Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([O:18][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of the crude alcohol 46 (2.2 g, 7.9 mmol) in DMF (12 mL), under argon, cooled to 0° C., imidazole (1.61 g, 23.7 mmol) and tert-butyldimethylsilyl chloride (3.57 mL, 23.7 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h and diluted with Et2O (50 mL). The organic layer was separated and washed with 10% HCl (50 mL), NaHCO3 (50 mL, sat) and NaCl (50 mL, sat), dried (Na2SO4), filtered, and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/9) to yield 47 (2.59 g, 98%) as colorless oil. Rf 0.31 (EtOAc/Hexanes 1/9). [α]D20=+5.30 (c=1, CH2Cl2). 1H-NMR (500 MHz, CDCl3): 0.07 (s, 6H), 0.84-0.91 (m, 15H), 1.42 (s, 9H), 1.98-2.01 (m, 1H), 2.43 (dd, J=6.0 and 19 Hz, 1H), 2.52 (dd, J=5.9 and 18.5 Hz, 1H), 3.47-3.48 (m, 1H), 3.65 (s, 3H), 4.17-4.19 (m, 1H), 4.41-4.44 (m, 1H). 13C-NMR (125 MHz, CDCl3): −3.6, 16.6, 17.60, 18.9, 25.7, 27.8, 28.2, 39.9, 51.5, 51.9, 59.5, 70.19, 155.9, 172.2. IR (neat) 3373.1, 2960.7, 1717.0, 1504.6, 1366.1, 1173.0, 837.0. HRMS m/z cald for C19H39NO5Si (M+Na): 390.2675 found 390.2676.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])([CH3:3])[CH3:2].[CH2:11]1[O:15][CH:12]1[CH2:13][CH3:14].[C:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[OH:26])([CH3:19])([CH3:18])C.C1OC1C>>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])([CH3:3])[CH3:2].[CH:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:11][CH:12]([OH:15])[CH2:13][CH3:14])([CH3:18])[CH3:19]
Reactant: CCC1CO1
Reactant: CC(C)(C)C1CCCCC1O
Agent: CC(C)C1CCCCC1O
Agent: CC1CO1
Product: CCC(O)COC1CCCCC1C(C)C

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 20.0 g (0.141 mol) of 2-isopropylcyclohexanol (cis:trans=6:4) and 10.1 g (0.141 mol) of 1,2-butyleneoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 6.5 g of 2-isopropylcyclohexanol and 16.6 g of 1-(2-isopropylcyclohexyloxy)-2-butanol (cis:trans=6:4) were obtained in a 55% yield.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[NH3:14]>>[NH2:14][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Reactant: N
Product: CCOC(=O)N1CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.4 g (72.3 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate (European Patent Application 189,370) are added dropwise to 60 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:27])[N:12]=1
Reactant: CSc1nccc(-n2ccc3c(Br)cccc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)c1nccc(-n2ccc3c(Br)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indole (5.0 g) in DCM (200 mL) at 0° C. was added MCPBA (4.01 g) in portions, and the mixture stirred at 0° C. for 1 h. The reaction mixture was quenched in 10% Na2SO3 (aq), partitioned between DCM and NaHCO3 (aq), the organic layer washed with NaHCO3 (aq), and dried over Na2SO4. The solvent was stripped to provide a light yellow solid, which was then treated with hot EtOAc/hexane (50:50), filtered, dried to provide 4-bromo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indole (4.98 g) as an off-white powder.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26]O.[OH-].[K+]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:23]3[CH2:24][CH2:25][CH2:26][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCCN12
Yield: 104.6 %

Procedure:
To a suspension of 11.3 g of 2-trichloroacetamido-5-chlorobenzophenone in 100 ml. of ethanol was added 4.51 g of 3-amino-1-propanol. The mixture was heated under reflux for 3 hours. Then, 1.7 g of potassium hydroxide was added thereto and the resulting mixture was further refluxed for 3 hours. After cooling, the precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure and to the residue was added 200 ml. of water. The resulting solid was collected by filtration, washed with water and dried to give 9.87 g of 10-chloro-3,4,7,11b-tetrahydro-11b-phenyl-2H,6H-[1,3]oxazino[3,2-C]quinazolin-6-one. Recrystallization from ethanol gave pale yellow prisms, having a melting point of 202°-203.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[CH:39]=[C:38]([S:40](Cl)(=[O:42])=[O:41])[S:37][C:36]=2[CH:44]=1>C(Cl)Cl.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:40]([C:38]3[S:37][C:36]4[CH:44]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=4[CH:39]=3)(=[O:42])=[O:41])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Reaction time: 16 h

Procedure:
To a solution of 4-(2-oxo-piperazin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.44 g, 4.8 mmol) in CH2Cl2 (75 mL) and MeCN (10 mL) is added diisopropylethylamine (1.3 mL, 4.8 mmol) followed by 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (1.29 g, 4.8 mmol), and the reaction is allowed to stir 16 h. The reaction is diluted with CH2Cl2 and washed with 1N HCl and NaHCO3, dried and concentrated. The residue is purified by column chromatography (silica, 40% EtOAc/CH2Cl2) to provide 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ 7.88-7.83 (m, 3H), 7.47 (dd, 1H), 4.1 (br, 2H), 3.86 (s, 2H), 3.46 (bs, 4H), 3.25 (br, 2H), 2.61 (t, 2H), 1.87-1.75 (m, 1H), 1.51 (d, 2H), 1.41 (s, 9H), 1.10 (ddd, 2H); MS (Ion spray) 528 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1.[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(Cl)nc1
Solvent: CCO
Product: CNc1ccc(C(=O)Nc2c(C)cccc2C)cn1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 5 g of 6-chloro-N-(2,6-dimethylphenyl)-3-pyridinecarboxamide and 6 g of methylamine (from a 40% aqueous solution) in 100 ml of ethanol were heated at 250° C. in a closed reaction vessel for 72 hours. The reaction mixture was cooled to room temperature, solvents were removed under reduced pressure, and the product was recrystallized from ethanol, providing 2.8 g of the desired title product, m.p. 207°-209° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=2[CH:14]=1)([O-])=O.CCN(CC)CC.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([C:32]([F:35])([F:34])[F:33])[CH:24]=1>C1COCC1.CCOC(C)=O.[Pd]>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:4]2[CH:5]=[CH:6][C:7]3[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=3[CH:14]=2)=[O:28])=[C:25]([C:32]([F:33])([F:34])[F:35])[CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)B(O)OCC2)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (100 mg, 0.52 mmol) in THF (10 mL) was passed through H-cube equipped with a 10% Pd/C cartridge. The collected light yellow solution was immediately treated with Et3N (144 μL, 2.0 mmol, 2.0 eq.), followed by 4-fluoro-2-trifluoromethyl-benzoyl chloride (94 μL, 0.62 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with EtOAc (20 mL), washed with 1N HCl (10 mL), H2O (10 mL), brine (10 mL) and then dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure and the crude material was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give the title compound as a white solid. LCMS (M/Z): 354 (M+H); 1H NMR (DMSO-d6) δ: 10.43 (s, 1H), 8.40 (s, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.75 (dt, J=5.9, 2.9 Hz, 2H), 7.58-7.67 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 4.03 (t, J=5.9 Hz, 2H), 2.80 (t, J=5.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[CH3:13][O:14][C:15](=[O:18])[CH2:16][SH:17].C(=O)([O-])O.[Na+]>Cl.CO>[CH3:13][O:14][C:15](=[O:18])[CH2:16][S:17][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CS
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CO
Product: COC(=O)CSc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-phenylamine (172 mg) was dissolved in 1M−HCl aqueous solution (2 ml), and sodium nitrite (82.8 mg) was added at 0° C. After stirring at 0° C. for 30 minutes, a methanol solution of mercaptoacetic acid methyl ester (127 mg) was added, and saturated sodium hydrogencarbonate aqueous solution was further added, to adjust the pH to 5. After stirring at room temperature for 1 hour, stirring was further carried out at 60° C. for 2 hours. This was extracted with ethyl acetate (10 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (hexane/ethyl acetate=20/1), to obtain (4-bromo-phenylsulfanyl)-acetic acid methyl ester as a crude product. This was further stirred in 10 ml of methanol and 5M-NaOH aqueous solution at room temperature for 1 hour. After the water vessel was washed with ethyl acetate (30 ml), 1M−HCl aqueous solution was added to adjust the pH to 3. This was extracted with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, to obtain the desired compound as a crude product (151 mg, 62%).
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](O)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>>[Cl:20][C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCSc1nn2c(=O)cc(O)nc2s1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCSc1nn2c(=O)cc(Cl)nc2s1
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of 23.5 g of the thus obtained 2-hexylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one, 17.8 g of phosphorus pentachloride and 50.4 g of phosphorus oxychloride was heated to 65°~90° C. and was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in toluene. The solution was washed with a potassium carbonate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and 10.2 g of 7-chloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 95°~96° C. Yield 41%.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12](=[O:38])[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)C.[OH-].[Li+]>O1CCCC1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:17]2([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:18][CH2:19][CH:14]([CH2:13][C:12]([C:8]3[O:9][CH:10]=[CH:11][C:7]=3[CH2:6][CH2:5][C:4]([OH:39])=[O:3])=[O:38])[CH2:15][CH2:16]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product from Example 146 (100 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was treated with a solution of lithium hydroxide (80 mg, 3.3 mmol) in water (2 mL). The reaction was stirred at room temperature for 3 hours, then evaporated and the residue taken up in water and ethyl acetate. The ethyl acetate layer was evaporated and purified by preparative thin layer chromatography (1% acetic acid, 33% ethyl acetate, 33% hexane, 33% dichloromethane).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:31])[C:8]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:31])[C:8]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[C:9]2[O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(O)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2ccc(O)cc2c(Oc2ccc(CCC(=O)O)cc2)c1-c1ccc(O)cc1

Procedure:
Synthesized in a manner similar to Example 47 using (2E)-3-(4-{[7-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (267). 1H NMR (CD3OD, 400 MHz) δ 7.68 (d, J=9.5 Hz, 1H), 7.54 (s, 1H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 2.78-2.74 (m, 2H), 2.49-2.47 (m, 2H), 2.18 (s, 3H). LRMS (ESI) m/z 413 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.21.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][CH:11]([C:14]2[C:15](=[O:25])[NH:16][C:17]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:18][N:19]=2)[CH2:12][CH3:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([CH2:7][C:8]2[N:19]3[C:14]([C:15](=[O:25])[NH:16][C:17]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18]3)=[C:11]([CH2:12][CH3:13])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)CC1CCCCC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(CC2CCCCC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.52 mmol) crude 2-cyclohexyl-N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:12]([O:13][CH3:14])[CH3:11])[N:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)Cc1csc(N)n1
Yield: 119.3 %

Procedure:
A mixture of 2-amino-4-chloromethyl-thiazole hydrochloride (27.8 g, 0.15 mol), N,O-dimethylhydroxylamine hydrochloride (87.8 g, 0.90 mol), and anhydrous THF (300 mL) was rapidly stirred and DIPEA (157 mL, 0.90 mol) was added. The resulting mixture was heated at 60 C for 10-15 hours. The mixture was cooled in an ice/salt bath and the solid byproduct (DIPEA hydrochloride) was removed by filtration and washed with cold THF (300 mL). The combined filtrate was concentrated to afford the title compound as a dark oil (31 g, >100% theory), which partially crystallized on standing. This product was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([C:10]3([NH:13][C:14](=O)OCC)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:26]1[CH2:30]OC[CH2:27]1>>[S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([C:10]3([NH:13][CH3:14])[CH2:12][CH2:11][CH2:30][CH2:26][CH2:27]3)[C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(=O)NC1(C2OCCc3sccc32)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CNC1(C2OCCc3sccc32)CCCCC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of ethyl 1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclopropylcarbamate (1.1 g, 4.1 mmol) in dry THF (20 mL) at 0° C. under N2 was added LiAlH4 (152 mg, 4.0 mmol) in one portion. The resulting mixture was refluxed for 2 h and then cooled to room temperature. Water (5 mL) was added to quench the reaction. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3×75 mL). The combined extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (700 mg, 84%).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH2:5]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:1]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=1)[CH:2]=[CH2:3]
Reactant: CC(C)CCCCCCCCCc1ccc(O)cc1
Reactant: C=CCCl
Product: C=CCOc1ccc(CCCCCCCCCC(C)C)cc1
Temperature: 63 °C

Procedure:
Next, 363 grams (4.75M) of allyl chloride were added, and mixed with the fluid initial reaction product. The mixture was then heated to 63° C., and exothermed slowly to 73° C. A sample was taken at this point, then acidified and stripped under reduced pressure. TLC revealed the presence on the sample of a small amount of unreacted p-isododecylphenol.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][Si](C(C)(C)C)(C)C)[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=2[CH3:33])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:36]=1[CH2:37][OH:38])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=2[CH3:33])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(C(O)C(C)(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(C)(C)C)ccc1-c1cccc(OCc2ccc(CO)c(CO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (3 mmol) of 1-{3′-(3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-2-methylbiphenyl-4-yl}-2,2-dimethyl-1-propanol are dissolved in 20 mL of THF and 7.7 mL (7.7 mmol) of 1 M tetrabutylammonium fluoride are added dropwise. After stirring for 1 hour at room temperature followed by the usual treatment, the residue obtained is purified by chromatography on silica gel. The desired product is obtained in the form of a colourless oil (m=1.15 g; Y=90%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[C:17]1([C:23]2[CH:29]=[C:27]([NH2:28])[C:26]([CH3:30])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:30][C:26]1[CH:25]=[CH:24][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][C:27]=1[NH:28][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1ccc(-c2ccccc2)cc1N
Product: Cc1ccc(-c2ccccc2)cc1Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 15.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 5-phenyl-o-toluidine (119 mg, 0.65 mmol) to provide 245 (25 mg, 14% yield) as a brown solid. LC-MS (M+H (parent)=378, obsd.=378). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.45 (m, 2H), 8.37 (d, 1H), 8.13 (d, 1H), 7.63 (m, 3H), 7.58 (s, 1H), 7.44 (m, 4H), 7.34 (m, 1H), 7.26 (m, 1H), 7.14 (dd, 1H). 2.28 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([CH3:26])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:15]([CH3:27])([CH2:14][CH2:13][CH:12]=[O:11])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(CCCO)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(CCC=O)C(=O)OCc1ccccc1
Reaction time: 0.42 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of oxalyl chloride (4.80 g, 37.8 mmol) in DCM (200 mL) was add DMSO (5.91 g, 75.6 mmol) dropwise over 10 minutes. After 25 minutes of additional stirring, a −78° C. solution of benzyl 5-hydroxy-2,2-dimethylpentanoate (4.06 g, 17.2 mmol, Step B) in DCM (200 mL) was added via cannula over 75 minutes. After stirring for an additional 30 minutes, triethylamine (13.9 g, 137 mmol) was added slowly over 25 minutes. The cooling bath was allowed to warm, while the reaction stirred for an additional 18 hours. Reaction solvent was then removed in vacuo, and the residue was dissolved in a mixture of diethyl ether and water (containing enough HCl to remain acidic). The organics were then dried over sodium sulfated, filtered and concentrated in vacuo to give the title compound (3.67 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][Si:3](OC)([O:6][CH3:7])[O:4][CH3:5].O1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:1][O:2][Si:3]([O:6][CH3:7])([O:4][CH3:5])[C:12]([CH:13]=[CH2:14])=[CH2:11]
Reactant: CO[Si](OC)(OC)OC
Reactant: C1CCOC1
Product: C=CC(=C)[Si](OC)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4.1 ml of the tetrahydrofuran solution of magnesium 2-(1,3-butadienyl)chloride and 6 ml of dried tetrahydrofuran were charged into a reactor in the stream of argon. Subsequently, the reactor was cooled down to 0° C., followed by gentle dropping of 1.2 ml (8 mmols) of tetramethoxysilane. While the reaction temperature was kept at 0° C., the reaction was continued for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain 2-(trimethoxy)silyl-1,3-butadiene (yield: 65%).