Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][C:43]#[N:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][C:43]#[N:44])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: N#CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC#N)CC1
Product: Cl

Procedure:
{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetonitrile hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and piperazin-1-yl-acetonitrile (example 16h) in an analogous manner as described in example 25. LR-MS: 618.5 [(M+H)+]
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([SH:19])[CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([S:19][C:4]2[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][N:12]=2)[CH2:15]1
Reactant: CN1CCC(S)C1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2ncccc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 80 g (2 mole) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylforamide, all heated to 60° C. and using nitrogen gas flow was added dropwise, a solution of 157.0 g (1 mole) of 2-chloronicotinic acid and 117 g (1 mole) of 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a rate which maintained a temperature of 60°-67° C. The mixture was heated to 65° C. for 6 hr and allowed to stand overnight at room temperature and then filtered. The collected solid was suspended in one liter of isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a pH of 6.2 was reached. The mixture was brought to a boil and filtered. The solid was dissolved in 2 liters of water and extracted with isopropyl ether. The pH was adjusted to 6.0 and the solution was concentrated to a volume of 800 ml and placed in a refrigerator. The resulting solid (85 g) collected by filtration, was a mixture consisting of about 85% of the title compound and 15% sodium chloride. A sample portion of this was crystallized once from ethanol and twice from isopropyl alcohol-water. The recrystallized product decomposed at about 225° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.C(OCC)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][O:19][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](CO)CC[C@@H]2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](COc3ccc(F)cc3)CC[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A solution of 0.39 g (1.4 mmol) of (7S,9aR)-2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.24 g (2.2 mmol) of 4-fluorophenol and 0.45 g (1.7 mmol) of triphenyl phosphine in 20 mL of dry THF was treated with 0.27 mL (1.7 mmol) of diethyl azodicarboxylate, and stirred at ambient temperature for 16 h. The solution was diluted with ethyl acetate and treated with, excess HCl(g) in ethyl ether. The solvent was evaporated and the white, solid residue was washed with 1:1 ethyl acetate:ethyl ether. The solid remaining was :dissolved in chloroform and washed with 1M NaOH, dried (magnesium sulfate), filtered and evaporated to give 0.45 g of (7S,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:11][C:8]=2[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(C(C)=O)CC2
Reactant: O=S(=O)(O)Cl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Temperature: 0 °C

Procedure:
3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) was added to chlorosulfonic acid (6 ml) which was stirred at 0°; the mixture was allowed to warm to 25° and stirred for 16 hours. The reaction was carefully poured into ice water and extracted with methylene chloride. The methylene chloride extracts were combined, washed, dried with magnesium sulfate and concentrated in vacuo to give 3-acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 153°-160°.
Reaction SMILES: CO.[CH2:3]([C:7]1[N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:50]=[N:49][N:48]=3)=[CH:37][CH:36]=2)[C:9]([C:13]([O:15][CH:16]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][C@@H:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])[CH3:17])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]>ClCCl>[CH2:3]([C:7]1[N:8]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:51][N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:9]([C:13]([O:15][CH:16]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][C@@H:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])[CH3:17])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A methanol (5 mL)/dichloromethane (5 mL) solution of 1-{[(5R)-5,6-bis(nitrooxy)hexanoyl]oxy}ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (713 mg, 0.756 mmol) was heated by microwave irradiation (120° C., 10 minutes). Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. Chromatography of the diastereomeric mixture over Chiralpak AD-H, eluting with methanol/carbon dioxide, afforded the separate diastereomers.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:32]#[C:31][CH2:30][CH:29]([C:25]4[O:24][CH:28]=[CH:27][CH:26]=4)[OH:33])[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCC(O)c1ccco1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccco3)oc21

Procedure:
Analogous to the procedures described in Example 88, 2-bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 79) is treated with 1-(2-furyl)but-3-yn-1-ol (Preparation 74) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27]O)[C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:60]([CH2:27][C:26]1[C:21]2[S:20](=[O:29])(=[O:30])[N:19]=[C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[CH:8]4[CH:13]([C:14]=3[OH:31])[CH:12]3[CH2:32][CH:9]4[CH2:10][CH2:11]3)[NH:23][C:22]=2[S:24][CH:25]=1)=[N+:61]=[N-:62].[N:60]([CH2:27][C:26]1[C:21]2[S:20](=[O:29])(=[O:30])[N:19]=[C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)[NH:23][C:22]=2[S:24][CH:25]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)C3C4CCC(C4)C3N(Cc3ccc(F)cc3)C1=O)N2
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-hydroxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.38 g, 0.76 mmol) in dichloromethane (9 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL, 4.03 mmol) and diphenylphosphoryl azide (0.84 mL, 3.88 mmol). The reaction was stirred at 25° C. overnight. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, (1R,2S,7R,8S)-5-(7-azidomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.21 g, 0.40 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.56-2.57 (1H, m), 2.82-2.87 (2H, m), 3.47 (1H, d, J=9.6 Hz), 4.21 (1H, d, J=14.8 Hz), 4.67 (2H, s), 5.15 (1H, d, J=14.4 Hz), 7.00-7.07 (2H, m), 7.19-7.23 (2H, m), 7.32-7.36 (1H, m).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.N1CCCCC1>C(O)C>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccs1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccs2)S1
Yield: 66.5 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 16.0 ml (171 mmol) of 2-thiophenecarboxaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 24.03 g of the desired compound (66.6% yield, pale yellow crystals).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.[CH:61]([N:64](CC)C(C)C)(C)[CH3:62].O(C(C)C)C(C)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:64][C@H:61]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH3:62])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a suspension of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (100 mg, 0.19 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (68 mg, 0.21 mmol) in DMSO (1 mL) was added S-(−)-α-ethylbenzylamine (25 μL, 0.19 mmol) and N,N-diisopropylethylamine (67 μL, 0.38 mmol) dropwise at room temperature under N2. The mixture was stirred at room temperature for 1 hour under N2, and then poured into H2O (20 mL) under stirring. The resulting precipitate was extracted with AcOEt (20 mL). The organic layer was washed with H2O (3 times) and 10% NaHCO3, dried over MgSO4, and evaporated to give yellow amorphous. The oily residue was separated by silica gel column chromatography (AcOEt/n-hexane=10/1) to give pale yellow amorphous, which was solidified by the treatment of i-Pr2O. The resulting solid was collected by filtration, washed with i-Pr2O, and dried at 40° C. for 3 days under reduced pressure to give the title compound as pale yellow crystal (92 mg, 77%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (d, J=7.0 Hz, 6H), 1.45 (d, J=7.3 Hz, 3H), 1.47 (s, 9H), 3.22 (septet, J=7.0 Hz, 1H), 5.16 (quintet, J=7.3 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 7.17-7.25 (m, 1H), 7.26-7.40 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.74 (br-d, J=8.4 Hz, 1H), 7.93 (br-s, 1H), 8.57 (s, 1H), 8.81 (d, J=7.3 Hz, 1H), 8.84 (d, J=8.5 Hz, 1H), 9.58 (s, 1H), 10.19 (s, 1H) MS ESI+ m/z: 635 (M+H)
Reaction SMILES: C(OC([NH:11][C@H:12]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]C(OCC2C=CC=CC=2)=O)=[C:16](I)[CH:15]=1)=O)C1C=CC=CC=1.[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=CC=1.C1CCCC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CO.CCOC(C)=O.CCCCCC>[CH:42]1([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[OH:20])[CH2:13][C@@H:12]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH2:11])[CH2:43][CH2:44][CH2:39][CH2:45]1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(=O)OCc2ccccc2)c(I)c1)NC(=O)OCc1ccccc1
Agent: C1=CCCC1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(C2CCCC2)c1
Temperature: 110 °C
Yield: 93 %

Procedure:
A 300 mL Parr bomb was charged with 5.13 g of tert-butyl N-((benzyloxy)carbonyl)4-O-((benzyloxy)carbonyl)-3-iodo-L-tyrosinate, 120 mL of toluene, 30 mL of cyclopentene and 0.49 g of tri-ortho-tolylphosphine. The solution was deoxygenated by bubbling nitrogen through for 10 min and was treated with 0.182 g of Pd(OAc)2 and 1.24 nL of Et3N. The bomb was flushed with nitrogen, sealed, and heated to 110° C. for 48 h. The vessel was cooled to RT, purged with nitrogen and opened. The reaction mixture was filtered to remove solids and the filtrate was concentrated in vacuo to dryness. The residue was dissolved in 200 mL of EtOAc and the solution was washed with water (4×100 mL), dried over anhydrous NaSO4 and concentrated to give a thick brown oil. Analysis by tlc (SiO2, 8:2 hexane:EtOAc) indicated two major componenets at Rf=0.50 and 0.40. The crude mixture was subjected to flash chromatography on silica gel (8:2 hexane:EtOAc). This afforded 2.0 g (43%) of the Rf=0.50 material identified as the bis(benzyloxycarbonyl) olefin mixture by 1H-NMR. In addition, 0.90 g (25%) of the Rf=0.40 material was obtained and was identified as the N-benzyloxycarbonyl olefin mixture resulting from loss of the O-benzyloxycarbonyl group. The bis(benzyloxycarbonyl) olefin mixture (2.00 g) was subjected to catalytic hydrogenation (45 psi) in the presence of 0.35 g of 10% Pd(C) in 70 mL of MeOH for 18 h. The crude product was purified by flash chromatography (SiO2, EtOAc) to give 0.99 g (93%) of tert-butyl 3-cyclopentyl-L-tyrosinate as a transparent glass. The N-benzyloxycarbonyl olefin mixture (0.90 g) was similarly hydrogenated and purified to afford 0.52 g (83%) of tert-butyl 3-cyclopentyl-L-tyrosinate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23](C)[CH3:24])=[O:22])[CH2:16][CH2:15]1.[CH2:26](N)[CH2:27]C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:26][CH3:27])=[O:22])[CH2:18][CH2:19]1
Reactant: CCCN
Reactant: CN(C)C(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Product: CCCNC(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1

Procedure:
The title compound was synthesized following the method described for 2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide (43), using propylamine. Rt=0.98 min (Method B). Detected mass: 378.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([CH2:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([C:13]3[CH:14]=[C:15]([Cl:20])[C:16]([Cl:19])=[N:17][CH:18]=3)=[O:12])=[CH:9][CH:8]=2)=[C:4]([Cl:26])[CH:3]=1.[N:27]([O-])=O.[Na+].Cl[Sn]Cl.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:34](=[N:27][NH:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11](=[O:12])[C:13]3[CH:14]=[C:15]([Cl:20])[C:16]([Cl:19])=[N:17][CH:18]=3)=[CH:21][CH:22]=2)=[C:4]([Cl:26])[CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=Cc1ccccc1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)c(Cc2ccc(C(=O)c3cnc(Cl)c(Cl)c3)cc2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: O=C(c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1)c1cnc(Cl)c(Cl)c1
Yield: 98.2 %

Procedure:
The title compound was prepared as yellow crystals at yield of 98.2%, in a similar manner as in Reference Example 13, by the reaction of 5-[4-(4-amino-2,6-dichlorobenzyl)benzoyl]-2,3-dichloropyridine, NaNO2, SnCl2 and benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)([CH3:13])=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:7]1[C:2]([NH:20][C@H:17]2[CH2:18][CH2:19][C@@H:14]([C:11]([CH3:13])=[CH2:12])[CH2:15][CH2:16]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: C=C(C)C1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Temperature: 25 °C

Procedure:
1.6 g (0.009 mol) of 4,5-dichloro-6-ethylpyrimidine and 1.2 g (0.009 mol) of 4-isopropenylcyclohexylamine were stirred with 1.8 g (0.013 mol) of K2CO3 in 10 ml of DMF at 80° C. for 6 hours. After cooling to room temperature, the mixture was placed in water and extracted with ether. The organic phase was washed with water, dried and filtered, and the filtrate was chromatographed on silica gel with petroleum ether/ethyl acetate 7:3 in order to separate the cis/trans isomers.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:12][OH:13])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:12][OH:13])=[C:8]([CH2:10][O:11][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(CO)n1Cc1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(CO)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-4,5-bis(hydroxy)methyl-1H-imidazole (Example 1(ii)) (310 mg, 1 mmol) in methylene chloride (5 mL) was treated with 4-dimethylaminopyridine (5.2 mg), triethylamine (1.5 mmol) and t-butyl dimethylsilyl chloride (192 mg, 1.24 mmol). The mixture was stirred at 25° C. for 20 hours, diluted with water and the organic layer was washed well with water, dried, concentrated and chromatographed over silica gel with an ethyl acetate/methanol gradient to afford 127 mg (24%) of the bis (4,5-t-butyldimethylsilyl) ether and 252 mg (59%) of 2-n-butyl-1-(2-chlorophenyl)methyl-4-t-butyldimethysilyloxymethyl-5-hydroxymethyl-1H-imidazole. This monoether (252 mg) was oxidized to the 5-carbox-aldehyde using manganese dioxide as described in Example 1(iii) to provide 170 mg of 2-n-butyl-1-(2-chlorophenyl)-methyl-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-carboxaldehyde as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[CH3:13]O>CN(C)C1C=CN=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:12]
Reactant: CO
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyano-2-fluorobenzoic acid (1 g; 6.06 mmol) was suspended in MeOH (10 mL) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.39 g; 7.27 mmol; 1.20 eq.) and 4-dimethylaminopyridine (70 mg; 0.61 mmol; 0.10 eq.) were added. The mixture was stirred at RT overnight.
Reaction SMILES: C([O:4][C:5]1[CH2:8][C:7](=[O:9])[CH:6]=1)(=O)C.[CH:10]1([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:17]1([NH2+:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1.[OH:9][C:7]1[CH2:8][C:5](=[O:4])[CH:6]=1
Reactant: CC(=O)OC1=CC(=O)C1
Reactant: C1CCC(NC2CCCCC2)CC1
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: O=C1C=C(O)C1
Reaction time: 1.5 h
Yield: 111.8 %

Procedure:
1000 g of distillation residue from diketene production, containing 22.0 percent of 3-acetoxy-2-cyclobuten-1-one (1.74 mol), was dissolved in 1078 ml of (970 g). 707.4 g of dicyclohexylamine (98 percent; 3.81 mol) was instilled in this black solution at 10° C. within 60 minutes. After 90 minutes, of stirring at +10° C., the suspension was filtered, suspended three times with ethyl acetate and dried under vacuum. 518 g of the title product with a content of 65.5 percent (HPLC), corresponding to a yield of 73.4 percent, relative to 3-acetoxy-2-cyclobuten-1-one, was obtained. Data for the title compound was:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42](Cl)=[O:43].O>C(OCC)(=O)C>[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12)=[O:43]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Yield: 100.6 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.4 g) and trimethylsilylacetamide (9.8 g) in ethyl acetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyryl chloride (syn isomer) (5.0 g) at -20° C. with stirring, and the stirring was continued at -20° to -5° C. for an hour. To the reaction mixture were added ethyl acetate and water, and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (10.1 g).