Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[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][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:57])[NH:26][CH:27]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:72]1[C:77](=[O:78])[CH2:76][CH2:75][C:73]1=[O:74])=[N+](C)C)C.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6](=[O:58])[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][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:57])[NH:26][CH:27]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46]([O:48][N:72]1[C:77](=[O:78])[CH2:76][CH2:75][C:73]1=[O:74])=[O:47])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.7 %

Procedure:
19-{1-tert-Butoxycarbonyl-3-[2-(2-{2-[2-(2-carboxyethoxy)ethoxy]ethoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (0.68 g crude solution in THF 40 mL, 0.82 mmol) and TSTU (0.296 g, 0.982 mmol) were mixed, pH was adjusted by addition of DIPEA (0.171 mL) and the resulting mixture was stirred at RT overnight. This resulted in a clear solution which was evaporated to dryness and treated with diethylether, which afforded 1.2 g of the title compound as a waxy mass which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24]O)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:28])=O>CC#N>[Cl:28][CH2:24][C:15]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH3:11])[CH3:10])=[CH:13][N:14]=1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CO)n1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of (5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methanol (402 mg, 1.06 mmol) in CH3CN (6 mL) at 0° C. was added thionyl chloride. After stirring 3 h, the solution was concentrated under reduced pressure, and azeotroped with DCM (3×) to give 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a yellow solid (420 mg) that was used directly for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1.N1C=CC=CC=1>[CH3:7][C:4]1[CH:3]=[C:2]([NH:1][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][N:5]=1
Reactant: Cc1cc(N)on1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(NC(=O)Oc2ccccc2)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
5-Amino-3-methylisoxazole (1 g) purchased from Aldrich Co. was dissolved in tetrahydrofuran (40 ml) and pyridine (1.5 ml), and after cooling to 0° C. under a nitrogen atmosphere, phenyl chlorocarbonate (1.4 ml) was added and the mixture was stirred at room temperature for 1.5 hours. Water was added, extraction was performed twice with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and n-hexane to obtain the title compound (450 mg, 20% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]2=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:23][CH3:24].[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH2:23]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:19])[CH3:24]
Reactant: O=c1[nH]c2cccnc2n1-c1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc([N+](=O)[O-])cc2)c2ncccc21

Procedure:
The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (10.0 g), 4-nitroaniline (8.0 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2 g) and sodium tert-butoxide (12.5 g) in toluene (160 mL)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) as a light brown solid. A mixture of 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.50 g), sodium hydride (0.400 g) and iodoethane (2.0 mL) in DMF (40 mL) was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a brown solid. A mixture of 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.00 g) as a brown solid.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][C:9]2([OH:12])[C:4]3([CH3:16])[CH2:5][CH2:6][CH:7]([CH2:15][CH:3]13)[C:8]2([CH3:14])[CH3:13].C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:13][C:8]1([CH3:14])[C:9]2([OH:12])[CH2:10][CH:11]=[CH:2][CH:3]3[CH2:15][CH:7]1[CH2:6][CH2:5][C:4]23[CH3:16]
Reactant: CC1(C)C2CCC3(C)C(C2)C(=O)CCC13O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C2CCC3(C)C(C=CCC13O)C2
Temperature: 25 °C
Yield: 66 %

Procedure:
9.3 mg of N-toluenesulphonylhydrazide was added to a solution of 11.1 mg of 1,2,3,4,4a,5,6,7,8,8a-decahydro-2-oxo-4a-hydroxy-5,5,8a-trimethyl-1,6-methanonaphthalene in hot acetic acid. The mixture was refluxed for 10 minutes, subsequently poured into saturated aqueous NaHCO3 solution, extracted with CH2Cl2 and evaporated. The solution of the residue in 4 ml of ether was treated slowly at 25° C. with a 1-N solution of methyllithium in ether (0.225 ml), then stirred at 25° C. under argon, then poured into water and extracted with CH2Cl2. Chromatography (SiO2 /CH2Cl2) and sublimation at 100°-120° C. gave (+)-norpatchoulenol (m.p. 135°-141° C., 6.8 mg, 68% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1.O>[NH:1]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 10 g (0.086 mol) of valine and 3.4 g (0.086 mol) of NaDH in 250 ml of dioxan: H2O (2:1) mixture was slowly added 20.5 g (0.094 mol) of ditertbutylcarbonate at 0° C. with vigorous stirring. The reaction mixture was then stirred for another hour at room temperature, dioxan was removed under reduced pressure, and BOC-Val-OH was obtained by acidifying the mixture to a pH of 2-3. The raw product consisting of 18 g of viscous oil was obtained after evaporating the solvent from the ethyl acetate extracts.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[O:19][CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2c(=O)n1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(OC)c2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
A suspension of ethyl 6-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.41 g, 5 mmol), methyl iodide (0.47 ml, 7.5 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.11 g, 75.5%) as crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([O:25][C@@H]7O[C@H](CO[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@@H](O[C@@H]8O[C@@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O[C@@H]6O[C@H](CO[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@@H](O[C@@H]7O[C@@H](C)[C@H](O)[C@@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Yield: 89.5 %

Procedure:
100 Parts of crude sarsasaponin is suspended in 255 parts of ethyl acetate and heated at reflux for 0.5 hour. The mixture is filtered hot and the filter cake washed with 89 parts ethyl acetate and dried. The dried residue is mixed with 1850 parts by volume of a 15% (v/v) solution of concentrated hydrochloric acid in water and heated at 95°-101° C. for 2 hours. The hot reaction mixture is then filtered to give a precipitate which is washed with water and dried to afford crude sarsasapogenin in an 89.5% yield. This crude material is treated with 50 parts alumina and 5 parts carbon in 440 parts toluene. Filtration affords a pale yellow solution, which upon standing, yields a solid. This solid is filtered, and recrystallized from hot n-hexane to give sarsasapogenin melting at about 200°-205° C. This compound exhibits an [α]D25 = -78.8° ±1.5 (c=0.996% in chloroform), an [α]36525 = -230.9° ±1.5 (c=0.996% in chloroform), and is represented by the following structural formula. ##STR1##
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][C:22]5([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.[OH-].[Li+].C(O)C.O>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:24][CH2:23][C:22]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 31.2 %

Procedure:
The mixture of (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)oxazolidin-2-one (324 mg, 0.000823 mol) and lithium hydroxide (294 mg, 0.0123 mol) in ethanol (7.1 mL, 0.12 mol) and water (2.4 mL, 0.13 mol) was heated to reflux for overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography purification with MeOH/CH2Cl2 (10:90 to 80:20) to give the product (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-1-ol as a white powder (94.5 mg, 31.2%). LCMS Rf=1.70 min 351.34 ([M-NH2]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.86 (d, J=1.6 Hz, 1 H), 7.78 (d, J=9.0 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.57 (dd, J=2.0, 8.7 Hz, 1 H), 7.22 (d, J=2.1 Hz, 1 H), 7.14 (dd, J=2.4, 8.9 Hz, 1 H), 4.53-4.44 (m, 1 H), 3.75 (d, J=11.0 Hz, 1 H), 3.70 (d, J=11.0 Hz, 1 H), 2.01-1.88 (m, 2 H), 1.80-1.65 (m, 4 H), 1.55 (s, 3 H), 1.50 (m, 8 H), 1.42-1.30 (m, 4 H).
Reaction SMILES: COC[CH2:4][O:5][CH2:6][CH2:7][NH2:8].[CH3:9][C@@H:10]1[CH2:12][C@H:11]1[C:13](O)=O>>[CH3:4][O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH3:13]
Reactant: COCCOCCN
Reactant: C[C@@H]1C[C@H]1C(=O)O
Product: COCCNCC1CC1C

Procedure:
Prepared from 2-(2-methoxyethoxy)ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylate (366 mg, 0.81 mmol) in a mixture of MeOH (30 ml) and THF (10 ml) was added 10 ml of 1M aq. NaOH solution and the solution was stirred for 18 hours at room temperature. The solvents were reduced in vacuo, and it was extracted using 1M HCl/EtOAc/THF. The organic layers were washed with brine and dried with Na2SO4, and the solvents were removed in vacuo to give the crude product which was used without further purification (200 mg, 62%). 1H-NMR (500 MHz, DMSO-D6): δ=9.33 (s, 1H), 8.11 (s, 1H), 7.69-7.68 (d, 1H), 7.35-7.33 (dd, 1H), 6.67-6.65 (d, br, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:30])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccccc1/C=C/C(=O)O
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3C)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:9].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].[Cl-].[NH4+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([C:10]1([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([N:24]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[CH2:22][CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:9]
Reactant: CCC1(CCN2CCC(Nc3ccc(C)cn3)CC2)CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Triethylamine (1.33 mL, 9.55 mmol) was added to a solution of 1-[2-(1-ethylcyclohexyl)ethyl]-4-(5-methylpyridin-2-yl)aminopiperidine (1.31 g, 3.98 mmol) in methylene chloride (13 mL). After adding 2-furoyl chloride (0.47 mL, 4.78 mmol) while cooling on ice, the mixture was stirred for 2 hours. A 25% aqueous ammonium chloride solution was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (80 g NH silica Chromatorex DM2035, hexane:ethyl acetate=2:1) to obtain the title compound as a light yellow solid (1.52 g, 3.59 mmol) (90% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1.C(OC(=O)C)(=O)C>CS(C)=O>[O:1]=[C:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@H](O)CS[C@H]12
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(3S,6R,7R)-3-Hydroxy-7-phenylacetamidocepham (29 mg.) in dimethylsulphoxide (1 ml.) was treated with acetic anhydride (0.2 ml.) After being kept at 24° for 16 hour the reaction mixture was partitioned between brine and ethyl acetate. Removal of the ethyl acetate gave (6R,7R)-3-keto-7-phenylacetamidocepham (22 mg.). T.1.c. and g.1.c. data were in agreement with those obtained on material prepared in Example 3a. EXAMPLE 3d
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-:25].[Na+]>>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([C:10]([C:6]([C:7]4[CH:8]=[CH:9][CH:13]=[CH:14][CH:15]=4)=[O:25])=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:18][CH3:19]
Reactant: [OH-]
Reactant: CCCN(CCC)C1Cc2cc3cc[nH]c3cc2C1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1Cc2cc3[nH]cc(C(=O)c4ccccc4)c3cc2C1
Temperature: 85 °C
Yield: 100 %

Procedure:
A mixture of dipropyl-(1,5,6,7-tetrahydro-1-aza-s-indacen-6-yl)amine (31 mg, 0.12 mmol) N,N-dimethylbenzamide (36 mg, 0.24 mmol) and phosphorous oxychloride (14 μL, 23 mg, 0.15 mmol) was heated at 85° C. overnight. After cooling, 3M sodium hydroxide (4 mL) was added and the resulting mixture was heated at 85° C. for 1 hour. The mixture was cooled and extracted (ethyl acetate) three times. The organic solution was dried (magnesium sulfate), filtered and evaporated to yield 46 mg (100%) of the desired material.: MS m/z (relative intensity, 70 eV) 360 (M+, 12), 331 (100), 105 (38), 260 (31).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[CH2:15][O:14][CH2:13]C1>>[C:1]([O:5][CH2:6][CH:7]([O:10][CH2:11][CH2:15][O:14][CH3:13])[CH2:8][O:9][CH2:2][CH2:1][O:5][CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCC(O)CO
Reactant: C1CCOC1
Product: COCCOCC(COC(C)(C)C)OCCOC

Procedure:
Compound 21 (31.0 g, 0.135 mol.) was added to a slurry of the di-sodium salt of 3-tert-butoxy-1,2-propane diol, (0.062 mol.), 17, in refluxing in dry THF (500 ml). The reaction mixture was stirred, heated and maintained at reflux under an atmosphere of dry nitrogen for 24 hours. The mixture was allowed to cool and filtered and the solvent was removed by evaporation under vacuum. The residue was extracted with chloroform, dried (MgSO4) filtered and solvent removed by vacuum rotary evaporation to yield a brown liquid (17.0 g). The crude product was washed with water (250 ml) and extracted with chloroform (300 ml). The organic fraction was separated from the aqueous and dried (MgSO4) filtered. The solvent was removed by rotary evaporation under vacuum to give a pale yellow oil (15.0 g, 94%). The crude product was distilled (bpt. 120°-125° C., 0.25 torr) to give a colorless oily liquid (11.1 g, 67%): IR 2975, 2875 (CH) cm-1, 1198 (COC) cm-1, 1108 (COC) cm-1, 1H-NMR (CDCl3), d (ppm) 3.3-3.85 (m, 19H), 1.3 (s, 9H, tert-butyl), 13C-NMR (CDCl3), d, (ppm) 78.95, 72.94, 72.21, 71.92, 71.74, 70.64, 69.69, 61.73, 58.98, 58.8, 27.43. Mass spectroscopy, m/e: 264 M+ ; 208 (M-C(CH3)3)+ base peak.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH:11]([CH2:10]/[CH:9]=[CH:8]/[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](O)([CH3:19])[CH3:18])=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][N:13]=1)=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([CH3:19])=[CH2:18])=[C:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)c1c(OCCN)noc1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1-hydroxyisopropyl)-5-phenylisoxazole (0.13 g) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution (10 ml), and the solution was stirred at 100° C. for one hour. After the reaction, the reaction mixture was left to be cooled, followed by evaporation of the solvent under reduced pressure. The residue was washed with ethyl acetate to obtain the title compound (0.10 g, 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[N:6]([CH2:10][CH2:11]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:16]>O>[Br:16][CH2:11][CH2:10][N:6]1[C:5]2[CH:13]=[C:14]([Cl:15])[C:2]([Cl:1])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Br
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCO
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCBr
Yield: 87 %

Procedure:
A mixture of 55 parts of 5,6-dichloro-1,3-dihydro-1-(2-hydroxyethyl)-2-H-benzimidazol-2-one and 450 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 4 hours. The reaction mixture is poured onto ice-water and stirred to room temperature. The precipitated product is filtered off, stirred in water, filtered off again and dried, yielding 55.5 parts (87%) of 1-(2-bromoethyl)-5,6-dichloro-1,3-dihydro-2H-benzimidazol-2-one.