Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([C@@H:17]3[C@@H:22]4[CH2:23][C@@H:19]([CH2:20][CH2:21]4)[N:18]3C(OC(C)(C)C)=O)=[N:10][C:9]=2[CH:8]=1.Cl.C(OCC)(=O)C>CO>[C@H:19]12[CH2:23][C@H:22]([CH2:21][CH2:20]1)[C@@H:17]([C:11]1[NH:12][C:13](=[O:16])[C:14]3[S:15][C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:8][C:9]=3[N:10]=1)[NH:18]2
Reactant: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2nc([C@H]3N[C@@H]4CC[C@H]3C4)[nH]c(=O)c2s1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a solution of tert-butyl (1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate (690 mg) in methanol (10 mL) was added 4M hydrochloric acid/ethyl acetate solution (2.0 mL) with stirring at room temperature. The reaction system was stirred with heating at 50° C. for 30 min, and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained colorless solid was crystallized from methanol/ethyl acetate to give the title compound (220 mg) as a colorless solid. The optical purity was 86% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK OD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: methanol, flow rate: 0.5 mL/min, column temperature: 30° C., detection 254 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:20])=[O:14])=[CH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(COc2ccc(C(=O)O)cn2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
6-(4-Methoxybenzyloxy)nicotinic acid (8.10 g, 31.2 mmol) obtained in Step 1 was dissolved in DMF (250 ml), and potassium carbonate (8.64 g, 62.5 mmol) and methyl iodide (3.89 mL, 62.5 mmol) were added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 6-(4-methoxybenzyloxy)nicotinate (3.78 g, 44%).
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.CC(C)([O-])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[CH:36][CH2:37][CH2:38][C:39]1[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=1>CCOCC.C1(C)C=CC=CC=1>[CH3:2][O:1][CH:5]=[CH:36][CH2:37][CH2:38][C:39]1[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)c1ccc(CCC=O)cc1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC=CCCc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
A 1.0 mole tetrahydrofuran solution (11.0 ml) of potassium tert-butoxide was added to a toluene solution (12 ml) of (methoxymethyl)triphenylphosphonium chloride (3.77 g) at 0° C., and after stirring for 10 minutes, a toluene solution (10 ml) of tert-butyl 4-(3-oxopropyl)benzoate (2.34 g) was added dropwise to the mixture at the same temperature, followed by stirring at 0° C. for 20 minutes. The reaction solution was admixed with ether (40 ml), and the organic layer was separated, then washed successively with water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the thus obtained residue was treated with hexane, followed by filtering out the resultant triphenylphosphine oxide. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (80 g of silica gel; ether-hexane=20:1) to give the subject compound (1.92 g).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](Cl)(=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: CC(C)CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 19.8 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), isovaleryl chloride (0.054 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-yl-3-methylbutanamide (27 mg). MS (ESI) m/z 311; HPLC purity 98.5% at 210-370 nm, 10.5 min.; 99.5% at 250 nm, 10.5 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C20H26N2O+H+, 311.21179; found (ESI, [M+H]+), 311.2120.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:13]Br.O.C(Cl)Cl>CC(O)=O>[Br:13][CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCC(=O)C(=O)OCC
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC(Br)C(=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution of ethyl 2-oxoheptanoate (2 g, 11.62 mmol) in AcOH (20 mL), was added Br2 (596 μL, 11.62 mmol). The mixture was stirred 20 minutes at 0° C., then the mixture was allowed to warm to rt. After the mixture was stirred for 3 h, water and CH2Cl2 were added. The organic phase was separated, dried (MgSO4), and evaporated to give crude ethyl 3-bromo-2-oxoheptanoate as a dark oil; 1H NMR (400 MHz, CDCl3) δ 5.05-5.01 (m, 1 H), 4.45-4.20 (m, 2 H), 2.18-1.94 (m, 2 H), 1.74-1.57 (m, 2 H), 1.48-1.17 (m, 5 H), 0.95-0.82 (m, 3 H). This compound was used without purification for the preparation of compounds of the invention such as 1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-butyl-1H-imidazole-4-carboxamide hydrochloride (Table entry 20).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[C:19]([C:32]([CH3:40])([CH3:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[OH:41])=[C:11]([N+:42]([O-])=O)[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH-].[Na+].S(=O)(=O)(O)O>[Zn].O.C(O)(C)C>[C:1]([C:9]1[CH:14]=[CH:13][C:12]2=[N:15][N:16]([C:17]3[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=[C:19]([C:32]([CH3:40])([CH3:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:18]=3[OH:41])[N:42]=[C:11]2[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)c1ccc(N=Nc2cc(C(C)(C)c3ccccc3)cc(C(C)(C)c3ccccc3)c2O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)CC(C)(C)c1ccc2nn(-c3cc(C(C)(C)c4ccccc4)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Temperature: 47 °C
Reaction time: 8 h

Procedure:
To a 300 ml 3-necked flask fitted with a stirrer, thermometer, reflux condenser and nitrogen inlet is charged 31 grams (0.05 mol) of the o-nitroazobenzene intermediate of Example 5 and 100 ml of toluene. To the resulting solution is added 15 ml of isopropanol and 15 ml of water. A nitrogen atmosphere is imposed and 8 grams (b 0.1 mole) of 50% aqueous sodium hydroxide is added. A flask containing 11.6 grams (0.177 gram-atoms) of zinc is connected to the reaction flask by Gooch rubber tubing and the zinc dust is added portionwise to the reaction mixture in essentially eight (8) equal portions with 15 minute intervals between additions. After all the zinc is added, the mixture is stirred at 47° C. overnight and then heated to reflux for two hours. The mixture is then cooled to 45° C. and acidified with 50 grams of 50% aqueous sulfuric acid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]C.[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:31])=[C:13]([C:29]=1[CH3:30])[C:14]([C:16]1[C:21](C)=[CH:20][C:19]([O:23][CH3:24])=[C:18]([O:25][CH3:26])[C:17]=1[O:27][CH3:28])=[O:15]>C(COC)OC>[Br:8][C:9]1[C:29]([CH3:30])=[C:13]([C:12]([CH3:31])=[CH:11][CH:10]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:23][CH3:24])=[C:18]([O:25][CH3:26])[C:17]=1[O:27][CH2:28][CH2:1][CH2:2][CH3:3])=[O:15]
Reactant: CCCCO
Reactant: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCOc1c(C(=O)c2c(C)ccc(Br)c2C)ccc(OC)c1OC
Temperature: 90 °C

Procedure:
A mixture of n-butanol (5 ml) and sodium hydride (60% in oil, 20 mmol) is stirred until the formation of H2 gas ceases. A mixture of 1C (2.0 g, 5.0 mmol) and dimethoxyethane (15 ml) is added to the resulting reaction mixture. Subsequently, the reaction mixture is heated to 90° C. with stirring for 14 hours and dimethoxyethane is distilled off. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated, concentrated and the residue is purified by column chromatography (petrol ether: ethyl acetate, 90:10 v/v) yielding the pure product as a yellow oil, 1.7 g (78.3%).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:3][CH2:4][C:5]([O:6][CH3:22])=[O:7])[C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.0 g of Boc-Glu-OtBu (39.6 mmol) are dissolved in 200 mL of DMF. Under argon atmosphere, 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq.) are added and the resulting suspension is stirred for 1 hour at RT. After this time, 2.47 mL of methyl iodide (39.6 mmol) are added and stirred at RT overnight. The solvent is removed in vacuo and the obtained residue is taken up in 400 mL of ethyl acetate. The undissolved solid is filtered and the filtrate is washed with respectively 75 mL of 10% citric acid, 10% NaHCO3 solution and brine 3 times. After drying of the organic phase over Na2SO4 the solvent is removed in vacuo. The product is obtained as yellow oil. The product can be used without further purification in the following reaction.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:2][CH2:3][CH2:4][CH:5]2[O:9][CH2:8][CH2:7][O:6]2)=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12]
Reactant: ClCCCC1OCCO1
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-chloropropyl-1,3-dioxolane (0.2 g, 1.35 mmol) in dimethyl formamide (14 mL), was added 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoic acid (Example 51 Step 3) (0.5 g, 1.39 mmol) and potassium carbonate (0.38 g, 2.78 mmol). The reaction was allowed to stir at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The organic extracts were washed with brine, dried (sodium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (0.63 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3c(F)cccc3F)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(F)cccc3F)c2O1)OCc1ccccc1
Yield: 98.8 %

Procedure:
Treatment of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.54 g, 5.17 mmol) with diisopropylethylamine (1.02 g, 7.76 mmol) and benzyl chloroformate (0.971 g, 5.69 mmol) generally according to the procedure described for Intermediate 12 gave 2.02 g (98%) of (±)-benzyl {[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C23H19F2NO3: C, 69.87; H, 4.84; N, 3.54. Found C, 69.54; H, 4.87; N, 3.31.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[S:20][CH:21]=2)[S:9][C:10]=1[Si](C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[S:20][CH:21]=2)[S:9][CH:10]=1
Reactant: CC(=O)Nc1nc(C=Cc2cc(C3OCCO3)c([Si](C)(C)C)s2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C=Cc2cc(C3OCCO3)cs2)cs1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of N-(4-{2-[4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (3.980 g, 10.09 mmol) in tetrahydrofuran (20 ml) was added 1M tetrabutylammoniumfluoride tetrahydrofuran solution (11.1 ml, 11.1 mmol) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Merck 7734 100 g, ethyl acetate:dichloromethane=1:4→1:2) to give N-(4-{2-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (3.03 g, 9.40 mmol, yield 93.2%) as an off-white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([O:65][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:73])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone-(10 mg) in acetonitrile (500 μl) was added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture stirred at room temperature. After 2.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (4 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4](O)=[O:5].[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]>C(O)C>[C:2]([C:3]1[C:4](=[O:5])[NH:17][C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)C(=O)C(=O)O
Solvent: CCO
Product: CC(C)(C)c1nc2ccccc2[nH]c1=O
Yield: 55.8 %

Procedure:
A 83 ml portion of ethanol was added to a mixture of 4.14 g of trimethylpyruvic acid synthesized in accordance with the method of Jaeger et al. (J. Am. Chem. Soc., pp.717-732, 1979) and 3.02 g of o-phenylenediamine. The thus prepared mixture was refluxed for 3 hours in an atmosphere of nitrogen. By concentrating the resulting reaction solution, 3.15 g of 2-t-butyl-3, 4-dihydro-3-oxoquinoxaline was obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:28][O:29]C(=O)C2C=CC=CC=2)([CH2:18][O:19]C(=O)C2C=CC=CC=2)[O:7][C@H:6]1[N:38]1[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]1=[O:40])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@H:9]1[C:8]([CH2:18][OH:19])([CH2:28][OH:29])[O:7][C@@H:6]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cc(C)c(=O)[nH]c2=O)OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a stirred solution of nucleoside 4 (9.00 g, 0.014 mol) in methanol (130 cm3) was added sodium methoxide (3.87 g, 0.0716 mol). The reaction mixture was stirred at room temperature for 4 h and then neutralized with dilute hydrochloric acid. The mixture was evaporated to dryness under reduced pressure followed by coevaporation using toulene (15 cm3×3) The residue was purified by silica gel column chromatography using dichloromethane/methanol (4–15% methanol, v/v) as eluent to give nucleoside triol 5 (4.82 g, 89%) as a white solid material after evaporation of the solvents under reduced pressure. δH (CD3OD) 7.89 (1H, d, J 1.2), 7.40–7.24 (5H, m), 5.97 (1H, d, J 6.2), 4.83–4.65 (2H, m), 4.53 (1H, t, J 6.2), 4.21 (1H, d, J 6.2), 3.84 (1H, d, J 12.0), 3.63 (1H, d, J 12.0), 3.59 (2H, d. J 2.6), 1.82 (1H, d, J 1.1). δC (CD3OD) 164.4, 150.9, 137.5, 136.6, 127.5, 127.0, 126.9, 109.8, 86.7, 86.4, 82.8, 78.0, 72.1, 62.3, 61.1, 10.5 (CH3). FAB-MS m/z 379 [M+H]+. Found (%) C, 56.2; H, 6.0; N, 7.0; C18H22N2O7,0.25H2O requires C, 56.5; H, 5.9; N, 7.3.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]12([P:17](Cl)(Cl)=O)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.Cl>C1COCC1>[C:7]12([PH2:17])[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: O=P(Cl)(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: PC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
LiAlH4 (3.5 g, 74 mmol) was added over 2 hours to a cooled solution (0° C.) of 1-adamantylphosphonic acid dichloride (15 g, 59 mmol) in THF (250 cm3). The reaction was then allowed to warm to ambient temperature and was stirred for 20 hours. The grey suspension was then cooled (0° C.) and HCl (75 cm3, 1M) was slowly added via syringe, to afford a two phase system with some solid present in the lower phase. Concentrated HCl (8 cm3, 11M) was then added to improve the separation of the two layers. The (upper) THF phase was removed via cannula and dried over magnesium sulphate. After filtration via cannula, the volatiles were removed in-vacuo to afford the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[S:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:30]2[S:31][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:9]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: COc1ccc(NC(=O)c2cc(Br)cnc2N)cn1
Product: COc1ccc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(6-methoxy-3-pyridyl)pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A40”; HPLC/MS: 1.29 min, [M+H]=426;
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8]2)[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)CCCCCCC>[OH:17][CH2:16][CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH:7]([CH3:13])[CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:14])[CH3:1]
Reactant: CC1CCC2NC(C)(C)CC(C)C2C1
Reactant: C1CO1
Solvent: CCCCCCCCO
Product: CC1CCC2C(C1)C(C)CC(C)(C)N2CCO
Temperature: 200 °C

Procedure:
1-(2'-hydroxyethyl)-2,2,4,6-tetramethyl decahydroquinoline was prepared. 50 grams of 2,2,4,6-tetramethyl decahydroquinoline and 50 milliliters of 1-octanol were placed into a reactor vessel equipped for heating and agitation and the mix heated to 200° C. Ethylene oxide was then slowly added to the reactor over a period of 7 hours. The reaction mixture was then distilled to yield a liquid product boiling at 106° C. at 0.5 mm Hg. The NMR and infrared spectra were consistent with the desired product. Calculated contents and analyzed contents of the product (formula of C15H29NO) were respectively: 75.26% carbon, 74.36% carbon found; 12.21% hydrogen, 12.24% hydrogen found; and 5.85% nitrogen, 6.04% nitrogen found.