME. The combined extracts were washed with aq. 1 M HCl (50 mL), aq. sat. Na2CO3, water, brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from n-heptane/EtOAc to afford the title compound as white needles. UPLC-MS (Condition 1) tR=3.42 min, m/z=421.9-422.9 [M+H]+, m/z=419.9-420.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 7.36 (d, J=8.3 Hz, 2H) 7.49 (d, J=8.3 Hz, 1H) 7.83-7.93 (m, 3H) 8.39 (d, J=2.0 Hz, 1H) 10.42 (s, 1H).
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][NH2:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CN(C)C=O>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][NH:15][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 10.0 g (0.043 mol) of (1f) and 10.3 g (0.036 mol) of N-BOC-L-alanine, N-hydroxysuccinimide ester in anhydrous N,N-dimethylformamide (50 ml) was cooled with an ice bath. To this was added 7.6 ml (0.054 mol) of triethylamine in anhydrous N,N-dimethylformamide (20 ml) over a period of 30 minutes. The reaction was stirred at ca. 5° C. for 1 hour, then at room temperature for 1 hour. The N,N-dimethylformamide was removed in vacuo and the resulting residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) and finally, with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 12.4 g (94% yield) of N-BOC-L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1g) as a white solid. TLC: Rf 0.67 (chloroform-isopropanol 9:1); 1H NMR(CDCl3) δ 1.27(d, 3H), 1.40(s, 9H), 3.32(m, 4H), 4.15(m, 1H), 5.06(s, 2H), 5.51(d, 1H), 5.90(m, 1H), 7.19(m, 1H), 7.31(bs, 5H); 13C NMR (CDCl3) δ 18.5, 28.2, 39.6, 40.5, 50.1, 66.5, 79.8, 127.9, 128.3, 136.3, 155.4, 156.9, 173.7.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:27](=[O:28])[CH2:26][C:25]([CH3:30])([CH3:29])[CH2:24][C:23]3=[O:31])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:23](=[O:31])[CH2:24][C:25]([CH3:29])([CH3:30])[CH2:26][C:27]3=[O:28])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)N(CCCCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Yield: 88.8 %

Procedure:
In an analogous manner to that described in Example 20b), from 9.2 g (21.56 mmol) of rac-cis-1-[6-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-hexyl]-4,4-dimethyl-piperidine-2,6-dione using pyridine hydrochloride there were obtained 7.9 g of (89%) rac-cis-1-[6-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-hexyl]-4,4-dimethylpiperidine-2,6-dione; yellowish crystals of m.p. 98.5°-99° after crystallization from ether/hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]([OH:22])=O)=[CH:5][CH:4]=1.COC1C=CC(C2OC(C3SC=CC=3)=[N:33]C=2C(O)=O)=CC=1.O.OC1C2N=NNC=2C=CC=1.N.O1CCOCC1.N=C=N>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]([NH2:33])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc(-c3ccccc3)nc2C(=O)O)cc1
Reactant: COc1ccc(-c2oc(-c3cccs3)nc2C(=O)O)cc1
Agent: N
Agent: N=C=N
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(-c2oc(-c3ccccc3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-2-phenyloxazole-4-carboxylic acid (prepared according to the method described for 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylic acid in Example M-1, 0.032 g, 0.11 mmol) and hydroxybenzotriazole monohydrate (0.02 g, 0.13 mmol) in DCM (2 mL) and DMF (1 mL) was added 0.5M ammonia in dioxane (1 mL, 0.5 mmol), followed by PS-carbodiimide resin. The resulting mixture was stirred at room temperature overnight. The mixture was passed through a MP-CO3 resin cartridge and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-phenyloxazole-4-carboxamide (0.008 g, 0.03 mmol, 27%) as a white solid. 1H NMR (DMSO) δ 3.85 (3H, s), 7.10 (2H, d), 7.60 (3H, m), 7.66 (1H, br. s), 7.78 (1H, br. s), 8.14 (2H, m), 8.37 (2H, d). LCMS (2) Rt: 3.16 min; m/z (ES+) 295.
Reaction SMILES: C[C:2]1[C:3]([N:11]=[C:12]=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[O:10].[N-]=[C:15]=O.[N-]=C=O.C1(CC2C=CC=CC=2)C=CC=CC=1.C1(N=C=O)C=CC=C(N=C=O)C=1.C(N=C=O)CCCN=C=O.COC1C=C(C2C=CC(N=C=O)=C(OC)C=2)C=CC=1N=C=O.CC1C=C(C2C=CC(N=C=O)=C(C)C=2)C=CC=1N=C=O.C1(N=C=O)C=CC(N=C=O)=CC=1.C1C=C(N=C=O)C2C=CC=C(N=C=O)C=2C=1.C1(CN=C=O)C=CC(CN=C=O)=CC=1.C1(CN=C=O)C=CC=C(CN=C=O)C=1.N(CC1CCCC(CN=C=O)C1)=C=O.N(CC1CCC(CN=C=O)CC1)=C=O.C1C(CC2CCC(N=C=O)CC2)CCC(N=C=O)C1.O=C=NC1CC(C)(C)CC(C)(CN=C=O)C1>>[CH3:15][C:4]1[C:3]([N:11]=[C:12]=[O:13])=[CH:2][C:7]([N:8]=[C:9]=[O:10])=[CH:6][CH:5]=1
Reactant: [N-]=C=O
Reactant: Cc1c(N=C=O)cccc1N=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: COc1cc(-c2ccc(N=C=O)c(OC)c2)ccc1N=C=O
Agent: Cc1cc(-c2ccc(N=C=O)c(C)c2)ccc1N=C=O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
2,6-tolylene diisocyanate; diphenylmethane diisocyanate (may be abbreviated as "MDI"); m-phenylene diisocyanate; tetramethylene diisocyanate; 3,3'-dimethoxy-4,4'-biphenylene diisocyanate; 3,3'-dimethyl-4,4'-biphenylene diisocyanate; 4,4'-diphenylene diisocyanate; paraphenylene diisocyanate; 4,4'-diisocyanato diphenyl ether; 1,5-naphthalene diisocyanate; p-xylylene diisocyanate; m-xylylene diisocyanate; 1,3-diisocyanato methyl-cyclohexane; 1,4-diisocyanato methylcyclohexane; 4,4'-diisocyanato dicyclohexane; 4,4'-diisocyanato dicyclohexylmethane; and isophorone diisocyanate.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:9]([CH3:33])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2)=[O:7])(=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:33][N:9]1[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][C:24]2=[O:32])[CH2:21][CH2:22]1
Reactant: CC(=O)NNC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N′-acetyl-9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carbohydrazide (85 mg, 0.19 mmol, 1 equiv) and triphenylphosphine (90 mg, 0.34 mmol, 1.8 equiv) were weighed out into a 2 dram vial and suspended in acetonitrile (1 mL). Diisopropylethylamine (165 mL, 0.95 mmol, 5 equiv) and carbontetrachloride (36 μL, 0.38 mmol, 2 equiv) were added and the reaction stirred at room temperature overnight during which time a precipitate formed. Analysis by LCMS indicated about a 40% conversion to the desired product. Neither heating to 80° C. for several hours, nor the addition of additional carbontetrachloride, DIPEA, or TPP furthered the cyclization. The precipitate was collected, dissolved in DMF (3.5 mL) and purified by preparative reverse-phase HPLC (acetonitrile/water with 1% formic acid). Fraction containing pure 1-{1-[9-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-9H-purin-6-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one were combined. The desired material precipitated upon concentration of the fractions, was collected by filtration, washed with water, and dried under vacuum, which resulted in the isolation of 16 mg of material. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.33 (s, 1H), 7.16-7.10 (m, 1H), 6.93-6.82 (m, 3H), 4.53 (t, 1H), 4.03 (s, 3H), 2.59 (s, 3H), 2.30 (d, 2H), 1.83 (d, 2H). MS (EI) for C21H21N9O2: 432 (MH+).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([CH3:13])([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:13][C:5]([OH:12])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:4]#[CH:3]
Reactant: CCCCCCC(C)(O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(C)(O)CCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-trimethylsilyl-3-methyl-l-nonyn-3-ol (l.94g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(CBr)no1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(COc2ccn(-c3nc(C)c(C(=O)NCc4ccccc4)s3)c(=O)c2)no1
Yield: 47 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 3-(bromomethyl)-5-methylisoxazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 47% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.9 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 5H), 6.38-6.35 (m, 2H), 6.26 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 437.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[O:12][C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:19][C:15]1[CH:14]=[C:13]2[C:18]([CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)[CH2:10][C:11]([CH3:21])([CH3:20])[O:12]2)=[CH:17][CH:16]=1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC3CO3)cc2O1

Procedure:
Reaction of 4-(3-Trifluoromethylphenyl)-2,2-dimethyl-7-chromanol with epichlorohydrin, by an analogous method to that described in Example 1, gave 7-(2,3-epoxypropoxy)-4-(3-trifluoromethylphenyl)-2,2-dimethylchroman. Reaction of this epoxide with methylamine, by an analogous method to that described in Example 2 gave 4-(3-trifluoromethyl-phenyl-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethylchroman, (benzoate salt, m.p. 145-157°).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([OH:44])[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([O:44][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.32 g of tert-butyldiphenylsilyl chloride and 2.32 g of imidazole were added in order to a dimethylformamide (60 ml) solution of 3.61 g of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.