Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.Cl.[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:13]([C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:15])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 4-(4-Fluorobenzoyl)piperidine hydrochloride (31.4 mg, 0.151 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.7 mg, 0.197 mmol) and triethylamine (59.8 mg, 0.591 mmol) were mixed in dichloromethane (2 ml) and stirred at room temperature over night. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H21FN2O3: 392.1536, found 392.1542.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].CCN(CC)CC.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(OCC)(=O)C>C(#N)C.[Cl-].[Na+].O>[CH3:2][O:3][C:4](=[O:8])[CH:5]([NH:6][C:16]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:23])[CH3:7]
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
(±)-Alanine methyl ester hydrochloride salt (35.2 g, 280 mmol) and Et3N (58.5 mL, 420 mmol) were sequentially added to a stirred solution of nicotinoyl chloride (19.8 g, 140 mmol) in acetonitrile (800 mL) and stirred at ambient temperature for 10 min and then 80° C. for 2 h. The reaction mixture was poured into a separatory funnel containing brine and ethyl acetate. The biphasic mixture was separated, and the organic layer was washed one time with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated in 80% ethyl acetate/hexanes overnight at ambient temperature. The solids were removed by filtration over Celite® and the filtrate was concentrated in vacuo to give the desired product as a clear brown oil (20 g, 69%): 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=2.2 Hz, 1H), 8.75 (dd, J=4.9, 1.4 Hz, 1H), 8.13 (dt, J=7.7, 1.9 Hz, 1H), 7.40 (dd, J=8.0, 4.9 Hz, 1H), 6.92 (br s, 1H), 4.82 (m, 1H), 3.81 (s, 3H), 1.55 (d, J=7.1 Hz, 3H); ESIMS m/z 209 (M+1), m/z 207 (M−1).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH:24][CH2:25][C@H:26]1[O:30][C:29](=[O:31])[CH:28]=[CH:27]1>CN(C)C=O>[Si:6]([O:24][CH2:25][C@H:26]1[O:30][C:29](=[O:31])[CH:28]=[CH:27]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C=C[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Imidazole (1.22 g, 17.6 mmol) and tert-butyl(diphenyl)silyl chloride (3.95 mL, 15.4 mmol) were added to a solution of (5S)-5-(hydroxymethyl)furan-2(5H)-one (1.60 g, 14.0 mmol) in N,N-dimethylformamide (50 mL), and the reaction mixture was stirred at room temperature for 18 hours. It was then partitioned between tert-butyl methyl ether and water; the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 5% to 30% ethyl acetate in heptane) afforded the product as a white solid. Yield: 5.20 g, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.63-7.66 (m, 4H), 7.38-7.49 (m, 7H), 6.19 (dd, J=5.7, 2.0 Hz, 1H), 5.06-5.10 (m, 1H), 3.93 (dd, half of ABX pattern, J=10.9, 4.5 Hz, 1H), 3.88 (dd, half of ABX pattern, J=10.8, 5.0 Hz, 1H), 1.05 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([N:24]([CH3:25])[C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNC1CCCN(Cc2ccccc2)C1
Reactant: Clc1ccnc2[nH]ccc12
Product: CN(c1ccnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Temperature: 200 °C
Yield: 130 %

Procedure:
A sealed melted mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.18 g, 0.0012 mol) in 1-benzyl-N-methylpiperidin-3-amine (0.50 g, 0.0024 mol) was heated to 200° C. overnight. The reaction mixture was partitioned between ethyl acetate (30 mL) and sat. NaHCO3 (20 mL), and the organic phase was washed with sat. NaCl, then dried and was reduced under vacuum to give 500 mg of orange oil. The product was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 192 mg of an orange oil (48.8% yield).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CC(=O)Cl
Reactant: c1ccoc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccco1

Procedure:
Acryloyl chloride (0.45 g), furan (0.34 g), and AlCl3 (0.66 g) were reacted in CH2Cl2 at −60° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH:22]=[CH:23][CH2:24]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][CH:23]=[CH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1CC=Cc1ccccc1
Yield: 88.6 %

Procedure:
To a suspension of 16.5 g (100 mmoles) of 4,5-dichloro-3(2H)-pyridazinone and 150 g (163 mmoles) of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide a solution of 16.8 g (110 mmoles) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide is dropped under stirring and cooling at a temperature below 15° C. The reaction mixture is stirred at room temperature for a day and poured onto 600 ml of water under stirring. The separated crystals are filtered, washed with water, dried and optionally purified by treating with aluminium oxide in a benzene solution. Thus 24.9 g (89%) of the desired compound are obtained. M.p.: 98°-99° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2].[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: COCCOCCl
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Reaction time: 8 h
Yield: 84.5 %

Procedure:
1 g of (75) was dissolved in 25 ml THF. 250 mg NaH was added, and then 1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was left with stirring overnight, another 100 mg NaH was added, and the reaciton continued another 4 hours. The reaction mixture was added to a 2N K2 CO3 solution and extracted with toluene. The organic phase was washed with water and brine, dried and evaporated. The resulting oil was extracted twice with boiling heptane, cooled, filtered, and evaporated giving 1.23 g of (80) as a yellow oil. 1H-NMR (ppm): 8.35(m, 1H); 7.44(m, 1H); 7.27(m, 2H); 5.62(s, 2H); 3.58(m, 2H); 3.47(m, 2H); 3.32(s, 3H); 2.65(s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:19]=[N+:20]=[N-:21])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(Cl)Cl.O>[N:19]([CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)=[N+:20]=[N-:21]
Reactant: Cc1ncc(CO)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ncc(CN=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (2-methylpyrimidin-5-yl)methanol (0.82 g, 6.6 mmol) in toluene (30 mL) and methylene chloride (40 mL) at 0° C. was treated with diphenylphosphonic azide (2.8 mL, 13 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 mL, 13 mmol) and stirred at 0° C. for 2 h. After being further stirred at rt for 16 h, the reaction mixture was diluted with water (50 mL) and methylene chloride (50 mL). The organic layer was separated and washed with brine, dried (Mg2SO4), filtered, and concentration. The residue was purified by silica gel column to yield a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:27])=O)C=CC=CC=1>CN(C=O)C>[NH2:27][N:7]1[C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH:2]1[CH3:1]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-methyl-5-oxo-1-piperazinecarboxylate (1.1 g) was dissolved in DMF (20 ml) and treated with sodium hydride (0.25 g, in oil) with cooling on ice. After stirring at 50° C. for 1 hour, O-diphenylphosphinyl hydroxylamine (1.3 g) was added and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain tert-butyl 4-amino-3-methyl-5-oxo-1-piperazinecarboxylate as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N:11]2[C:15]([CH2:16][CH3:17])=[C:14]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[OH:29])[C:13]([CH2:30][CH3:31])=[N:12]2)=[C:6]([CH3:32])[CH:5]=1.I[CH2:34][CH3:35]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH3:32])[C:7]([N:11]2[C:15]([CH2:16][CH3:17])=[C:14]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[O:29][CH2:34][CH3:35])[C:13]([CH2:30][CH3:31])=[N:12]2)=[C:8]([CH3:10])[CH:9]=1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1Cc1c(O)ccc2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.337 g, 8.4 mmol) was added portionwise to a solution of 1-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-naphthalene-2-ol (1.30 g, 8.4 mmol) in 12 ml anhydrous tetrahydrofuran. After stirring 5 minutes, iodoethane (1.12 ml, 14 mmol) was added, and the resulting reaction mixture was stirred 16 hours at ambient temperature. The solvent was removed in vacuo, and the residue was then extracted with methylene chloride/water (25 ml of each). The aqueous phase was twice extracted with 25 ml portions of fresh methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an oily solid (1.92 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes =6:94 in volume) afforded 1.1 g of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].ClCCl.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:6][O:7][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH2:8][O:9][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC(CO)(CO)CC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CC(C)C
Temperature: 0 °C

Procedure:
0.9 g of 2,2-diisobutyl-1,3-propandiol was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, thereto was added 2.0 ml of triethyl amine, followed by the addition of 1.58 ml of trimethylsilyl chloride. The mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.45 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][O:15][CH:14]([CH3:17])[CH2:13]1.CC1CC(O)CO1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:16][O:15][CH:14]([CH3:17])[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CC1CC(N)CO1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: CC1CC(O)CO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC2COC(C)C2)c1Cl
Temperature: 85 °C

Procedure:
1.5 g of 4,5-dichloro-6-ethylpyrimidine (8.5 mmol), 0.86 g (8.5 mmol) of 4-amino-2-methyltetrahydrofuran (prepared from 2-methyltetrahydrofuran4-ol analogously to the route given for Example A) and 2 ml (14 mmol) of triethylamine were heated for 6 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (8:2, 7:3). This gave 1.73 g (84% of theory) of a colorless oil (diastereomers 2:1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:21]=3)=[CH:18][C:17]([C:33]([F:36])([F:35])[F:34])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:21]=3)=[CH:18][C:17]([C:33]([F:35])([F:36])[F:34])=[N:16]2)=[CH:13][CH:14]=1
Reactant: NC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of N-(2-{4-[l-[4-(benzyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea obtained by Example 80 (10.33 g) in methanol (100 ml) was added palladium on carbon (10% wet, 2 g), and the mixture was stirred vigorously at room temperature under hydrogen atmosphere for 3 hrs. The whole mixture was filtered and evaporated to give oil (8.23 g). The oil was purified with silica gel column chromatography [250 ml, 3% methanol/chloroform (500 ml), 5% methanol/chloroform (500 ml), and 10% methanol/chloroform (500 ml)] to give the target compound (8.07 g, 95.4%) as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.[CH:15]1([C:18]#[CH:19])[CH2:17][CH2:16]1.[Cl-].[NH4+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH:15]1([C:18]#[C:19][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#CC2CC2)cc1
Temperature: 110 °C
Reaction time: 0.02 h

Procedure:
To a mixture of 4-bromobenzaldehyde (2.00 g), bis(triphenylphosphine)palladium(II) dichloride (228 mg), copper(I) iodide (20.6 mg), N,N-dimethylformamide (2.00 mL) and triethylamine (15.1 mL), cyclopropylacetylene was added and thereafter the mixture was stirred in a sealed tube at 110° C. for one minute under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with a liquid mixture of n-hexane/ethyl acetate (1:1) three times. The combined organic layers were washed with saturated brine and dried over added anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) to give 4-(cyclopropylethynyl)benzaldehyde as a brown oil (1.79 g).
Reaction SMILES: C([O-])(=O)C.[Na+:5].C(O)C.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:37])[C:27]([C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:28][O:29][CH3:30])[C:23](=[O:38])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[CH3:10]>O>[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:37])[C:27]([C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:28][O:29][CH3:30])[C:23](=[O:38])[N:18]2[C:19]=1[C:20]([O-:22])=[O:21])(=[O:11])[CH3:10].[Na+:5]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 6 g of sodium acetate in 20 ml of water was added with stirring at 20° C. to 50 ml of 98% ethanol and with continued stirring 25 g of an ethanol solvate of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid were added thereto. After dissolution occured, the solution was cooled to 0° C. and 50 ml of 98% ethanol were added thereto dropwise with stirring. Activated carbon was added to the solution which was then filtered and the filtrate was heated to 20° C. Crystallization spontaneously occured shortly thereafter and filtration by aspiration was effected at room temperature 16 hours later. The recovered product was washed with a 1-7 water-ethanol mixture, with ethanol and then with ether to obtain colorless crystals of the D form of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4 -carboxylate which after drying under reduced pressure contained 4.8% of water (by Fischer). The spectrum of X-ray diffraction and the infrared spectrum in nujol confirmed the D form.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH2:39])=[S:38])=[N:20]1.N>O1CCOCC1.O>[CH2:9]([O:8][C:6]([C:5]1[S:38][C:37]([NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2/[CH:29]=[CH:28]/[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)=[N:39][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC=CC(=O)OCC
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: N
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
Ethyl 3-ethoxyacrylate (0.22 mL, 1.5 mmol) was dissolved in dioxane (4.0 mL) and water (4.0 mL) and after cooling to −10° C., the solution was added with N-bromosuccinimide (0.29 g, 1.6 mmol), followed by stirring at room temperature for 1 hour. The mixture was added with Compound 161 (0.40 g, 1.4 mmol), followed by stirring at 80° C. for 1 hour. The reaction mixture was added with aqueous ammonia to stop the reaction. The precipitated crude product was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2) and triturated in ethyl acetate to obtain Compound 165 (45 mg, 8%).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:11]([OH:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:11]([OH:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCC[C@H](NCC(O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1CCCC[C@H](NCC(O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O

Procedure:
A solution of the phenylmethyl ester product from part (a) (2.0 mmole) in 95% ethanol (50 ml.) containing 10% palladium on carbon catalyst (0.2 g.) is hydrogenated under atmospheric pressure overnight. The catalyst is filtered, washed with 95% ethanol and the filtrate concentrated under reduced pressure into an oily residue which is then treated for 5 minutes with 1.4N hydrochloric acid/acetic acid (10 ml.). The reaction mixture is concentrated under reduced pressure to yield a solid residue. The crude product is purified on an HP-20 column (5% methanol/0.01N hydrochloric acid→90% methanol/0.01N hydrochloric acid) to give (S)-3-[[3-(benzoylamino)-2-hydroxy-4-phenylbutyl]amino]-hexahydro-2-oxo-1H-azepine-1-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCOCCC1CCCCC1)C(=O)OCC

Procedure:
11.2 g of 6-(2-cyclohexylethoxy)-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example 1b from 16.5 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid ethyl ester, 1.97 g of paraformaldehyde, 12 ml of pyridine and 0.7 ml of piperidine.