Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]=2[CH:4]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].N([O-])=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[C:4]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccsc1Cc1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2c(c1-c1ccsc1Cc1ccccc1)C(=O)OC2
Yield: 84 %

Procedure:
0.5 g of (-)-ethyl 2-methyl-4-(2-benzylthiophenyl)-5-oxo-1,4,5,7-tetrahydro-furo[3,4-b]pyridine-3-carboxylate are dissolved in 15 ml of glacial acetic acid. In the course of 10 min, 0.5 g of NaNO2 is added to the solution which is situated in an 18×180 mm test tube, nitrous gases bubbling through the solution. The batch is then immediately poured into a solution of 25 g of K2HPO4 in 50 ml of water, stirred, extracted with ethyl acetate and chromatographed on silica gel. 418 mg (84% of theory) of (+)-ethyl 2-methyl-4-(2-benzylthiophenyl)-5-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate are obtained.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:16][CH:15]2[O:17][CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:10]1)C1C=CC=CC=1.CO>C(#N)C>[ClH:1].[CH:11]12[O:17][CH:15]([CH2:16][NH:9][CH2:10]1)[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reaction time: 1 h

Procedure:
Hydrochloride salt from step (iii) above (146 g, 0.411 mol) and 20% Pd(OH)2-C (7.5 g) were charged to a Parr hydrogenator bottle. Methanol (0.5 L) was added and the bottle was shaken vigorously under an atmosphere of hydrogen at 3.5 bar. The reaction was monitored by GC analysis and was found to be complete after one hour. The catalyst was filtered and the filtrate was concentrated to afford an off-white crystalline product. The crude product was dissolved in hot acetonitrile (1.2 L), and then filtered while hot. The filtrate was diluted with ethyl acetate (1.2 L). The clear solution was allowed to stand overnight at room temperature. The first crop of crystals was collected and dried under vacuum to afford 52 g of sub-title compound as a white solid. The filtrate was concentrated to near dryness, then dissolved in hot acetonitrile (0.4 L), and diluted with ethyl acetate (0.4 L). A second crop of crystals (38 g) was obtained after cooling the solution to 10° C. Both crops were found to be comparable by GC analysis and 1H NMR analyses. Combined yield: 90 g (83%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N:13]=[O:14]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-amino-3-propyl-1,3-dihydropyrimidine-2,4-dione (5.6 g) in a mixture of 50% acetic acid/water (160 ml) at 70° C. was added sodium nitrite (4.5 g) in portions over a period of 15 minutes. The mixture was stirred at 70° C. for 45 minutes, then the reaction mixture concentrated to a low volume under reduced pressure. The solid was filtered off, and washed with water, to provide 6-amino-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (11).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=2)=[O:47])=[CH:44][N:43]=[CH:42]1.[NH4+].[Cl-]>C1COCC1.O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=3)([C:48]3[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: Cn1cncc1C(=O)c1cncn1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3cncn3C)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (1.6 M in hexanes, 0.34 mL, 0.56 mmol) was added dropwise to a mixture of 6-bromo-2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinoline (0.20 g, 0.467 mmol, Intermediate 12: step d) and bis(1-methyl-1H-imidazol-5-yl)methanone (0.097 g, 0.513 mmol, Intermediate 55: step b) in dry THF at −78° C. over a 30 minute period. Stirring was continued at −78° C. for 10 minutes. The reaction mixture was warmed up to 0° C., stirred for 35 minutes and then saturated aqueous NH4Cl was added. The mixture was warmed to room temperature, H2O was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, evaporated in vacuo and chromatographed (10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.21 (br. s., 1H), 7.75 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.36-7.46 (m, 3H), 7.27-7.32 (m, 2H), 6.33 (br. s., 2H), 4.31 (br. s., 2H), 4.07 (s, 3H), 3.44-3.56 (m, 6H); MS (ESI) [M+H]+
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[CH:13]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(#N)C=C>>[CH:23]1[C:24]2[N:25]([CH:3]([CH3:4])[C:2]#[N:9])[C:26]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:18][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [OH-]
Solvent: C=CC#N
Product: CC(C#N)N1c2ccccc2Sc2ccccc21
Temperature: 80 °C
Yield: 66 %

Procedure:
2.5 ml of a 40% strength methanolic solution of benzyltrimethylammonium hydroxide are added dropwise to a reactor containing 100 g (0.5 moles) of phenothiazine and 530 g (10 moles) of acrylonitrile and cooled to a temperature below 10° C. The whole is heated to 80° C. for 1 hour 30 min. The excess acrylonitrile is removed by vacuum distillation. The solid is recrystallized twice from acetone. 10-Phenothiazinylproprionitrile is obtained in a 66% yield (83.9 g). M.p.: 156°-157° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>C(O)C.C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)n1ncc(C(=O)O)c1Br
Yield: 84.8 %

Procedure:
A mixed solution of the compound (13.5 g, 49.07 mmol) obtained in step 2 and 1N aqueous sodium hydroxide solution (65 mL, 65.00 mmol) in ethanol (70 mL) and THF (70 mL) was stirred at 60° C. for 2.5 hr. The organic solvent was evaporated under reduced pressure, and water and 1N hydrochloric acid (70 mL) were added thereto. The precipitate was collected by filtration, and washed with diethyl ether and hexane to give 5-bromo-1-tert-butyl-1H-pyrazole-4-carboxylic acid (10.29 g, 41.6 mmol, 85%) as a white powder.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([P+](CCCC)(CCCC)CCCC)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 847 mg (2 mmol) of tetrabutylphosphonium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 15 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 416.6 mg and 73%, respectively.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[N:26]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][S:30]([NH:29][C:27]([C:25]1[N:26]=[C:22]([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)[S:23][CH:24]=1)=[O:28])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)NC(=O)c1csc(Br)n1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CS(=O)(=O)NC(=O)c1csc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Under argon, 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine (0.1 g, 0.37 mmol), 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide (0.105 g, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (0.013 g, 0.011 mmol) were added to a mixture, degassed by means of argon, of sodium carbonate solution in water (1.5 ml, 2 M/L) and acetonitrile (3.8 ml). The reaction mixture was stirred at 70° C. for 16 h. After cooling, the reaction mixture was poured onto water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was subsequently stirred with diethyl ether and filtered off with suction. This gave 0.23 g (97% of theory) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-sulphonamide.
Reaction SMILES: [CH:1]([C:3]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=C.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:13][C:12]1[C:3]([CH:1]=[O:30])=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1F
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)c(F)c1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-ethenyl-3-fluoro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.12 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.35 g), and the mixture was stirred at room temperature for 3 hr under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-fluoro-2-formyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate as a crude product. The obtained crude product (20% v/v) was dissolved in THF (2.00 mL), (tetrahydrofuran-2-yl)methanamine (0.006 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with acetic acid (1.00 mL). Sodium triacetoxyborohydride (0.03 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC (water/acetonitrile, containing 0.1% TFA). The fractions were combined, saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.90 mg).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].Cl[CH2:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=[O:11]>CO>[C:3]([CH2:2][S:1][CH2:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=[O:11])([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: O=C(O)CC(=O)CCl
Solvent: CO
Product: O=C(O)CSCC(=O)CC(=O)O
Temperature: 23.5 °C

Procedure:
To a round bottom flask containing mercaptoacetic acid (0.1 mol) dissolved in methanol (25 mL) is added 4-chloro-3-oxobutanoic acid (0.1 mol). The resulting mixture is heated at reflux temperature for about 2 hours. When the reaction is complete, the mixture is allowed to cool to room temperature (22-25° C.). Volatiles are removed under vacuum and the resulting residue is purified by column chromatography to yield 4-(carboxymethylthio)-3-oxobutanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[CH3:30][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:15])=[O:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: C[C@H]1CNCCN1S(=O)(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 153 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.6 (d, 1H) 8.5 (d, 1H) 8.3 (d, 1H), 8.1 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.1 (d, 2H), 6.6 (d, 2H), 3.9-3.8 (m, 3H), 3.4-3.3 (m, 2H), 3.2-3.1 (m, 3H), 3.0-2.9 (m, 3H), 1.2 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([CH:26]1[CH2:28][O:27]1)[CH2:23][CH2:24][CH3:25]>>[OH:27][CH:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:28][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCCCC1CO1
Product: CCCCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 162 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-butyloxirane and conditions outlined in procedure X. M.p.=160-163° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 3.7 (m, 1H), 2.95 (m, 3H), 2.8-2.7 (m, 2H), 2.5-2.35 (m, 3H), 2.15 (d, 2H), 1.95-1.8 (m, 2H), 1.5-1.3 (m, 6H), 0.9 (t, 3H); LCMS: 402 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][CH:12]3[CH2:14][CH2:13]3)=[N:9][N:10]=[C:4]2[C:3]=1[C:15]#[N:16].[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:12]1([CH2:11][C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][CH:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:24][CH2:25]4)=[C:3]([C:15]#[N:16])[C:4]3=[N:10][N:9]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1c(Cl)ccn2c(CC3CC3)nnc12
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(CC3CC3)nnc12
Temperature: 150 °C
Yield: 48.8 %

Procedure:
A mixture of compound D5 (0.2 g, 0.86 mmol), 4-phenylpiperidine (0.166 g, 1.031 mmol), K2CO3 (0.148 g, 1.074 mmol) in CH3CN (5 ml) was heated in a sealed tube at 150° C. under microwave irradiation for 5 min. The mixture was then cooled to r.t. and the solvents evaporated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield compound E13 as yellow solid (0.150 g, 49%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]>O1CCCC1>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: C1CCOC1
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Reaction time: 24 h

Procedure:
(RS)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine-D-tartrate (461 g) is dissolved in tetrahydrofuran (900 ml) while hot. After cooling down to lab temperature, the mixture is stirred for 24 hours. The precipitated crystals are re-crystallized from tetrahydrofuran (400 ml) once more using the same procedure. The yield is 117 g (25%). Optical purity is 99% ee (CE).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[OH:21][C@@H:22]1[CH2:27][O:26][C:24](=[O:25])[CH2:23]1.[C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH3:29].Cl>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:32]([O:31][C:28](=[O:30])[CH2:29][C:24](=[O:25])[CH2:23][C@H:22]([OH:21])[CH2:27][OH:26])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C1C[C@H](O)CO1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO
Temperature: 5 °C
Yield: 5.7 %

Procedure:
To 30 mL (45 mmol) of a solution of n-butyllithium in hexane (1.5 mol/L) was added a solution of diisopropylamine (5.01 g, 49.5 mmol)-tetrahydrofuran (5 mL) dropwise under stirring at 5° C., and the mixture was stirred under argon for 1 hour to prepare a lithium diisopropylamide solution. In a separate vessel, 1.02 g (10 mmol) of (S)-β-hydroxy-γ-butyrolactone and 2.32 g (20 mmol) of tert-butyl acetate were dissolved in 8.0 mL of tetrahydrofuran and the mixture was stirred under argon at 0 to 5° C. To this solution, the lithium diisopropylamide solution prepared above was added dropwise over 30 minutes, and the mixture was further stirred at 5 to 20° C. for 16 hours. In a separate vessel, 35 mL of 3N-hydrochloric acid and 30 ml of ethyl acetate were stirred to mix and the above reaction mixture was poured therein. After standing, the organic layer was taken, washed with saturated aqueous sodium chloride solution, and dehydrated over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:ethyl acetate=2:1) to give 124 mg of (5S)-5,6-dihydroxy-3-oxohexanoic tert-butyl ester (yellow oil). Yield 6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:16])[CH2:14][NH2:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:20]2[S:27][CH:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:16])[CH2:14][NH:15][C:19]2[C:20]3[S:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2ccsc12
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(O)CN)s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)CNc2ncnc3ccsc23)s1

Procedure:
Compound 62.4 (0.16 mmol), 4-chloro-thieno[3,2-d]pyrimidine (0.16 mmol.) and DIEA (0.28 mmol) is heated in DMA at 90° C. for 5 hours. The reaction mixture is cooled, concentrated and purified by preparative TLC (10% MeOH in EtOAc) to afford {5-[1-hydroxy-2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (compound 62.5).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[CH:28]1[CH2:33][C:32](=[O:34])[CH:31]=[CH:30][CH2:29]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[C@H:28]1[CH2:29][C@H:30]([CH3:2])[CH2:31][C:32](=[O:34])[CH2:33]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a 0° C. solution of dimethyl copper lithium (2.47 mmole) in ether (3 ml) and hexane (2 ml) was added dropwise a solution of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-cyclohexen-1-one (500 mg, 1.24 mmole) in ether (1.5 ml). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium cloride (300 ml). The quenched reaction was extracted with three 50 ml portions of ether, the combined ether extracts washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 475 mg (92%) of the title compound as an oil.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.O[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: OCCc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCc1ccccn1

Procedure:
2-(2-Pyridyl)ethyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) of bis(tributyltin) oxide and 24.6 gm (0.2 mole) 2-(β-hydroxyethyl)pyridine in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes refluxing water began to collect in the Dean-Starke tube and after refluxing 22 hours a total of 2.0 ml of water (theory 1.8 ml) had collected. This is evaporated on a rotating evaporator to provide 82.6 gm of straw colored liquid, which fractionated at reduced pressure. 66.4 gm. of a straw colored liquid are collected at 155°-158° C. at 0.5 mm. (Percent yield - 80.6). Infrared spectral analysis shows this to be the desired ether.