Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:7](=[O:16])[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([OH:6])=O.CCN(CC)CC.C(Cl)(C(C)(C)C)=[O:25].[CH2:31]([C@H:38]1[CH2:42][O:41][C:40](=O)[NH:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[O:25]=[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:32]1[CH2:31][C@H:38]1[CH2:42][O:41][CH2:40][N:39]1[C:4](=[O:6])[CH2:3][N:2]([CH3:1])[C:7](=[O:16])[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(CC(=O)O)C(=O)C#Cc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(=O)N1COC[C@@H]1CC1C=CC=CC1=O)C(=O)C#Cc1ccccc1
Temperature: -20 °C
Yield: 75.6 %

Procedure:
To a −30° C. solution of 2-(N-methyl-3-phenylprop-2-ynoylamino)acetic acid (100.0 g, 0.460 mol, 1.1 equiv) and Et3N (117 mL, 0.836 mol, 2 equiv) in THF (1100 mL) was added a solution of PivCl (57 mL, 0.460 mol, 1.1 equiv) in THF (100 mL) at such a rate that the temperature was maintained below −20° C. The resulting white slurry was stirred at −20° C. Meanwhile, a −78° C. solution of (S)-(−)-4-benzyl-2-oxazolidinone (74.1 g, 0.418 mol) in THF (900 mL) was treated with a solution of n-BuLi (2.5M in hexane, 185 mL, 0.460 mol, 1.1 equiv) at such a rate that the temperature was maintained below −68° C. The reaction was stirred at −78° C. for 15 min. To this mixture was added via cannula a −78° C. solution of the mixed anhydride prepared above. The reaction was allowed to warm to −10° C. over 30 min and treated with a saturated NH4Cl solution (500 mL). The resulting mixture was concentrated under reduced pressure and the residue was partitioned between water (200 mL) and EtOAc (500 mL). The organic layer was washed with water (3×300 mL), a saturated NaHCO3 solution (2×300 mL) and a saturated NaCl solution (2×300 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient from 25% to 65% EtOAc/hex) to give N-{2-[(4S)-2-oxo-4-benzyl(1,3-oxazolidin-3-yl)]-2-oxoethyl}-N-methyl-3-phenylprop-2-ynamide (119.6 g, 74%) as a white foam. Analytical data of this product was identical to Intermediate R obtained by Method 1.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3>C(O)(=O)C>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@@H:20]3[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH2:9][C:10]2=[O:11]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 19-nortestosterone 52 (26.85 g, 97.85 mmol) in acetic acid (200 mL) was added a CrO3 (7.4 g, 74 mmol) in acetic acid (150 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to half of its initial volume, poured into 1 M hydrochloric acid (500 mL) and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and then concentrated to afford dione 53 as a white solid (25.3 g, 95%): 1H NMR (300 MHz, CDCl3) δ 0.94 (s, 3, CH3), 5.85 (s, 1).
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:13]([C:29]#[N:30])[C:14](=[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]=1[Cl:19])[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:13]2[C:14](=[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]=1[Cl:19])[C:15](=[NH:16])[NH:30][C:29]2=[NH:2]
Reactant: CCCCCCCCOc1c(Cl)c(Sc2ccccc2N)c(OCCCCCCCC)c(C#N)c1C#N
Reactant: N
Agent: [Na]
Solvent: CCCO
Product: CCCCCCCCOc1c(Cl)c(Sc2ccccc2N)c(OCCCCCCCC)c2c1C(=N)NC2=N
Temperature: 55 °C
Reaction time: 20 h
Yield: 44.4 %

Procedure:
To a solution of sodium metal (0.9 g) in n-propyl alcohol (265 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 35.8 g of 4-(2-aminophenylthio)-5-chloro-3,6-di-n-octyloxyphthalonitrile was added and the mixture was stirred at 50-60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 16.4 g (yield 44.4%) of 5-(2-aminophenylthio)-6-chloro-1,3-diimino-4,7-di-n-octyloxyisoindoline of the following chemical formula. ##STR10##
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1

Procedure:
trans-Methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexane carboxylate (29.00 g, 93.02 mmol) was dissolved in anhydrous MeCN (930 mL), anhydrous DMF (9 mL) and POCl3 (10.4 mL, 110 mmol) and heated at 55° C. under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, then, the solid residue was taken up in DCM, then, basified to pH 10 with 2M ammonia in isopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM, and then loaded onto TEA-basified silica gel. The crude product was purified by a silica gel column chromatography (eluted with 2:3 EtOAc/DCM) to obtain the title compound as a yellow powder; 1H NMR (CDCl3, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85 (ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H), 2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt, J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH+]. HPLC: tR=2.85 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17]Cl)[C:6]2=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17][N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]2=[O:19]
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: COc1cc2ncn(CCCCl)c(=O)c2cc1OC
Solvent: CO
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCN(CCCn2cnc3cc(OC)c(OC)cc3c2=O)Cc2ccccc2)cc1OC

Procedure:
1-(6,7-Dimethoxy-4(3H)-quinazolinone-3-yl)-3-[N-benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane was prepared analogous to Example 1 (a) by reaction of 1-(6,7-dimethoxy-4(3H)-quinazolinone-3-yl)-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-benzyl amine in chlorobenzene. Rf -value (chloroform/methanol = 9.1) : 0.75.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH2:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=[CH2:5].C(O)(=[O:18])C.C(OO)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH2:36]>S(=O)(=O)(O)O.C(Cl)Cl.CO>[Cl:15][C:2]([Cl:14])([Cl:1])[CH2:3][C:4]([C:6]1[CH:7]=[C:8]([Cl:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1)([OH:18])[CH2:5][OH:36]
Reactant: CC(=O)O
Reactant: C=C(CC(Cl)(Cl)Cl)c1cc(Cl)cc(Cl)c1
Reactant: O
Agent: CC(=O)OO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: OCC(O)(CC(Cl)(Cl)Cl)c1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
α-(2,2,2-trichloroethyl)-3,5-dichlorostyrene (10.0 grams, 0.033 mole) was mixed with 75 ml. of glacial acetic acid and 10 drops of concentrated sulfuric acid and 16.5 ml. of 40% peracetic acid were added thereto. The resulting reaction mixture was heated at about 60° C., with stirring, for a period of about 72 hours. The reaction mixture was subsequently diluted with 200 ml. of water and 200 ml. of methylene chloride. The organic layer of the resulting mixture was separated and washed successively with 2-100 ml. portions of water, 2-100 ml. portions of a 10% sodium carbonate solution, 100 ml. portion of a 5% sodium bisulfite solution and another 100 ml. portion of water. The organic layer of the resulting mixture was separated therefrom, dried over sodium sulfate and the solvent removed in vacuo. The residual oil thus obtained was dissolved in about 75 ml. of methanol and 0.3 gram of p-toluenesulfonic acid were added thereto. The resulting mixture was heated under reflux conditions for a period of about 11 hours and then cooled and diluted with 200 ml. of water and 200 ml. of methylene chloride. The organic layer of the resulting mixture was separated, dried over sodium sulfate. The solvent was removed in vacuo to obtain the desired 4,4,4-trichloro-2-(3,5-dichlorophenyl)-2-hydroxybutanol product as a clear oily liquid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:19][C:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)=[S:21])[CH:17]=[CH2:18]>>[BrH:1].[CH2:16]([N:19]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:22][CH:23]1[CH2:25][CH2:24]1)[CH:17]=[CH2:18]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: C=CCNC(=S)NC1CC1
Product: Br
Product: C=CCN1C(=NC2CC2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3.1 g of 1-allyl-3-cyclopropylthiourea were reacted and worked up according to the prescription given in Example 12. Colorless, amorphous solid body: decomposition beginning at 90° C., γC=N 1600 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[CH2:39][Cl:38])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CCl)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.52 g of the compound obtained in Example 5 step B), 25 ml of DCM and 0.5 g of pyridine were mixed. 0.54 ml of chloroacetyl chloride in 10 ml of DCM was then added over 5 minutes at 20° C. The reaction mixture was stirred for 2 hours at 20° C. and then concentrated under vacuum at 20° C. The residue was extracted with AcOEt and washed with water, then with 1N hydrochloric acid and then with water. It was dried over sodium sulfate and the solvent was evaporated off to give the expected product, which crystallized from isopropyl ether. m=0.6 g. M.p.=232° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].C(N(CC)C(C)C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[C:20]=[O:21]>ClCCl.C(OCC)(=O)C>[OH:8][C@@H:4]1[CH2:5][N:6]([C:20]([NH:19][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:21])[CH2:7][C:3]1([CH3:9])[CH3:2]
Reactant: CC1(C)CNC[C@H]1O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To 200 mg (1.3 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.25 mL (1.3 mmol) of N,N-diisopropylethylamine in 4 mL of dichloromethane was added dropwise 0.19 mL (1.3 mmol) of 1-isocyanato-4-(trifluoromethyl)benzene. The reaction mixture was stirred at room temperature for 18 h. It was then diluted with ethyl acetate, and the resulting solution was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 390 mg (quantitative yield) of (4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 5.08 (s, 1H), 3.74-3.55 (m, 2H), 3.27-3.09 (m, 3H), 0.97 (s, 3H), 0.95 (s, 3H). Cl-LCMS m/z 303 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.C([O:21][C:22](=O)[C:23](=[O:34])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)C>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:22](=[O:21])[C:23]([OH:34])=[C:24]2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(Cl)c1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C1C(O)=C(c2c[nH]c3ccccc23)C(c2cccc(Cl)c2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3-Chloro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
(2-Nitro-phenyl)-acetic acid (2.0 g, 11.04 mmol), 4-amino-1-benzylpiperidine (2.25 mL, 10.03 mmol), 1-hydroxybenzotriazole (1.49 g, 11.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.3 g, 12.03 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.1 mmol) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 3.5 g (98%) of the desired product.
Reaction SMILES: CC(C)([O-:4])C.[K+].C(C([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][C:22](OCC)=O)[CH2:15]1)C)(OCC)=O.Cl>C1(C)C=CC=CC=1>[N:14]12[CH2:15][CH:16]([CH2:17][CH2:18][CH2:19]1)[C:20](=[O:4])[CH2:21][CH2:22]2
Reactant: CCOC(=O)CCC1CCCN(C(C)C(=O)OCC)C1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCN2CCCC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous potassium t-butoxide (45.8 g) in anhydrous toluene (1.0 dm3) was heated at reflux and 1-carboethoxyethyl-3-carboethoxyethylpiperidine (35.0 g) in toluene (250 ml) was added over 2 hours. Reflux was maintained for a further 4 hours before cooling to room temperature and concentrated hydrochloric acid (300 ml) was added. The mixture was stirred for 1 hour, then the organic layer was separated and extracted with concentrated hydrochloric acid (225 ml×4). The combined acid extracts were heated at reflux for 16 hours, then basified to pH 10 with potassium carbonate and extracted with chlorofeny (300 ml×6). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to an orange semi-solid (9.7 g). This was purified by chromatography (Alumina grade III) by gradient elution in 3-10% methanol in ethyl acetate. The title compound was isolated as light orange semi-solid (3.5 g). δH (360 MHz, CDCl3), 1.55 (1H, m, CHH), 1.7-1.8 (1H, m, CHH), 1.95 (2H, m, CH2), 2.4 (1H, s, CH), 2.55 (2H, m, CH2CO), 3.1-3.4 (6H, m, 3×CH2N); m/z 139 (M+) (100%).
Reaction SMILES: [C:1]1([P:7]([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.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:45]([NH:46][C:47](=[O:84])/[C:48](=[N:74]\[O:75][CH2:76][C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])/[C:49]3[N:50]=[C:51]([NH:54][C:55]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[S:52][CH:53]=3)[C:44](=[O:85])[N:26]2[C:27]=1[C:28]([O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(OCC)(=O)C>[Br-:20].[C:80]([O:79][C:77]([CH2:76][O:75]/[N:74]=[C:48](/[C:49]1[N:50]=[C:51]([NH:54][C:55]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)([C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[S:52][CH:53]=1)\[C:47]([NH:46][C@@H:45]1[C:44](=[O:85])[N:26]2[C:27]([C:28]([O:30][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:29])=[C:22]([CH2:21][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:23][S:24][C@H:25]12)=[O:84])=[O:78])([CH3:81])([CH3:82])[CH3:83]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: [Br-]
Yield: 68 %

Procedure:
A solution of triphenylphosphine (0.524 g) and diphenylmethyl (6R,7R)-3-bromomethyl-7-[(Z)-2-(t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylate (0.985 g) [prepared according to the method of UK Patent Specification No. 2036738A] in ethyl acetate (10 ml) was stirred at ambient temperature for 16 hr. During this time, a solid was deposited. This was filtered off, washed with ethyl acetate, and dried in vacuo to give the title compound (0.848 g); νmax (CHBr3) 3385, 3280 (NH), 1790 (β-lactam), 1728, 1720 (ester), 1680, 1522 cm-1 (amide).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=O>C1COCC1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CN1C(=O)COc2ccccc21
Solvent: C1CCOC1
Product: CN1CCOc2ccccc21
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 4-methyl-4H-benzo[1,4]oxazin-3-one (2.18 g, 13.37 mmol) in THF (5 mL) was added borane-tetrahydrofuran complex (4.02 g, 46.8 mmol) at room temperature. After stirring the solution for 2 h, the reaction mixture was refluxed for 4 h. After complete conversion, reaction mixture was quenched by adding MeOH (10 mL) and evaporated the solvents. The residue obtained was extracted with ethyl acetate (30×2 mL) and the organic layer was washed with water (20 mL), brine (20 mL) and evaporation of solvent gave 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH2:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2([OH:23])[CH2:19][CH2:18][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][CH:26]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:22][CH2:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(F)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To (3-chloro-4-fluorophenyl)magnesium bromide (6.8 ml of a 0.5 M solution in tetrahydrofuran, 3.4 mmol) was added a solution of 1-(3-methoxybenzyl)piperidin-4-one (500 mg, 2.28 mmol) from Step B of Example 12 in tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and then was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(3-chloro-4-fluorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (209 mg, 26%): 1H NMR (CDCl3, 500 MHz) δ 7.59-7.55 (m, 1H), 7.39-7.33 (m, 1H), 7.27-7.22 (m, 1H), 7.13-7.07 (m, 1H), 6.95-6.93 (m, 2H), 6.83-6.80 (m, 1H), 3.84 (s, 3H), 3.60-3.55 (m, 2H), 2.82-2.73 (m, 2H), 2.48-2.40 (m, 2H), 2.18-2.02 (m, 2H), 1.72-1.68 (m, 2H), 1.59-1.56 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:5])[CH3:4].[N:20]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)C1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCc2c(c3ccccc3n2CCN2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1.20g; 50% dispersion in oil) was added to a solution of 3-tert-butyl-1,2,3,4-tetrahydrocarbazole (5.68g) in dry dimethylformamide (25ml) and the mixture was heated over a steam bath for 1/2 hour. 2-Pyrrolidinoethyl chloride (3.34g) was then added, and the mixture was heated over the steam bath for a further 4 hours. Thereafter the mixture was cooled at room temperature, allowed to stand for about 16 hours, and poured into water. The aqueous mixture was extracted with diethyl ether, and the ethereal solution was evaporated in vacuo to afford 3-tert-butyl-9-(2-pyrrolidinoethyl)-1,2,3,4-tetrahydrocarbazole as an oil. The latter was distilled under reduced pressure, the principal fraction collected having a b.p. of 185°-195°C/0.05mm. mercury pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Product: CCOCCn1c(NC2CCN(CC[C@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.