Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[CH2:10][CH2:9][CH2:8][NH:7][C@H:6]1[CH2:5][CH2:4][CH2:3][NH:2]2.[CH2:11]=O>[Pd]>[CH3:11][N:2]1[CH2:3][CH2:4][CH2:5][C@H:6]2[C@H:1]1[CH2:10][CH2:9][CH2:8][NH:7]2
Reactant: C1CN[C@@H]2CCCN[C@H]2C1
Reactant: C=O
Agent: [Pd]
Product: CN1CCC[C@@H]2NCCC[C@H]21
Reaction time: 10 h

Procedure:
A mixture of trans-2,7-diazabicyclo[4.4.0]decane (1.4 g, 10 mmoles), 37% aqueous formaldehyde solution (0.6 ml, 8 mmoles) and 0.5 g of palladium on charcoal (10%) was hydrogenated for 10 hours at 60° C. under a pressure of 3 to 4 bar. Hydrogenation under the conditions given above was continued after adding a further 0.3 ml of the 37% aqueous formaldehyde solution, the reaction mixture was then concentrated and digested with petrolether. The petrolether solution was concentrated under reduced pressure and the oily residue (1.2 g) was used for further reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10](Cl)[N:9]=2)[CH2:5][O:4][CH2:3]1.[S:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.O>CN(C)C=O>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([N:22]3[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:19][CH2:20][CH2:21]3)[N:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: NC1(CNc2nc(Cl)nc3ccccc23)COC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC1(CNc2nc(N3CCSc4ccccc4C3)nc3ccccc23)COC1
Temperature: 130 °C
Yield: 14.1 %

Procedure:
To a solution of N-[(3-aminooxetan-3-yl)methyl]-2-chloroquinazolin-4-amine (200 mg, 0.756 mmol) in N,N-dimethylformamide (4 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (125 mg, 0.756 mmol) and triethylamine (230 mg, 2.268 mmol). After being heated at 130° C. for 4 hours under microwave irradiation, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was 14%). MS obsd. (ESI+) [(M+H)+] 394, 1H NMR (400 MHz, CD3OD) δ ppm 7.75-7.73 (t, J=6.4, 1.2 Hz, 1 H), 7.56-7.53 (m, 1 H), 7.52-7.47 (m, 2 H), 7.43-7.41 (d, J=8.0 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.15-7.08 (m, 2 H), 5.06 (s, 2 H), 4.69-4.67 (d, J=6.8 Hz, 2 H), 4.55-4.53 (d, J=6.4 Hz, 2 H), 4.42 (s, 2 H), 4.09 (s, 2 H), 2.97-2.95 (t, J=4.8, 4.4 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[NH:6][N:5]=[N:4]1)[CH3:2].Cl[CH:10]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][N:12]1[CH2:17][CH2:16][C:15]([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:18][O:19][CH3:20])[CH2:14][CH2:13]1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[CH2:1]([N:3]1[C:7](=[O:8])[N:6]([CH:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:11][N:12]2[CH2:17][CH2:16][C:15]([N:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:18][O:19][CH3:20])[CH2:14][CH2:13]2)[N:5]=[N:4]1)[CH3:2]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(Cl)c2ccccc2)CC1
Reactant: CCn1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(c2ccccc2)n2nnn(CC)c2=O)CC1
Temperature: 70 °C
Yield: 65 %

Procedure:
A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 8 parts of N-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 0.2 parts of potassium iodide, 5 parts of sodium carbonate and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is cooled to room temperature and 150 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of petroleum-ether and 2,2'-oxybispropane. The product is filtered off and dried, yielding 5.7 parts (65%) of N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-2-phenylethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide; mp. 125.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17]C(C)C)=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1.[OH-].[Li+].CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(C)C)n2)cc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ncn(/C=C\C(=O)O)n2)cc(Cl)n1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with Thermometer pocket and rubber septum, (Z)-isopropyl 3-(3-(2-chloro-6-methoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate (0.7 g, 1.0 eq.) dissolve in THF (4 ml) was added lithium hydroxide (0.182 g, 2.0 eq.) (dissolved in water), resulting reaction mixture was stir at RT. The progress of the reaction was followed by TLC analysis on silica gel with 20% EtOAc-hexane as mobile phase which shows that starting material was consumed after 5 h. THF was removed under reduce pressure, aqueous layer washed with ethyl acetate then acidified to 3-5 pH and extract by ethyl acetate (30 ml×3), combined organic layer were dried over sodium sulfate and concentrate under reduce pressure to obtain crude material (0.228 g), crude material was subjected to column purification. The crude compound was purified by column chromatography using 60/120 silica gel and ethyl acetate in hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection. The compound started eluting from 10% ethyl acetate in hexane. Fractions containing such TLC profile were collected together to obtain pure compound 0.180 g yield (29.97%); LCMS (%): 93.46% [M+H]+ 280.81 RT: 3.213 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C)C=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 1-(2-hydroxyethyl)-pyrrolidine [Aldrich], (1.87 ml, 16 mmol) in dimethylformamide was added portionwise sodium hydride [60% dispersion in oil, (544 mg, 16 mmol). After stirring at room temperature for 10 minutes a solution of 1-chloro-2-methoxy-4-nitro-benzene [Avocado] (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hrs then concentrated. The residue was dissolved in ethyl acetate (200 ml) and washed with water (3×50 ml). The organic phase was dried with magnesium sulphate, evaporated and the residue purified by flash chromatography on silica gel using dichloromethane-aq. ammonia-methanol as eluent to afford 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine as a brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[CH2:19]([NH:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31](Br)[CH:30]=[C:29]2[O:34][CH2:35][O:36][C:28]=12)[CH2:20][CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C>[CH2:19]([NH:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH:30]=[C:29]2[O:34][CH2:35][O:36][C:28]=12)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1c[nH]cn1
Reactant: CCCCCNC(=O)Cc1cc(Br)cc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)Cc1cc(-c2ncc[nH]2)cc2c1OCO2
Temperature: 200 °C
Reaction time: 10 h
Yield: 45.6 %

Procedure:
Imidazole (1.11 g, 16.3 mmol), potassium carbonate (2.78 g, 20.1 mmol), cuprous chloride (0.31 g, 3.1 mmol), and N-methylpyrrolidone (25 ml) were added to N-pentyl-(5-bromo-2,3-methylenedioxyphenyl)acetamide (4.65 g, 14.8 mmol), and the mixture was stirred at 200° C. for 10 hours. The reaction mixture was cooled and added with ethyl acetate (30 ml) and the precipitates were removed by filtration. The ethyl acetate layer was successively washed with 10% aqueous ammonia and with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 100 g, eluent: methanol/chloroform=1/50-1/20) to give N-pentyl-(5-imidazolyl-2,3-methylenedioxyphenyl)acetamide (2.13 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)Nc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.10 g of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 19b) and aniline are reacted to afford the title compound as a colourless oil. Rf=0.50 (dichlormethane-methanol 10:1); Rt=5.40.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH:22]3[CH2:24][CH2:23]3)[C:18](=[O:21])[NH:19][N:20]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]([CH:22]3[CH2:24][CH2:23]3)[C:18](=[O:21])[N:19]([CH2:2][C:3]3[N:4]=[CH:5][NH:6][C:7]=3[CH3:8])[N:20]=2)=[CH:14][CH:15]=1
Reactant: Cc1[nH]cnc1CO
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cnc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O

Procedure:
Analogously to the compound in Example 96A, 181 mg (1.62 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 381 mg (1.62 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 670 mg (4.85 mmol) of potassium carbonate were reacted with one another. This gave 180 mg (47% of theory) of the target compound in a purity of 76%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:14][CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (1.40 g, 0.035 mole) in anhydrous dimethylformamide (60 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole) and stirred for 30 minutes at room temperature. 2-Chloro-N,N-diethylacetamide (5.40 g, 0.036 mole) was added, and the mixture was stirred at 100°-110° C. for 3 hours until gas chromatography indicated absence of 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester. The solution was cooled and added to ice water (350 ml), then extracted with ether (3×200 ml). The combined organic solution was dried (magnesium sulfate) and concentrated in vacuo. Filtration through alumina (eluted with 3% methanol/methylene chloride) and trituration from petroleum ethers (30°-60°) afforded 8.66 g (92%) of 4-amino-5-chloro-2-[2-(diethylamino)-2-oxoethoxy]benzoic acid methyl ester as a colorless solid; mp 97.5° -99.5° C. (ethyl acetate/hexane).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23](C(OC(C)(C)C)=O)[C:22]([C:34]1[C:35](=[O:44])[NH:36][C:37]3[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21]2)[S:12]([CH:15]=C)(=[O:14])=[O:13])=O)(C)(C)C.O.CSC.FC(F)(F)C(O)=O>ClCCl>[O:13]=[S:12]1(=[O:14])[CH2:15][CH2:6][NH:8][CH2:9][CH2:10][N:11]1[CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:34]1[C:35](=[O:44])[NH:36][C:37]3[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21]2
Reactant: C=CS(=O)(=O)N(CCNC(=O)OC(C)(C)C)Cc1ccc2c(c1)cc(-c1cc3ccccc3[nH]c1=O)n2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2ccccc2cc1-c1cc2cc(CN3CCNCCS3(=O)=O)ccc2[nH]1
Reaction time: 5 h

Procedure:
The sulfonamide 11-3 (67 mg, 0.11 mmol) was dissolved in 3.0 mL of dichloromethane, 100 μL of water, and 150 μL of dimethyl sulfide at ambient temperature. Trifluoroacetic acid (2.0 mL) was then added via pipette to afford a dark yellow solution. The reaction was stirred for 5 hours until completion via LCMS analysis. The reaction solution was concentrated and the residue partitioned between ethyl acetate (15 mL) and half-saturated NaHCO3 solution (100 mL). The layers were separated and the aqueous layer was extracted several times with ethyl acetate (10×30 mL). The combined organic layers were washed with brine, separated, dried (Na2SO4) and concentrated in vacuo to afford a yellow solid. Reverse-phase chromatography (0.01% TFA present) (90% water to 90% acetonitrile) followed by free-base extraction into ethyl acetate and concentration afforded 11-4 as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1 H), 11.62 (s, 1 H), 8.55 (s, 1 H), 7.74 (d, 1 H, J=7.2 Hz), 7.53 (m, 3 H), 7.38 (d, 1 H, J=8.1 Hz), 7.32 (d, 1H, J=1.5 Hz), 7.25 (app t, 1 H, J=7.5 Hz), 7.11 (dd, 1 H, J=8.7, 1.2 Hz), 4.48 (s, 2H), 3.41 (m, 2 H), 3.05 (m, 2 H), 2.50 (m, 4 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CCS(=O)(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method the same as for Preparation 6 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) and ethanesulphonylchloride (54 μl, 0.57 mmol) as starting materials. The reaction was carried out at 0° C.
Reaction SMILES: [CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[F-].[Cs+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]1[O:37][C@H:36]1[CH2:38][OH:39]>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:35][C@@H:36]([OH:37])[CH2:38][OH:39])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:15])[CH3:16])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: OC[C@H]1CO1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(C)(C)O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(C)(C)O)c(C)c1)c1ccc(OC[C@@H](O)CO)c(C)c1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To a solution of 4-{1-ethyl-1-[4-(3-hydroxy-3-methylbutyl)-3-methyl-phenyl]propyl}-2-methylphenol (0.14 g, 0.40 mmol) in anhyd DMF (2 mL) was added CsF (67 mg, 0.44 mmol), Cs2CO3 (26 mg, 80 □ mol) and (S)-glycidol (29 μL, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling, the mixture was diluted with DCM (40 mL), washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25) to provide the title compound (80 mg, 47%) as a white powdered solid: 1H-NMR (CD2Cl2) δ 7.01 (1H, d, J=8.1), 6.96 (1H, dd, J=2.3, 8.3), 6.88-6.94 (3H, m), 6.73 (1H, d, J=8.3), 3.97-4.11 (3H, m), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.62 (2H, m), 2.53 (1H, d, J=5.1), 2.24 (3H, s), 2.16 (3H, s), 2.05 (4H, q, J=7.3), 1.99 (1H, t, J=6.1), 1.67 (2H, m), 1.27 (6H, s), 0.58 (6H, t, J=7.3); 13C-NMR (CD2Cl2) δ 155.0, 147.2, 142.0, 138.4, 135.7, 131.2, 130.4, 128.5, 126.9, 126.3, 126.2, 110.9, 71.4, 71.3, 70.1, 64.6, 49.3, 45.2, 29.8, 29.6, 28.3, 20.0, 17.0, 8.9.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([O:19][CH3:20])[CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>CO.Cl.[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([O:19][CH3:20])[CH3:18])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(C)(C)CCCC(C)CCC(O)c1ccc(C(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(C)(C)CCCC(C)CCCc1ccc(C(C)C)cc1

Procedure:
The reaction mixture containing 1-(p-isopropylphenyl)-4,8-dimethyl-8-methoxynonan-1-ol as obtained above (Example III) (9.9 g) was submitted to hydrogenolysis by dissolution in an acidic lower alkanol, e.g., methanol (50 ml) and conc. HCl (1 ml) and was then hydrogenated with H2 in the presence of 5% Pd-C (0.4 g). After uptake of hydrogen ceased, the catalyst was removed by filtration with the aid of a filter aid (Celite). The filtrate was washed with aq. NaHCO3, brine and dried over MgSO4. Evaporation of solvent left a yellow oil (8.4 g). Distillation gave the desired product (1-(p-isopropylphenyl)-4,8-dimethyl-8-methoxynonane) (2.8 g, bp. 120°-125°/0.05 torr). The NMR spectrum showed the following signals 1.08 (6H, s), 1.22 (6H, d, J.=6.5 Hz): (CDCl3) 0.88 (3H, d, J=6.5 Hz), 2.60 (2H, t, J=7 Hz), 2.90 (1H, m), 3.14 (3H, s), 7.10 (4H, s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:23][Mg]Br.C1COCC1>>[OH:17][C@:14]1([CH3:23])[C:13]([CH3:19])([CH3:18])[C:12](=[O:20])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:10]=2)[C@@H:15]1[CH3:16]
Reactant: C[Mg]Br
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: C[C@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C(C)(C)[C@@]1(C)O

Procedure:
Using 2-(trifluoromethyl)-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and methylmagnesium bromide-THF solution (3.22 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 77 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][NH:11][C:10]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:20]=[S:21]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C:20](=[S:21])[NH:19][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:10]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Reactant: CC(C)(C)OC(=O)CN=C=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=S)N1C[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3-[[(t-butyloxy)carbonyl]amino]-2-azetidinone (186 mg, 1 mmol) in 6 ml of dry tetrahydrofuran at -75° C. was treated with 0.65 ml (1.1 mmol) of 1.68N n-butyl lithium. After 30 minutes, a solution of t-butyl isothiocyanatoacetate (0.17 ml, 1.1 mmol) in 1 ml of dry tetrahydrofuran was added to the reaction mixture. After stirring at -75° C. for 2 hours, the reaction mixture was placed at -70° C. overnight.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:26][CH3:27])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[C:20]([O:24][CH3:25])[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:34]([O:36][CH3:37])=[O:35])#[C:29][C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:21]4[C:20]([O:24][CH3:25])=[CH:19][CH:18]=[C:17]([N:22]34)[C:16]=2[CH2:26][CH3:27])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OC)ccc12
Reactant: COC(=O)C#CC(=O)OC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OC)ccc1n32
Yield: 80 %

Procedure:
The general synthetic pathway outlined in example 23, step 1-5, have been applied to proper starting materials in the preparation of 2-(4-benzyloxyphenyl)-1-ethyl-6-methoxyindolizine, which was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 3-(4-benzyloxyphenyl)-4-ethyl-7-methoxypyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate as a red oil in 80% yield. 1H-NMR (CDCl3, 200 MHz) δ: 1.36 (t, 3H); 3.02 (q, 2H); 3.60 (s, 3H); 3.98 (s, 3H); 4.14 (s, 3H); 5.15 (s, 2H); 7.04-7.52 (m, 10H); 7.81 (d, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]1[O:46][CH2:45]1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.O1CCOCC1>[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]([OH:46])[CH2:45][N:1]=[N+:2]=[N-:3])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCOCC(COCC1CO1)OCCCCCCCCCCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCOCC(COCC(O)CN=[N+]=[N-])OCCCCCCCCCCCCCCCC
Yield: 62 %

Procedure:
A solution of sodium azide (0.5 g., 7.7 mmoles) in water (5 ml.) was added to a refluxing solution of 1,2-di-O-(n-hexadecyl)-3-O-(2,3-epoxypropyl)-glycerol (3.3 g., 5.5 mmoles) in 1,4-dioxane (100 ml.), and the resulting solution stirred at reflux for 16 hours. Since the reaction was not yet complete, additional sodium azide (0.5 g., 7.7 mmoles) was added and the reaction stirred at reflux for another 16 hours. The reaction solution was then cooled, concentrated in vacuo, diluted with water (100 ml.) and extracted with ether (3×100 ml.). The combined ether extract was washed with water (100 ml.), dried (MgSO4), filtered and evaporated in vacuo to an oil which solidified on standing [2.2 g., 62% yield, ir (CHCl3) 2105 cm-1 ].