Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH:17]([C:23]([O:25]CC)=[O:24])[C:18](=[O:22])[NH:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>[Cl-].[Na+].CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH:17]([C:23]([OH:25])=[O:24])[C:18](=[O:22])[NH:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc2c(c1)NC(=O)C(C(=O)O)C2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 7-benzyloxycarbonylamino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (7.8 g) in a mixed solvent of THF (80 ml) and methanol (80 ml) was added 1N aqueous sodium hydroxide (32 ml) under 10° C. The reaction mixture was stirred at room temperature for 4 hours, to which was added 1N hydrochloric acid (35 ml) under 1° C. The reaction mixture was diluted with a saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated to obtain the entitled compound (7.20 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22][CH2:21]N(C(OC(C)(C)C)=O)CC1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCC1C[CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH2:17][CH:22]1[CH2:21][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])[CH2:61][CH2:60]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl 4-(2-bromoethyl)-1-piperidinecarboxylate. TLC chloroform/methanol 9:1:Rf 0.81
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.O>CCOCC>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of 1,3-dibromo-5-methoxybenzene (15 g, 56.40 mmol) in anhydrous Et2O (200 mL) under nitrogen was cooled to −78° C. n-BuLi (38.80 mL of a 1.6 M solution in Et2O, 62.00 mmol) was added dropwise, and the solution was aged at −78° C. for 45 m. To the resulting heterogeneous mixture was added anhydrous DMF (4.78 mL, 62.00 mmol), and the solution was slowly warmed to RT. The mixture was poured into H2O (200 mL), and the aqueous phase was extracted with Et2O (3×125 mL). The combined organic fractions were washed with brine (100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent provided 11.70 g (96%) of 3-bromo-5-methoxybenzaldehyde (115).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[CH:6]=[C:7]([F:9])[CH:8]=1.FC(F)(F)C(O)=O.[F:20][C:21]([F:36])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(#N)C>[F:36][C:21]([F:20])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[CH:6]=[C:7]([F:9])[CH:8]=3)[CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: OCCc1cc(F)cc(CBr)c1
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of 2-(3-(bromomethyl)-5-fluorophenyl)ethanol (example 41, step b) (3.6 g) and 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (5.66 g) in acetonitrile (80 mL) was treated with triethylamine (5.38 mL) and the mixture stirred at 20° C. for 20 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 4.9 g.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: COCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -50 °C
Yield: 50 %

Procedure:
To a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.59 mmol) and THF (6 mL) was added triethylamine (165 μL, 1.18 mmol) to form a clear solution. The mixture was cooled to −50° C. external temperature, and a 1:1 mixture of 2-methoxyethyl chloroformate (65 μL) and THF (65 μL) was added dropwise. After complete addition, the reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 gave (R)-2-methoxyethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-Page 66 of 141 yl)pyrrolidin-3-ylcarbamate (compound 1) (130 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.58 (s, 1H), 7.33 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.69 (m, 1H), 4.22 (m, 1H), 4.04 (m, 5H), 3.84 (m, 1H), 3.48 (t, J=4.6 Hz, 2H), 3.23 (s, 3H), 2.52 (s, 3H), 2.20 (m, 1H), 2.02 (m, 1H) ppm. LC/MS: m/z 441.5 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CS.OC[CH2:5][S:6]([CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15])(=O)=O>C(#N)C.O.C(Cl)Cl>[CH3:5][S:6][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18])[CH3:15]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1S(=O)(=O)CCO
Agent: CS
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
1.17 g (16.7 mmol) of the Na salt of methyl mercaptan are added to a solution of 4.48 g (11.1 mmol) of 4-(2-hydroxyethylsulphonyl)-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one in 11 ml of acetonitrile and 11 ml of H2O at 0° C., and the mixture is stirred at 0° C. for 20 minutes. The reaction mixture is diluted with 100 ml of methylene chloride and 25 ml of H2O, and, after separating off the organic phase, the aqueous phase is extracted three times with 25 ml of methylene chloride in each case. The combined organic phases are dried over MgSO4, filtered and the solvent is removed in vacuo, to give 3.80 g of the title compound as a slightly yellowish non-crystalline compound. NMR spectrum in CDCl3 : δ=1.45 (d, J=7 Hz, 3 H), 2.12 (s, 3 H), 3.3 (dd, J=7 Hz, J=2 Hz), 4.70 (d, J=2 Hz, 1 H), 5.12 (m, 1 H), 5.20 (s, 2 H), 6.45 (broad s, 1 H), 7.50 (d, J=8.5 Hz, 2 H), 8.20 (d, J=8.5 Hz, 2 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC(C)([O-])C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCOCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)thiazolo[5,4-b]pyridine (0.201 g, 0.471 mmol) in 2.5 mL THF was added a solution of trimethylsulfoxonium iodide (0.207 g, 0.943 mmol) and potassium tert-butoxide (0.106 g, 0.943 mmol) in 2.5 mL DMSO. The yellow slurry was sealed and heated to 60° C. After 6 h, the reaction mixture was cooled, quenched with ice and sat'd aq. NH4Cl. The reaction mixture was partitioned between satd aq NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was purified by silica gel chromatography, 0-50% EA/hexanes, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)thiazolo[5,4-b]pyridine as a solid. MS (ESI) m/z: Calculated: 440.2; Observed: 441.1 (M++1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[F:9][C:10]([F:20])([C:17](O)=O)[C:11]([F:16])([F:15])[C:12](O)=O>>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:12]=1[C:11]([F:16])([F:15])[C:10]([C:17]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)([F:20])[F:9]
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Reactant: Nc1ccccc1N
Product: FC(F)(c1nc2ccccc2[nH]1)C(F)(F)c1nc2ccccc2[nH]1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
In a 250 mL 35/25 ball joint flask, 1,2-phenylenediamine (5.92 g, 54.7 mmol) was combined with tetrafluorosuccinic acid (5.2 g, 27.36 mmol). Polyphosphoric acid (83 g) was added directly to the solid mixture. The flask was fitted with an air-driven mechanical stirring shaft and heated to 160° C. under a nitrogen purge maintained with a septum and needle. The molten mixture was stirred for 7 hours and subsequently poured slowly into a large (1 L) excess of cold water. A Waring™ blender was used to grind the solid product/water slurry. The water was then neutralized to a pH of ˜8 with ammonium hydroxide. The brown particulate product, 1,2-bis(benzimidazol-2-yl)-1,1,2,2-tetrafluoroethane, was isolated by filtration, dried in a vacuum oven, ground to a fine powder with a mortar and pestle, and once again slurried in ca. 1 L water which was then neutralized to pH 8 with ammonium hydroxide. The solid was again collected by filtration and dried under diffusion pump vacuum at 110° C. for several days (7.96 g, 87%; C16H10F4N4, FW=334.27). A small amount of water was still present by 1H NMR (br s, 3.35 ppm). 1H NMR (d6-DMSO): δ 13.66 (br s, 2 H, NH), 7.67 and 7.34 (each br s, 4H, aryl C—H. 13C{1H} NMR (solid state): δ 142.2, 135.5 (C—N), 124.2, 120.2, 114.4 (aryl) (C═N and CF2 not observed). 19F NMR (d6-DMSO, vs. CFCl3): δ−110.61. IR (KBr pellet, cm−1): 3063 (m), 3011 (m), 2947 (m), 2864 (s), 2749 (s), 2699 (sh), 2647 (s), 2546 (m), 2527 (m), 1942 (w), 1903 (w), 1778 (w), 1622 (w), 1591 (m), 1537 (w), 1492 (m), 1456 (s), 1441 (s), 1389 (w), 1317 (m), 1279 (m), 1231 (m), 1202 (w), 1161 (vs), 1140 (vs), 1030 (m), 1014 (m), 999 (m), 941 (m), 909 (m), 887 (m), 789 (w), 766 (w), 739 (s), 675 (w), 619 (w), 590 (m), 545 (w), 434 (m). Elemental analysis calculated for C16H10F4N4: C, 57.49; H, 3.02; F, 22.73; N, 16.76. Found: C, 56.74; H, 2.82; F, 21.95; N, 16.70. FD-MS m/z (%): 334 (M+, 100), 167 (C8H5F2N2, 6). Melting point (DSC, maximum): 383° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Br-].[CH2:24]([Zn+])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Pd].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.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.C1COCC1>[CH2:24]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Reactant: [Zn+]Cc1ccccc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
THF (4 ml) was added to an argon purged glass tube (20 mL) containing methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (135 mg; 0.423 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.47 mg; 0.021 mmol). The mixture was stirred at room temperature for 10 min and, after dissolution of the solids, benzylzinc bromide (1.694 ml; 0.847 mmol; 0,5 M in THF) was added dropwise. Stirring at room temperature was continued for 15 min followed by stirring at 60° C. for 8 h. The reaction was quenched by adding a saturated ammonium chloride solution. To this suspension was added a saturated disodium ethylenediamine tetraacetate solution and the mixture was stirred at room temperature for 15 min. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine and dried over magnesium sulphate. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 101 mg (64%) of the title compound. ESI/APCI(+): 375 (M+H). ESI/APCI(−): 373 (M−H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl.CCN(C(C)C)C(C)C.[F:20][C:21]([F:44])([F:43])[C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([NH:39][CH3:40])=[CH:32][C:31]=2F)[CH2:24][CH2:23]1>O.CC#N>[F:20][C:21]([F:43])([F:44])[C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([NH:39][CH3:40])=[CH:32][C:31]=2[N:5]2[CH2:6][CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:4]2)[CH2:24][CH2:23]1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CNc1cc(N2CCC(C(F)(F)F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 4.5 h

Procedure:
A mixture of 3-trifluoromethyl-pyrrolidine×HCl (53 mg, 0.30 mmol), DIPEA (0.40 ml, 2.4 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (100 mg, 0.28 mmol) and MeCN (2 mL) is stirred for 4.5 h at reflux. Then the mixture is diluted with water and the formed precipitate is filtered, washed with water and dried
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[CH3:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24]Cl)=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([CH3:15])=[CH:17][CH:18]=3)[CH:22]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(Oc2cccc(CCl)c2)cc1
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Oc2cccc(COCC(C)(C)c3ccc(Cl)cc3)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 15.0 g of a 50% aqueous solution of NaOH were added 6.0 g of 2-(4-chlorophenyl)-2-methylpropyl alcohol, 8.1 g of 3-(4-methylphenoxy)benzyl chloride and 1.1 g of tetrabutyl ammonium bromide, and the mixture was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature and water was added, and the mixture was extracted with toluene and the toluene extract was washed with water and dried over Na2SO4, and evaporated under reduced pressure, and the obtained crude ether was purified by column chromatography on 250 g of silica gel (1:1 mixed solvent of toluene and n-hexane was used as eluent) to give 9.9 g of the desired ether (the yield was 80% of the theoretical yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1.Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>CCO>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1
Reactant: Brc1ncccn1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
A mixture of methyl (±)-8-(3-amino-1-propyloxy)-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate trifluoroacetate salt (0.75 g, 2 mmol), 2-bromopyrimidine (0.5 g, 3 mmol), NaHCO3 (1.4 g, 17 mmol), and EtOH (10 mL) was heated to reflux. After 24 hr, the mixture was filtered and the insoluble material was washed with MeOH. The filtrate and washings were combined and concentrated, and the residue was purified by chromatography on silica gel (1%-6% MeOH/CH2Cl2) to give the title compound (0.54 g, 82%) as a white foam: MS (ES) m/e 385.5 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]([CH3:21])[N:19]=[N:18][C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nnc2c3nc(O)c(O)nc3ccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c3nc(O)c(O)nc3cc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol) in 20 ml of conc. sulfuric acid at 0° C. After 1 h the ice bath was removed and the mixture was stirred over night at room temperature. Then an additional amount of potassium nitrate (0.47 g) was added and stirring was continued over night at room temperature. The solution was poured into ice/water and the precipitated solid was collected, washed with water, and dried to give 1.0 g (83%) of the pure nitro compound; m.p.>300° C.; IR (KBr): 1710 cm-1 ; 1H-NMR (DMSO-d6): 4.50 (s, 3H, CH3), 8.18 (s, 1H, ArH), 12.13 (broad s, 1H, OH), 13.17 (broad s, 1H, OH).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:23]1([C:29]2([C:34]([NH:36][NH2:37])=O)[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH:23]1([C:29]2([C:34]3[N:10]4[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]4=[N:37][N:36]=3)[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C1(C2CCCCC2)CCCC1
Agent: CO/C1=N/CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C1CCCn2c(nnc2C2(C3CCCCC3)CCCC2)CC1
Temperature: 105 °C
Reaction time: 72 h
Yield: 13.9 %

Procedure:
(1E)-8-Methoxy-2,3,4,5,6,7-hexahydroazocine (614 mg) and p-toluenesulfonic acid monohydrate (207 mg) were added to a toluene (20 ml) solution of 1-cyclohexylcyclopentanecarbohydrazide (762 mg), followed by stirring at 105° C. for 3 days. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=97:3) to obtain 152 mg of 3-(1-cyclohexylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (pale brown solid).
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].II.[OH2:12].N.CO>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[CH2:8]1[O:9][C@@H:1]2[O:7][C@H:6]1[C@@H:5]1[O:12][C@@H:4]1[C@@H:2]2[OH:3]
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: O
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: II
Solvent: CC(=O)O
Solvent: CO
Product: O[C@@H]1[C@@H]2OC[C@@H](O2)[C@@H]2O[C@H]12
Temperature: 25 °C
Yield: 93.8 %

Procedure:
0.13 g (1.00 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose represented by the above formula [3] was dissolved in 4.6 ml of acetic acid, and further 0.33 g (2.00 mmol) of silver acetate was added thereto. While vigorously stirring the solution at room temperature, 0.27 g (1.05 mmol) of iodine was gradually added to the solution. After the reaction mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere, 40 ml of 25% ammonia water was gradually added to the solution while ice-cooling to convert it to a basic solution. Further 40 ml of methanol was added to the basic solution, which was stirred for overnight at room temperature. Undissolved material was filtered off, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane: ethyl acetate=1: 1), thereby obtaining 1.09 g (yield: 93.8%) of 1,6:3,4-dianhydro-β-D-talopyranose represented by the following formula [4] . This was recrystallized from a hexane-diethyl ether mixed solvent (hexane:diethyl ether=1:4). ##STR13##
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([N:15]=[C:16]=O)([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5]2)[O:3]C1.O1CCCC1.O.[OH-].[Na+]>[H-].[Al+3].[Li+].[H-].[H-].[H-]>[CH3:16][NH:15][C:7]1([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: O=C=NC1(c2cccs2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1(c2cccs2)CCC(=O)CC1
Reaction time: 4 h
Yield: 35 %

Procedure:
A solution of 2.21 g. (8.3 mmole) of 4-isocyanato-4-(2-thienyl)cyclohexanone ethylene ketal in 40 ml. tetrahydrofuran (THF) is added to a suspension of 0.32 g. (8.4 mmole) in lithium aluminum hydride (LAN) in 5 ml. THF. Following 4 hours' stirring under reflux the mixture is cooled in ice. There is then added in turn 0.32 ml. water, 0.32 ml. 15% NaOH and 0.96 ml. water. The inorganic gel is collected on a filter and the filtrate taken to dryness. A solution of the residue in a small amount of ether is treated with a just-sufficient amount of 3 N hydrogen chloride in ether. The precipitated salt is recrystallized from methylene chloride:ethyl acetate to afford 0.84 g. (35% yield) of 4-methylamino-4-(2-thienyl)cyclohexanone, ethylene ketal hydrochloride, m.p. 211°-214° C.