Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[NH:17][C:16]3[C:15]4=[N:18][C@H:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][N:14]4[C:13](=[O:28])[N:12]([CH2:29][CH2:30][CH3:31])[C:11]=3[N:10]=2)[CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1.C(=O)([O-])O.[Na+].C(Cl)[Cl:51]>>[ClH:51].[C:32]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[NH:17][C:16]3[C:15]4=[N:18][C@H:19]([CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][N:14]4[C:13](=[O:28])[N:12]([CH2:29][CH2:30][CH3:31])[C:11]=3[N:10]=2)[CH2:7][CH2:8]1)(=[O:34])[CH3:33]
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c([C@H]3CC[C@H](CN)CC3)nc21
Reactant: CC(=O)OC(C)=O
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c([C@H]3CC[C@H](CNC(C)=O)CC3)nc21
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 62 (50 mg, 0.119 mmol) obtained in Example 62 was dissolved in methylene chloride (500 μL), to the solution were added acetic anhydride (11 μL, 0.119 mmol, 1.0 equivalent) and pyridine (10 μL, 0.120 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 98:2) to obtain the title compound in the free form (50 mg). The free compound was converted into hydrochloride with a 4 mol/L solution of hydrogen chloride in dioxane and the product was recrystallized from ethanol to obtain the title compound (51 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.C1C=C2C(C=C(NCNCCCC(O)=O)C=C2)=CC=1.C=O.[C:45]([O:48][CH2:49]C)(=O)C>CO>[CH2:15]([C:12]1[S:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][CH2:45][O:48][CH3:49])=[N:3][CH:4]=2)=[CH:14][CH:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Agent: C=O
Agent: O=C(O)CCCNCNc1ccc2ccccc2c1
Solvent: CO
Product: COCNc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 6-amino-N-(5-benzylthiophen-2-ylmethyl)-nicotinamide described in Example A-144 (210 mg, 0.65 mmol) and 5,5-dimethylimidazo phospho-2,4-dione (92 mg, 0.71 mmol) in methanol (15 mL) was added an aqueous solution of 37% formaldehyde (2.5 mL) under reflux in three time, and the solution was stirred for 1 hour. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (210 mg, 0.57 mmol, 87.6%) was obtained as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].C(N(CC)CC)C.[CH3:17][C:18]1[S:19][C:20]([C:24](Cl)=[O:25])=[C:21]([CH3:23])[N:22]=1.Cl.C(N(CC)CC)C>C(OC(=O)C)C.O>[C:7]([CH:6]([NH:9][C:24]([C:20]1[S:19][C:18]([CH3:17])=[N:22][C:21]=1[CH3:23])=[O:25])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)#[N:8]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccco2)s1
Yield: 90 %

Procedure:
In 120 ml of ethylacetate were dissolved 6.2 g of alpha-(2-furyl)-alpha-aminoacetonitrile and 6.0 g of triethylamine, and with stirring, the 2,4-dimethylthiazole-5-carboxylic acid chloride was added dropwise to the solution, and the mixture was stirred at room temperature for 1 hour. Water (150 ml) was added, and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water, and dried over sodium sulfate The dried ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was recrystallized from isopropyl ether to give 11.65 g (yield 90.0%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: COC(OC)[N:4]([CH3:6])C.[NH:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CO.[OH-].[Na+].[C:25]1(C)C=CC=C[CH:26]=1>O>[C:6]([CH2:25][CH2:26][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:4]
Reactant: C1CNCCNCCNCCN1
Reactant: Cc1ccccc1
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCN1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. 9.24 g (174.15 mmol) of acrylic acid nitrile is instilled under a nitrogen atmosphere and heated slowly to 75° C. It is stirred for 9 hours at this temperature. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of water is added. It is stirred for 10 minutes at room temperature. Then, 13.93 g (348.3 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40° C. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with hot toluene (80° C.). The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:19][C:20]#[N:21])=[CH:7][N:6]=1.[N-:28]=[N+:29]=[N-:30].[Na+].Cl.C(N(CC)CC)C.[OH2:40]>C1(C)C=CC=CC=1.Cl>[CH3:18][O:17][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[O:15][CH3:16])[C:5]([C:4]([C:3]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:2]=1[F:1])=[O:40])=[N:6][CH:7]=[C:8]2[CH2:19][C:20]1[NH:30][N:29]=[N:28][N:21]=1
Reactant: COc1ccc(F)c(Cc2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Reactant: O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(C(=O)c2ncc(Cc3nnn[nH]3)c3cc(OC)c(OC)cc23)c1
Reaction time: 2.5 h

Procedure:
183 mg (0.5 mmol) of [1-(2-Fluoro-5-methoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetonitrile was dissolved in 15 mL toluene. The solution was warmed to 95 C. and 100 mg (1.53 mmol) of sodium azide and 210 mg (1.52 mmol) of triethyl amine hydrochloride was added and the mixture heated at 100 C for 60 minutes. Because ms and tlc suggest significant quantities of starting material is present an additional 100 mg of sodium azide and 210 mg of triethyl amine hydrochloride were added and heating at 100 C continued for 150 minutes at which time another 100 mg of sodium azide and 210 mg of triethyl amine hydrochloride and heating at 100 C continued for 120 minutes followed by room temperature stirring for 16 hours. The mixture was diluted with 15 mL of toluene and 20 mL of water. The stirring mixture was treated with 2 drops of conc. HCl in the fume hood and the resulting solid filtered giving ˜65 mg of the tetrazole as a white solid. The aqueous phase of the filtrate was separated and treated with stirring with another 2 drops of conc. HCl and solid filtered and washed with water to provide an additional 30 mg of the tetrazole. Thin layer chromatography show both crops to be homogeneous. Spectroscopy (nmr and ms) are compatible.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[N:5]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:4](=[O:8])[NH:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(C)NC(=O)N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of tert-butyl 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetate (100 mg, 0.44 mmol) in DMF (1 mL) was added potassium carbonate (120 mg, 0.88 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.48 mmol) and the reaction mixture stirred at rt overnight. The mixture was diluted with EtOAc (30 mL) and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane followed by 10% MeOH/DCM to give Compound 26c (102 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 6.12 (br. s., 1H), 4.14 (q, J=8.5 Hz, 2H), 2.78-2.62 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13].[BH4-].[Na+]>C(Cl)Cl>[CH2:10]([NH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
2-Phenethylamine (12.5 mL, 12.1 g, 99.5 mmol), butyraldehyde (13.2 mL, 10.8 g, 150 mmol), and 3 Å molecular sieves were stirred at 50 ° C. for 1 h, then at RT for 5.5 h. The reaction was then diluted with CH2Cl2, filtered through celite, then concentrated to an oil. That oil was dissolved in absolute EtOH (150 mL-previously cooled to 0 ° C.), and NaBH4 (5.7 g, 150 mmol) was added. The reaction was stirred at RT overnight, concentrated, partitioned between water and Et2O, then the organic layer was washed with water and brine. After drying over Na2SO4, filtration, and concentration, the compound was purified by vacuum distillation using a 6″ Vigeraux column (98-100° C./9 mm). Recovered 8.2 g (46%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(-c2ccccc2F)nn1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a mixture of 6-chloropyridazin-3-amine (3.00 g, 23.1 mmol), 4-fluorophenylboronic acid (34.7 mmol), Na2CO3 (69.3 mmol) in 2-propanol (150 mL) and water (50 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(1.15 mmol). The mixture is heated at 80° C. for 12 hours, concentrated under reduced pressure, added sat. aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of CH2Cl2 to 70% CH2Cl2:EtOAc:methanol (1:1:0.1) to afford the title compound (3.82 g, 87%) as a white solid: Rf 0.37 (1:1:0.1 CH2Cl2:EtOAc:methanol); LCMS (m/z)=190.2 [M+H]+, tR=0.44 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:3]1=2.I[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:3]2[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(OCc2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1ccc(COc2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 67 %

Procedure:
In a manner similar to that of Example 1g, by reacting 1.22 g (3.3 mmol) of 1-[5,5,8,8-tetramethyl-4-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 680 mg (2.8 mmol) of 4-iodobenzoic acid in the presence of 27 mg of copper iodide and 49 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of beige-colored crystals (m=900 mg; yield=67%; m.p.=219° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7](=[O:9])/[CH:56]=[C:51]2\[S:52][C:53]([CH3:55])=[N:54][N:50]\2[CH2:46][CH2:47][CH2:48][CH3:49])[CH:10]=1
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 5-bromo-2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.68-1.76 (m, 2 H) 2.51 (s, 3 H) 4.16 (t, 2 H) 6.26 (s, 1 H) 7.42-7.46 (m, 1 H) 7.58-7.63 (m, 1 H) 7.65-7.68 (m, 1 H); MS (ESI) m/z 387 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=3)[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[CH:4][C:3]=1[CH3:28].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl.[OH-].[Na+].[CH2:36]1[CH2:40][O:39][CH2:38]C1>CO.CC(CC(C)=O)C.CS(C)=O>[CH2:29]([O:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]([C:9]2([C:19]3[CH:20]=[C:21]([CH3:27])[C:22]([O:26][CH2:36][CH:40]4[O:39][CH2:38]4)=[C:23]([CH3:25])[CH:24]=3)[CH:10]3[CH2:11][CH:12]4[CH2:13][CH:14]([CH2:15][CH:16]2[CH2:17]4)[CH2:18]3)=[CH:6][C:7]=1[CH3:8])[CH:31]1[O:33][CH2:32]1
Reactant: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C3CC4CC(C3)CC2C4)cc(C)c1O
Reactant: ClCC1CO1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(C2(c3cc(C)c(OCC4CO4)c(C)c3)C3CC4CC(C3)CC2C4)cc(C)c1OCC1CO1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
In a separable flask having an inner volume of 500 ml, equipped with a reflux condenser, a stirrer, and a thermometer were charged 50.2 g (0.13 mol) of 2,2-bis(4-hydroxy-3,5-dimethylphenyl)adamantane, 99.6 g (1.06 mol) of epichlorohydrin, 75 mL of MIBK, and 150 mL of DMSO, and the mixture was heated to 45° C. Then, 13.2 g (0.33 mol) of sodium hydroxide was added into this solution by small portions during a period of 1.0 hour. Then, the reaction temperature was raised to 65° C., and the reaction was carried out for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, added by 250 mL of MIBK, and washed by water until the aqueous layer became neutral. The resulting organic layer was concentrated to obtain a crude product as pale yellowish viscous liquid. After the crude product was dissolved in 70 mL of THF, the resulting solution was added drop-wisely into 350 mL of methanol to precipitate solids, which were collected by filtration and dried to obtain 60.5 g of 2,2-bis(4-glycidyloxy-3,5-dimethylphenyl)adamantane having the following formula (94% purity by LC, epoxy equivalent of 259).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH3:53])[C:15]([CH3:52])([CH3:51])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1>C(OCC)(=O)C>[OH:13][CH:14]([CH3:53])[C:15]([CH3:51])([CH3:52])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.6 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-({4-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.70 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated aqueous sodium hydrogen carbonate solution and 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 pale-yellow amorphous solid (0.34, 43%).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:4].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:4])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)C1CNc2ccccc2C1
Reactant: CCCCN
Product: CCCCNC(=O)C1CNc2ccccc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 500 mg of 3(R,S)-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (Example 1r) and 1 ml of n-butylamine is stirred at 60° C. for 1 h. Purification of the crude product by means of FC over 50 g of silica gel (mobile phase Z) gives 3(R,S)-butylaminocarbonyl-1,2,3,4-tetrahydroquinoline: Rf (Z)=0.21.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH2:18]([N:20]([CH:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19]>>[CH2:18]([N:20]([CH:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH3:19]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: CCN(C(=O)OC(C)(C)C)C(C)c1ccccc1-c1c(OC)ccc2[nH]c(=O)c3sccc3c12
Yield: 37.6 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (770 mg, 2.5 mmol) was reacted with tert-butyl ethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (1.4 g, 3.7 mmol) to afford the desired product (450 mg, 40%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:26])=[O:25]
Reactant: CCOC(=O)COc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of ethyl 2-(3-(hydroxymethyl)phenoxy)acetate (2.00 g) and triethylamine (1.44 g) in THF (10 mL) was added methanesulfonyl chloride (1.31 g) at 0° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed 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 (ethyl acetate/hexane) to give the title compound (2.80 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O.[BH4-].[Na+]>C(O)(=O)C.O>[CH:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1)([CH3:34])[CH3:31]
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC(C)C)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (3 g) and acetone (0.54 cc) in acetic acid (45 cc), brought to 15° C., is slowly added sodium borohydride (1.14 g) so as to maintain the temperature below 22° C. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is then poured in distilled water (150 cc) and extracted with ethyl ether (2×100 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The oily residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 as a yellow oil).
Reaction SMILES: [CH3:1][I:2].[CH2:3]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[C:5](=[S:15])[S:4]1>C(Cl)Cl>[I-:2].[CH3:1][S:15][C:5]1[S:4][CH2:3][CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N+:6]=12
Reactant: CI
Reactant: S=C1SCC2Cc3ccccc3N12
Solvent: ClCCl
Product: CSC1=[N+]2c3ccccc3CC2CS1
Product: [I-]
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Methyl iodide (40 cc) is added to a solution of (RS)-9,9a-dihydrothiazolo[3,4-a]indole-3-thione (30.0 g) in methylene chloride (150 cc). After stirring for 20 hours at about 20° C., the resulting crystals are filtered off, washed with diethyl ether (2×50 cc) and then dried at 20° C. under reduced pressure (20 mm Hg). (RS)-3-Methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (50.2 g), melting at 135°-140° C. with decomposition, is thus obtained.