Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][O:35][CH2:36]Cl>CN(C)C=O>[CH3:34][O:35][CH2:36][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Cc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 7-hydroxy-8-methyl-2-oxo-2H-chromen-3-ylcarbamate 7 (975 mg, 3.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (1.01 mL, 7.5 mmol) over 5 minutes at room temperature. The resulting solution was stirred for 30 minutes and cooled to 0° C. To it was added methoxymethylchloride (1.25 mL, 7.5 mmol) dropwise and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by water and the precipitate was filtered, washed with diethyl ether and dried under vacuum to give compound 8 as a white amorphous solid (931 mg, 82%). 1H NMR (500 MHz, acetone-d6) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.42 (m, 6H), 7.15 (d, 1H, J=8.7 Hz), 5.34 (s, 2H), 5.26 (s, 2H), 3.49 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, acetone-d6) δ 158.8, 157.2, 154.2, 149.9, 137.4, 129.3, 129.0, 128.9, 126.2, 123.1, 112.8, 115.0, 114.9, 112.3, 95.6, 67.6, 56.4, 8.3. IR (KBr) νmax 3321, 2948, 2931, 28591, 1724, 1693, 1608, 1541, 1367, 1213, 1155, 898 cm−1. HRMS (ESI+) m/z [M+Na+] calcd for C20H19NNaO6 392.1110. found 392.1104.
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1CN(C(C)(C)C)CC2(CCNCC2)O1
Reaction time: 0.25 h
Yield: 104 %

Procedure:
Tert-butyl 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (530 mg, 1.56 mmol) was dissolved in dichloromethane and treated with a solution of HCl in dioxane (8.0 mL of 4 M, 33 mmol) and stirred for 15 min. The reaction mixture was diluted with dichloromethane and washed with 1:1 saturated NaHCO3/1 M NaOH. The organic layer was dried over Na2SO4, filtered and concentrated to provide 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 99%) as an oily solid. ESI-MS m/z calc. 240.2. Found 241.3 (M+1)+; Retention time: 0.21 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@H](C2C=CC=CC=2)C)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reaction time: 8 h

Procedure:
(3R, 4R)-3-Methyl-4-(1-(S)-phenyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (810 mg, 2.55 mmol) was dissolved in methanol (15 mL). Palladium hydroxide (20%, 100 mg) was added and the mixture was shaken under a hydrogen atmosphere overnight at 55 psi. The reaction was filtered and concentrated in vacuo to give the title compound as a clear oil. Wt.: 500 mg (92%). NMR (300 MHz, CDCl3) δ 4.06 (m, 1H), 3.96 (m, 1H), 2.73 (m, 1H), 2.34 (m, 2H), 1.77 (m, 1H), 1.43 (s, 9H), 1.27 (m, 2H), 0.94 (d, 3H); LC/MS m/z 215 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Cl:17])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=2[O:13][CH3:14])[N:3]=1.C[O-:19].[Na+]>CO>[Cl:1][C:2]1[N:11]=[C:10]([OH:19])[C:9]2[C:4](=[C:5]([Cl:17])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=2[O:13][CH3:14])[N:3]=1
Reactant: COc1cc(Cl)c2nc(Cl)nc(Cl)c2c1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c2nc(Cl)nc(O)c2c1OC
Yield: 9 %

Procedure:
A mixture of 2,4,8-trichloro-5,6-dimethoxyquinazoline (2.0 g, 0.0068 moles), sodium methoxide (0.367 g, 0.0068 moles) and methanol (100 ml) was stirred at reflux for 3 hours. The solvent was removed in vacuo and the residue was treated with water (50 ml), followed by acidification with glacidal acetic acid. The resulting aqueous mixture was extracted with dichloromethane (3×100 ml) and the combined organic extracts were dried over anhydrous sodium sulfate. After filtration and removal of solvent in vacuo the residue was recrystallized twice from methanol. The crystals were dried under vacuum at 40° C. to afford the product (0.168 g), mp 252°-253° C.
Reaction SMILES: [CH3:1]/[C:2](/[CH:15]=[CH:16]/[CH:17]=[C:18](\[CH3:30])/[CH:19]=[CH:20]/[C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])=[CH:3]\[C:4]([N-:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])=[O:5].CN1CCOCC1.[C:38](Cl)(=[O:42])[CH2:39][CH2:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:38]([O:14][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])/[CH:3]=[C:2](\[CH3:1])/[CH:15]=[CH:16]/[CH:17]=[C:18](\[CH3:30])/[CH:19]=[CH:20]/[C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])(=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(=O)Cl
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)[N-]c2ccc(O)cc2O)C(C)(C)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(=O)Oc1cc(O)ccc1NC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoyl]-(2,4-dihydroxy)phenylamide (KCBG08) (0.10 g, 0.24 mmol) was dissolved in anhydrous CH2Cl2 (15 mL), and NMM (0.049 g, 0.49 mmol) was added. To the resulting mixture was added dropwise butyryl chloride (0.050 mL, 0.49 mmol) at 0° C., and the resulting solution was stirred for 0.5 h. Finely ground K2CO3 (0.30 g) and MeOH (3 mL) was added to the reaction mixture. After stirring for 1 h, the completion of the reaction was confirmed by TLC. The mixture was washed with CH2Cl2 (30 mL) and H2O (20 mL). The organic layer was dried over anhydrous MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (EtOAc:hexane=1:4) to give 2-[(2E,4E,6E,8E]-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoylamino)-5-hydroxyphenyl butanoate (KCBG10, 97 mg, 83%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 17.5 h
Yield: 35 %

Procedure:
A chilled solution of 4-nitrophenol (1.14 g, 8.12 mmol), triphenyl phosphine (3.21, 12.2 mmol) and 1-benzyl-4-hydroxypiperidine (2.6 g, 14 mmol) in THF was treated with diisopropyl azodicarboxylate (DIAD) (2.4 mL, 12 mmol), stirred at ambient temperatures, under nitrogen, for 17.5 hours, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 30-40% ethyl acetate in hexane to give 1-benzyl-4-(4-nitro-phenoxy)-piperidine as a yellow semi-solid, 0.880 g (35% yield); Mass spectrum (+EI, [M+H]+) m/z 313. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.24-7.30 (m, 4H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 2H), 4.53-4.59 (m, 1H), 3.45 (s, 2H), 2.60-2.64 (m, 2H), 2.20-2.26 (m, 2H), 1.91-1.95 (m, 2H), 1.58-1.67 ppm (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:3]
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CC(=O)O/N=C(\C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (20.6 ml) was added formic acid (16.6 ml) at 15° C. The mixture was stirred at room temperature for 30 minutes. To the mixture was 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (10 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 20 hours. To the mixture was added isopropyl ether (37.2 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting precipitate was collected by filtration to give 2-(2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (9.39 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:47]2[C:48]([C:53]#[N:54])=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]([CH3:45])[C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[NH:3][C:4](=[O:7])[O:5][N:54]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]([CH3:45])[C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (7.5 g), sodium hydrogen carbonate (12 g) and dimethyl sulfoxide (50 mL) was stirred at 40° C. for 30 min. 3′-Fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (retention time: short, 4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (100 mL). N,N′-Carbonyldiimidazole (1.4 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) were successively added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with 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 colorless amorphous solid (4 g, 91%, >99% ee).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[CH:51](=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(CC)CC)C>[CH2:51]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(Cc4ccccc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (130 mg) in dichloromethane (4 mL) and triethylamine (0.10 mL) was treated with benzaldehyde (0.10 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 578.3 (M+H)+.
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.Cl[C:11]1[CH:12]=[C:13]([CH3:21])[C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1.[CH3:22][CH2:23][CH:24]([OH:27])[CH2:25][CH3:26]>CN(C=O)C>[CH2:23]([CH:24]([O:27][C:11]1[CH:12]=[C:13]([CH3:21])[C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1)[CH2:25][CH3:26])[CH3:22]
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)Oc1cc(C)c2nnc(N)n2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Pentanol (10.2 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (511 mg). The suspension formed was heated to 55° C. for 30 min and admixed with portions of 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine trifluoroacetate (W2.002b; 500 mg), suspended in 3-pentanol (5 ml) and DMF (10 ml). After stirring at 55° C. for 1.5 h, the mixture was left to stand at RT overnight, the DMF was removed under reduced pressure, and the residue was then admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 198 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride (260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([O:16][CH3:17])[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:10][CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][O:10][C:9]1[CH:12]=[C:13]([CH:14]=[CH:15][C:8]=1[O:16][CH3:17])[C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reaction time: 6 h
Yield: 64 %

Procedure:
70 g (0.7 mol) of succinic anhydride and 96.6 g (0.7 mol) of veratrol were dissolved in 2000 ml of methylene chloride, and 237 g (1.75 mol) of anhydrous aluminum chloride was added thereto at room temperature. The mixture was stirred at the same temperature for 6 hours. The reaction solution was allowed to stand for 15 hours, and then 1600 ml of 6N hydrochloric acid was dropwise added under stirring. The mixture was stirred for 1 hour, and the organic layer was separated. 300 ml of water was added to the organic layer and adjusted to pH7.5 with a saturated sodium hydrogencarbonate aqueous solution. The water layer was separated, adjusted to pH2.5 with 6N hydrochloric acid and allowed to stand in a refrigerator for 2 days. The precipitated crystals were collected by filtration, washed and dried to obtain 106.8 g (yield: 64%) of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [OH:1][CH:2]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:3]([O:5][CH3:6])=[O:4].[O:17]=C(C12CC3CC(CC(C3)C1)C2)C(OC)=O>>[OH:17][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4])([CH2:14]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)C(=O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C(O)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)C(=O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
As shown in Scheme IV, in this method, adamantyl bromide (Formula A) is alkylated via zinc chloride catalysis to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) is then esterified using acetyl chloride in methanol to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C) is then converted to α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) by Swern oxidation. α-Oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) is then hydroxylated to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula I), which is then hydrolyzed to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula II). Also see Examples 21 through 25 herein.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: NC1CC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(CCl)cc1

Procedure:
4-Chloromethyl-benzoyl chloride (2.82 g, 15 mmol) and cyclopropylamine (1.26 ml, 18 mmol) were reacted in CH2Cl2 (30 ml) and in the presence of Hünig's base (3.1 ml, 18 mmol) for 1 h. A precipitate was formed which was resolubilzed by adding ethyl acetate. The reaction mixture was washed with a 5% KHSO4/10% K2SO4 solution, NaCl sat. solution and dried (Na2SO4). The organic phase was filtered and concentrated under reduced pressure to yield a semi-solid which was triturated in hexanes: solid 3.1 g (95%); 1H NMR (CDCl3) δ 0.60-0.64 (m, 2H), 0.85-0.90 (m, 2H), 2.89-2.92 (m, 1H), 4.60 (s, 2H), 6.20 (br, 1H), 7.44 (d, 2H), 7.71-7.74 (m, 2H); MS: m/e=210.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:26][CH2:27][OH:28].Cl>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[OH:28][CH2:27][CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: OCCI
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
10 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (1.45 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is then stirred for 30 minutes at room temperature, 5.22 g of 2-iodoethanol are added dropwise thereto, and the mixture is then stirred for 15 minutes at room temperature and poured into a mixture of 30 ml of 2 N hydrochloric acid and 400 ml of ice-water. After being left to stand for some time the oil which separates crystallises and is taken up in 200 ml of methylene chloride. The solution is dried over magnesium sulphate and concentrated to dryness by evaporation. To crystallise, the residue is triturated with diethyl ether. 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 83°-84° is obtained.
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[CH2:5][CH2:6][C:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([NH2:10])=[O:9])([CH3:3])[CH3:2].[H][H].CCCCCC>C(O)C.C(Cl)Cl.[Ru](=O)=O>[CH:11]1([C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:26]([CH3:28])[CH3:27])([CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[C:8]([NH2:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1)C(C)C
Agent: O=[Ru]=O
Solvent: ClCCl
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)C1CCCCC1)C(C)C
Temperature: 125 °C
Reaction time: 24 h

Procedure:
10 Parts of α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetamide is dissolved in 130 parts by volume of ethanol and the solution placed in pressure shaker with 1 part of ruthenium dioxide. Hydrogen is introduced at 1000 psi and the reaction mixture heated at about 125° C. and shaken for about 24 hours. Then, the reaction mixture is cooled to room temperature and filtered. The filtrate is stripped of solvent to give an oil. This oil is dissolved in methylene chloride, then hexane added to the solution, methylene chloride evaporated, and the hexane mixture cooled to give α-(cyclohexyl)-α,α-bis[2-(diisopropylamino)ethyl]acetamide, as a crystal solid melting at about 114°-115° C. This compound has the following structural formula ##STR49##