Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCO.[Li]CCCC.[CH:12]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:13]1.[C:26](=[O:28])=[O:27]>CCCCCC.C(OCC)C>[CH:12]1([C:15]2[C:20]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25]3)=[CH:19][C:18]([C:26]([OH:28])=[O:27])=[N:17][CH:16]=2)[CH2:14][CH2:13]1
Reactant: O=C=O
Reactant: c1cc(OCC2CC2)c(C2CC2)cn1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
To a solution of N,N-Dimethylethanolamine (CAN 108-01-0, 2.372 g, 3.08 mL, 30.6 mmol) in hexane cooled at −15° C. under an argon atmosphere was slowly added BuLi 1.6M in Hexane (38.2 mL, 61.1 mmol). The reaction was stirred at −15° C. during 20 minutes and was then cooled down to −78° C. before addition of 3-cyclopropyl-4-cyclopropylmethoxypyridine (Example 42b, 2.314 g, 12.2 mmol). The reaction was stirred 1 hour at −78° C. followed by addition of carbon dioxide (2.09 g, 47.6 mmol) (pellets from a dry ice dispenser) into the mixture. A white precipitate formed and the reaction was slowly warmed up to −20° C. The reaction was quenched with water, stirred 5 minutes and the volatiles were removed in vacuo. The residue was suspended into ethylacetate and extracted with 19 mL of a 2.0M aqueous solution hydrochloric acid. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness to give an yellow oil. The former oil was dissolved in diethylether which gave a white precipitate. The suspension was stored at 0° C. for 1 hour and the solution was separated from the white solid. The white solid was dried under high vacuum to give the titled compound (815 mg, 66%). MS (ESI, m/z): 234.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCCN1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCN1CCOCC1
Reaction time: 10 h
Yield: 68.2 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.22 ml (0.01525 mol) of N-(3-aminopropyl)-morpholine were added thereto and the mixture was boiled for 43 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with ethyl acetate/methanol 5:1, dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.58 g (68%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 65°-67° and 0.93 g (18%) of oily material from the mother liquors.
Reaction SMILES: BrC1C2C(C(C3C=CC4C(=CC=CC=4)C=3)=C3C=1C=CC=C3)=CC=CC=2.Br[C:27]1[CH:40]=[C:39]2[C:30]([CH:31]=[C:32]3[C:37](=[CH:38]2)[CH:36]=[CH:35][CH:34]=[CH:33]3)=[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=12.[CH:45]1[C:50]2=[C:51]3[C:60](=[CH:61][CH:62]=[C:49]2[C:48](B(O)O)=[CH:47][CH:46]=1)[CH:59]=[C:58]1[C:53]([CH:54]=[CH:55][CH:56]=[CH:57]1)=[CH:52]3.C1C2C3C(C=C(B(O)O)C=2C=CC=1)=CC1C(=CC=CC=1)C=3>>[CH:45]1[C:50]2=[C:51]3[C:60](=[CH:61][C:62]([C:41]4[CH:29]=[C:30]5[C:39]([CH:38]=[C:37]6[C:32](=[CH:31]5)[CH:33]=[CH:34][CH:35]=[CH:36]6)=[C:40]5[CH:27]=[CH:28][CH:44]=[CH:43][C:42]=45)=[C:49]2[CH:48]=[CH:47][CH:46]=1)[CH:59]=[C:58]1[C:53]([CH:54]=[CH:55][CH:56]=[CH:57]1)=[CH:52]3
Reactant: OB(O)c1cccc2c1ccc1cc3ccccc3cc12
Reactant: Brc1cc2cc3ccccc3cc2c2ccccc12
Agent: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: OB(O)c1cc2cc3ccccc3cc2c2ccccc12
Product: c1ccc2cc3c(cc(-c4cc5cc6ccccc6cc5c5ccccc45)c4ccccc43)cc2c1

Procedure:
Preparation analogous to Example 7. The 19.2 g (50 mmol) of 9-bromo-10-(2-naphthyl)anthracene are replaced by 15.4 g (50 mmol) of 5-bromobenz[a]anthracene, and the benz[a]anthracene-4-boronic acid is replaced by benz[a]anthracene-5-boronic acid. Recrystallisation four times from o-dichlorobenzene (about 15 ml/g); sublimation (p=5×10−5 mbar, T=320° C.). Yield: 15.0 g (33 mmol), 66.0%, purity 99.9% (HPLC), Tg=141.2° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[N:36]=2)[CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:36]1[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=[C:35]1[C:31]1[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1cncc(-c2nc3ccccc3[nH]2)c1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(-c4cccnc4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(pyridin-3-yl)-1H-benzo[d]imidazole were reacted to give 219. LCMS m/z: 568.3 (MH+)
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:1]=[N:3][CH:4]=[C:5]2[CH:10]=1)=[O:15]
Reactant: COC(=O)CCCc1ccnc(CNC=O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1ccn2cncc2c1

Procedure:
2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine (33 mg) is dissolved in 1 ml of toluene and heated at 90° with phosphorus oxychloride (44 mg) for 18 hours under nitrogen. The solvent is evaporated and the residue is suspended in methylene chloride, cooled to 0° and made basic with saturated ammonium hydroxide solution. The aqueous phase is extracted with methylene chloride (4×15 ml) which is dried over sodium sulfate and evaporated to yield 7-(3-methoxycarbonylpropyl)imidazo[1,5-a]pyridine as an oil, after purification by preparative thin layer chromatography (silica gel, 3:1 ethyl acetate-methanol); NMR (CDCl3) 3.70 (s, 3H); 6.45 (q, 1H), 7.2 (s, 1H), 7.32 (s, 1H), 7.90 (d, 1H); 8.08 (s, 1H); IR (CH2Cl2) 1730 cm-1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=2[OH:14])=[CH:2]1>CO.[C].[Pd]>[CH3:13][C:8]1[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:7]=1[OH:14]
Reactant: Cc1cc(C)c(O)c(-c2ccoc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(O)c(C2CCOC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
2-(furan-3-yl)-4,6-dimethylphenol (Compound 6-2) (0.6 g, 3.2 mmol) was dissolved in methanol. Palladium carbon (0.06 g) was added thereto, followed by stirring under hydrogen balloon at room temperature for 6 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain 2,4-dimethyl-6-(tetrahydrofuran-3-yl)phenol (0.45 g, 73%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1([C:13]2[O:17][N:16]=[C:15]([CH:18]3[CH2:23][CH:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH2:21][N:20]([C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:19]3)[N:14]=2)[CH2:12][CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C:9]1([C:13]2[O:17][N:16]=[C:15]([CH:18]3[CH2:23][CH:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=4)[CH2:21][N:20]([C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:35])[CH2:19]3)[N:14]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)no2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2nc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)no2)CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.4 ml (1.7 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 100 mg (0.17 mmol) of the compound from Example 166 in 0.25 ml of dioxane. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, again taken up in 0.25 ml of dioxane, and once more 0.4 ml (1.7 mmol) of a 4N solution of hydrogen chloride in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated to dryness under reduced pressure and dried until the weight remained constant. Yield: 92 mg (100% of theory).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=[N:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[N:16]=[CH:15]1
Reactant: c1ccc(CN2CCc3c(ncn3-c3ccccn3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: c1ccc(-n2cnc3c2CCNC3)nc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-benzyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.13 g, 0.45 mmol) in DCE (5 mL) was added 1-chloroethyl chloroformate (0.10 mL, 0.90 mmoL). The reaction was allowed to stir for 15 min then heated at reflux for 4 h. The reaction was let cool, concentrated, dissolved in MeOH and heated again at 60° C. for 1 h. The reaction was concentrated and the product was used in the next step without further purification (0.075 g, 83%). MS (ESI): mass calculated for C11H12N4, 200.1. m/z found 201.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10]Cl)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:33]C(C)=O>C1COCC1.OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10][OH:33])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(CCl)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The acyl chloride prepared in Step A was dissolved into 150 mL of tetrahydrofuran and was chilled to -78° C. under argon. To this pale brownish solution at -78° C. was added 8.0 mL lithium aluminum hydride in THF solutions (1.0 Molar). Analytical TLC after 15 minutes showed only one mobile spot at Rf =0.23 (50% EtOAc in hexanes v/v). The crude reaction mixture was diluted with 2M H2SO4 (20 ml). The aqueous layer was extracted with ethyl acetate (40 mL=2). Organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The crude allylic alcohol was used immediately in the next step without further purification. MS (CI): m/e=328 for (M+H)+ ;
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH3:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[K+].[K+].O.[CH2:21]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>CO.C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH3:13][C:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:12][CH2:11][N:10]([CH:29]2[CH2:30][CH2:31][CH2:32][N:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:27][CH2:28]2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1CCCC(N2CCC(C)(C(=O)OCC)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
Ethyl-4-methylpiperidine-4-carboxylate hydrochloride (0.50 g, 2.42 mmol) was dissolved in methanol (10 mL) and treated with K2CO3 (0.33 g, 2.42 mmol) in a minimum of water to de-salt. Reaction mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and 4-oxoazepane-1-carboxylic acid ethyl ester (0.45 g, 2.42 mmol) were dissolved in DCM (20 mL) at rt and titanium isopropoxide (0.76 g, 0.8 mL, 2.66 mmol) was added. The reaction mixture was stirred at rt for 5 h. STAB (2.05 g, 9.66 mmol) and acetic acid (0.3 mL) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was quenched with the addition of water (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.37 g, 45.0%) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>N1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1

Procedure:
20.5 Grams of p-toluenesulphonyl chloride were added to a mixture of 17.7 g 8-chloro-1-octanol and 50 ml of pyridine at 0°. After an hour the solution was added to ice and the mixture was extracted with ether. The ethereal solution was washed with dilute hydrochloric acid, dried with magnesium sulfate, and evaporated to yield the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][CH:5]2[CH:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C:9]3([CH2:11][OH:12])[O:4][CH:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OCC2OC3(CO)OC(C)(C)OC3C2O1
Temperature: -10 °C
Yield: 171 %

Procedure:
A mixture of 20 g (111 millimoles) of L-sorbose, 200 μl (2.3 millimoles) of trifluoromethanesulfonic acid (TFMSA) and 400 ml of acetone (H2O content 0.1%) was refluxed for 4.5 hours. 40 g of a molecular sieve (3 Å) were present in a Soxhlet extractor between the reaction flask and the reflux condenser. When the reaction was complete, the reaction mixture was cooled to -10° C. and 10 ml of aqueous NaHCO3 solution were added. Thereafter, the acetone was distilled off under reduced pressure, the residue was taken up in 35 ml of H2O and the solution was extracted with 3 times 110 ml of toluene at 70° C. The combined toluene phases were washed with 7.5 ml of H2O and dried over Na2SO4, and the toluene was distilled off under reduced pressure to give 24.7 g (85.5%) of 2,3:4,6-di-O-isopropylidene-α-L-sorbofuranose (DAS). After the product had been recrystallized from toluene, its melting point was measured as 78°-79° C.
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30]Br)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][S:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this example, heterocylic-protected glycine is synthesized by first forming an Nα-(auxiliary group)-substituted glycine, followed by deprotection and then cyclization by reaction with formalehyde. Triphenylmethyl mercaptan (Aldrich), 4 mmol, and 4′-methoxy-2-bromoacetophenone (Aldrich), 4 mmol, are dissolved in 2 mL DMF, after which 4 mmol DIEA is added. The mixture is stirred at room temperature for 1 hour, after which it is poured in diluted HCl, extracted with ethylacetate, and dried over sodium sulfate. The resulting oil is dissolved in ethylacetate and precipitated by addition of petroleum ether, which after evaporation gives a white solid, 4′-methoxy-2-(triphenylmethylthio)-acetophenone. This compound, 1.44 mmol, and aminoxyacetic acid, 4.3 mmol, are dissolved in 20 mL of trimethylorthoformate (TMOF), after which 0.047 mL of methanesulfonic acid is added as a catalyst. After incubation at room temperature for 48 hours, the solvent is evaporated and the residue taken up in ethylaceetate, washed with 1M monohydrogenpotassium sulfate and dried over sodium sulfate, after which the crude product is purified with silica gel chromatography and an oxime complex is isolated. 0.556 mmol of the oxime complex is dissolved in 2 mL of tetrahydrofuran (THF) and 1.67 mL of 1 M BH3/THF complex is added. After 24 hours, 3 mL of water and 1.5 mL of 10 N sodium hydroxide is added and the mixture is refluxed for 1 hour, after which the mixture is extracted with ethylacetate (4×) and dried over sodium sulfate. The final product of 1-amino-1-(4-methoxyphenyl)-2-(triphenylmethylthio)-ethane, is purified using silica gel chromatography. The 1-amino-1-(4-methoxyphenyl)-2-(triphenylmethylthio)-ethane is then reacted with BrNα-glycine in the presence of a base to give the Nα-(auxiliary group)-substituted glycine, preferably attached to a solid phase support. After deprotecting the sulfhydryl of this compound by treatment with TFA/TIS as described above, the cyclization reaction is carried out by treatment with formaldehyde. The final product is cleaved from the solid phase support by conventional means.
Reaction SMILES: [CH3:1][N:2](C)[C:3](Cl)=O.[CH2:7]([NH:15][C:16](=O)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:3])[C:16](=[N:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17]
Reactant: CCCCCCCCNC(C)=O
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCN=C(C)N(C)C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Dimethylcarbamyl chloride (6.29 g, 58.4 mmol) was added slowly to 10.0 g (58.4 mmol) of N-octyl acetamide in 10 mL of dry toluene and the solution was refluxed under a nitrogen atmosphere for 16 h. The volatile materials were removed on a rotary evaporator and in vacuo. The residue, dissolved dichloromethane (30 mL), was stirred strongly for 30 min with a solution of 2.34 g (58.4 mmol) of sodium hydroxide in 40 mL of water. Calcium carbonate (2.34 g) was added to the mixture and it was stirred an additional 30 min. The organic phase was separated and the aqueous phase was washed with dichloromethane (30 mL×3). The combined organic phases were dried (calcium carbonate) and the volatile materials were removed on a rotary evaporator. The residue was distilled at 72-77° C./0.25 Torr to yield 7.1 g (61%) of product (purity 99% by GC). IR (neat) 2955, 2924, 2853 (C—H), 1627 (N═C) cm−1. 1H NMR 3.17 (t, 2H, JHH 6.9 Hz, —CH2—N═), 2.86 (s, 6H, —N—(CH3)2); 1.87 (s, 3H, —N═C(CH3)—N); 1.5 (m, 2H, —CH2—CH2—N═); 1.25-1.4 (m, 10H, CH3—(CH2)5—); 0.88 (t, 3H, JHH 6.1 Hz, CH3).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O)[CH3:17].Cl>CN(C)C=O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:18]([CH2:16][CH3:17])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:8])[CH3:11]
Reactant: CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To a 40 ml. solution of NaOEt (1.0 g. Na-0.042 mole) was added 6.8 g. (0.042 mole) of diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solution formed and to this was added 5.7 g. (0.021 mole) of 1-ethyl-7-phenyl-2H-pyrimido[4,5-d][1,3]-oxazine-2,4(1H)-dione and the mixture heated at reflux for 2 hours. The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water. Recrystallization with hexane-ethyl acetate gave 5.1 g. of the title product--m.p. 177°-180° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:18])([F:17])[C:7]([NH:9][C@@H:10]1[C:15](=[O:16])[O:14][C:12](=[O:13])[CH2:11]1)=[O:8].[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>ClCCl>[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:7](=[O:8])[C:6]([F:5])([F:18])[F:17])[C:15]([OH:16])=[O:14]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a dichloromethane (50 mL) suspension of aluminum chloride (3.19 g, 0.024 mol) at 0° C., under an inert nitrogen atmosphere was added via a solid addition funnel an intimate mixture of N-trifluoroacetyl-L-aspartic acid anhydride (3.01 g, 0.0142 mol) and dibenzofuran (2 g, 0.0119 mol). The resulting brick-red suspension was allowed to warm to room temperature over 12 hours. The reaction mixture was poured into ice water (250 mL), and the resulting colorless biphasic mixture was extracted with ethyl acetate (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine (2×100 mL) and dried over magnesium sulfate. The mixture was filtered, and the organic solution was concentrated by evaporation of the solvent in vacuo to yield a white solid. The solid was recrystallized from 10% ethyl acetate/hexane (v/v) to give (S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid (2.16 g, 48%) as a while solid; mp 174-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:18][O:19][CH3:20]
Reactant: COCCl
Reactant: COc1c(O)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1c(Br)ccc(O)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 43.7 %

Procedure:
To a stirring solution of 4-bromo-2-methoxybenzene-1,3-diol (4.5 g, 20.54 mmol) in acetone (40 mL) at 0° C. was added potassium carbonate (2.83 g, 20.54 mmol) and methoxymethyl chloride (1.32 g, 17.39 mmol). The resultant reaction mixture was stirred at RT for 7 h. The reaction mixture was quenched with ice-cold water, the solid was filtered and the filtrate was concentrated under reduced pressure to leave a residue having the crude product. The crude product was purified by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) to afford 4-Bromo-2-methoxy-3-(methoxymethoxy)phenol as a liquid (2 g, 37%).