Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38]I>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:29])[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:38][CH2:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ICCOC1CCCCO1
Reactant: O=C(Cc1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Product: O=C(c1ccc(OCCOCCOCc2ccccc2)cc1)C(CCOC1CCCCO1)c1ccccc1

Procedure:
is prepared by using the method described in the example 4d starting from 1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenylethanone (8.4g, 21.5 mmol) and 2-(tetrahydropyran-2-yloxy)ethyl iodide (6.6 g, 25.8 mmol). The product (11.7 g) is used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>O1CCCC1>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: O=C1Nc2ccccc2CC[C@H]1NCc1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)N(Cc1ccccc1)[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
A solution of 90 mg (0.34 mmol) of 3(R)-(benzylamino)-2,3,4,5-tetrahydro-1H-benzazepin-2-one in 1.5 mL of tetrahydrofuran under nitrogen at room temperature was treated with 73 mg (0.34 mmol, 1 eq.) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) followed by 94 mg (0.38 mmol, 1.1 eq.) of 2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline (EEDQ). Most of the solvent was evaporated under a stream of nitrogen and the resulting reaction mixture (thick syrup approx. 0.3 mL) was stirred for 3 days. The mixture was evaporated to dryness under vacuum and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to afford 45 mg (mmol, 33%) of product. 1H NMR (200 MHz, CDCl3): 1.28 (s,3H), 1.32 (s,3H), 1.35 (s,9H), 2.16 (m,2H), 2.35 (d,14 Hz,1H), 2.58 (d,14 Hz,1H), 2.60 (m,1H), 2.81 (m,1H), 4.70 (d,18 Hz,1H), 4.99 (d,18 Hz,1H), 5.37 (t,10 Hz,1H), 5.83 (br s,1H), 6.98 (d,7 Hz,1H), 7.05-7.45 (m,5H), 7.50-7.85 (m,3H), 8.13 (t,8 Hz,1H), 8.90 (m,1H). FAB-MS: calculated for C27H35N3O4 465; found 466 (M+H,48%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1.[F:30][C:31]([F:36])([F:35])[C:32](O)=O.FC(F)(F)COS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:32][C:31]([F:36])([F:35])[F:30])[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(C3CCN(CC(F)(F)F)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 25 mg, 0.040 mmol), trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (9.8 mg, 0.042 mmol) and Na2CO3 (21 mg, 0.20 mmol) in 1 mL of DMF was stirred at RT for 8 h. Treated with 30 mL of EtOAc, the mixture was washed with H2O (2×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (40% EtOAc/hexane) gave 11 mg (55%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 10.7 (s, 1H), 9.20 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.47 (dd, 1H, J=3.1, 1.4 Hz), 7.10 (d, 1H, J=1.8 Hz), 7.04 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (dd, 1H, J=3.1, 1.4 Hz), 2.90-3.14 (m, 6H), 2.72 (dd, 2H, J=11.5, 11.5 Hz), 2.41-2.52 (m, 3H), 1.74-1.90 (m, 6H), 1.60 (br s, 1H), 1.34-1.44 (m, 2H), 1.09 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C25H30F3N5O, 474.2 (M+H), found 474.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH3:16].[SH-:17].[Na+].Cl>O>[CH3:15][C:4]1[C:3]([CH3:16])=[C:2]([SH:17])[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=1
Reactant: [SH-]
Reactant: COC(=O)c1nc2nc(C)c(C)c(Cl)n2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nc(C)c(C)c(S)n2n1
Reaction time: 1.5 h

Procedure:
The product obtained in Step 2 was added all at once at 0° C. to a solution of sodium hydrosulfide (40 g) in 800 ml of water with stirring under a nitrogen stream, the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1.5 hours, its pH was lowered to 2.0 with concentrated hydrochloric acid. The formed crystals were collected by filtration and washed with 300 ml of water and 200 ml of ethanol, affording 36 g of the objective compound as yellow crystals.
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:6]2)[CH2:2]1.[Br:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:3]3([CH2:4][CH2:5][N:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2]3)[CH2:6][N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])=[O:15])[C:8]2=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (15.2 g, 36.5 mmol) was dissolved in t-butanol (240 mL) and water (40 mL). Thereafter, N-bromosuccinimide (7.9 g, 44.4 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 60° C. for 15 hours. Thereafter, an aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (12.9 g, 71%) in the form of a white amorphous product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>COCCOC>[F:16][C:5]1[C:6]([NH:32][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CCN)cc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2F)cc1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 329 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].Br[CH2:20][CH2:21]Cl.O>CS(C)=O.C1COCC1.CCOCC>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([C:13]([O:15][CH3:16])=[O:14])[CH2:21][CH2:20]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCCBr
Reactant: COC(=O)Cc1cccc2ccc(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1(c2cccc3ccc(C)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of methyl 2-(2-methylquinolin-8-yl)acetate (0.78 g, 3.62 mmol) in DMSO (10 mL) and THF (5 mL) was added 60% NaH (0.72 g, 18.12 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 1-Bromo-2-chloroethane (0.90 mL, 10.87 mmol) was added slowly, and the reaction mixture was stirred at ambient temperature for 40 hours. Water (10 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give methyl 1-(2-methylquinolin-8-yl)cyclopropanecarboxylate (0.416 g, 47.6%) as an oil.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.O.[OH-].[NH4+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(#N)C>[ClH:1].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Acetonitrile (800 ml) is added to 2-aminoindan hydrochloride (50 g, 0.295 mole) followed by the addition of water (100 ml) and concentrated ammonium hydroxide (100 ml). To the resulting stirring solution tert-butyl bromoacetate (60 g, 0.308 mole) in acetonitrile (150 ml is added dropwise at room temperature and the resulting mixture stirred overnight at room temperature. The acetonitrile is evaporated on a rotary evaporator, water added to the residue and the product extracted several times into methylene chloride. The combined methylene chloride extract is washed twice with water, dried over magnesium sulfate, filtered and evaporated to afford the crude product as a tan oil. The crude product is purified further by silica-gel chromatography (chloroform). The desired fractions are concentrated and the hydrochloride prepared with ether-hydrochloric acid to afford tert-butyl N-(2,3-dihydro-1H-inden-2-yl)glycinate hydrochloride as a colorless solid (60 g, 72%); m.p. 175°; mass spectra (CI): 248(m+1, 100%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=O)[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCOC(C)=O>[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=[CH2:1])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a three necked flask equipped with additional funnel which was cooled to −78° C. was added a solution of methyl(triphenyl)phosphonium bromide (43 g, 121 mmol) in anhydrous tetrahydrofuran (200 mL) under nitrogen protection. 1 M KHMDS in tetrahydrofuran (105 mL, 105 mmol) was then introduced dropwise over 40 minutes while the internal temperature was kept below −60° C. After addition, the mixture was stirred at −78° C. for 15 minutes. Then a solution of tert-butyl(3-oxocyclobutyl)carbamate (14 g, 81 mmol) in 100 mL of tetrahydrofuran was added slowly while the internal temperature was kept below −60° C. The resulting mixture was then warmed naturally to room temperature and stirred overnight. The resulting reaction mixture was diluted with EtOAc, and then washed with saturated aqueous solution of ammonium chloride and brine, then dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (EA:PE=1:10 to 1:2) to afford tert-butyl(3-methylidenecyclobutyl)carbamate (7.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.4 %

Procedure:
A solution of 20E (123 mg, 0.149 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.081 mL, 0.164 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.208 mL, 1.489 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred at rt for 16 h. The solvent was concentrated and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (60 mg, 47.3% yield). The diastereoisomers were separated by a prep chiral HPLC to give 20F (22 mg, 0.026 mmol, 37.9% yield).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[CH3:8][N:9]1[CH2:14][CH:13]([C:15](OC)=O)[CH2:12][N:11]=[CH:10]1.C(O)C>C1COCC1>[CH3:8][N:9]1[CH2:14][CH:13]([C:15]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)[CH2:12][N:11]=[CH:10]1
Reactant: CC(N)=NO
Reactant: COC(=O)C1CN=CN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(C2CN=CN(C)C2)n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Sodium hydride (60% dispersion in mineral oil 112 mg, 2.8 mmol) and acetamidoxime (207 mg, 2.8 mmol) are suspended in dry THF (16 ml) in an oven dried round bottom flask under nitrogen with stirring at 0° C. After 10 minutes the grey suspension is refluxed for 30 minutes giving a white suspension. 1-Methyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (593 mg, 2.8 mmol) dissolved in dry THF (4 ml) and anhydrous ethanol (1 ml) is added via syringe and reflux continued 15 hours. The suspension is evaporated in vacuo to a yellow gum and chromatographed (silica, chloroform/methanol, 9:1) to yield 24 mg (rf=0.07, 4%) solids identified by 300 MHz nmr and ms m/z=180.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>>[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:1][CH2:2][CH3:3])=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC=O
Reactant: Nc1ccc(-n2ccnc2)cc1
Product: CCCNc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react propanaldehyde with 4-(1H-imidazol-1-yl)benzenamine to obtain the title compound.
Reaction SMILES: C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[OH:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][C:34]=1[OH:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1ccc(OCc2ccccc2)c(O)c1
Yield: 33 %

Procedure:
This compound was prepared according to procedure used in preparation of 3,5-dibenzyloxybenzylamine, starting from 4-benzyloxy-3-hydroxybenzonitrile. Yield was 33%. MP 122–125° C.; 1H NMR (DMSO-d6, 400 MHz) δ8.9 (br, 1H), 7.44 (d, 2H, J=7.4 Hz), 7.35 (dd, 2H, J=7.0 and 7.7 Hz), 7.28 (dd, 1H, J=7.0 and 7.3), 6.85 (d, 1H, J=7.6 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.61 (dd, 1H, J=7.4 and 2.2 Hz), 5.05 (s, 2H), 3.55 (s, 1H), 2.50 (br, 2H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:27]1[N:31]=[C:30]([NH2:32])[S:29][N:28]=1)[C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([O-:24])=[O:23])=[C:14]([CH2:17]OC(=O)C)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[Na+].[CH3:34][N:35]1[C:39]2[CH2:40][CH2:41][CH2:42][C:38]=2[CH:37]=[N:36]1.[I-].[Na+].P(=O)(O)(O)O.Cl>O.C(#N)C>[CH2:1]([O:4][N:5]=[C:6]([C:27]1[N:31]=[C:30]([NH2:32])[S:29][N:28]=1)[C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([O-:24])=[O:23])=[C:14]([CH2:17][N+:36]3[N:35]([CH3:34])[C:39]4[CH2:40][CH2:41][CH2:42][C:38]=4[CH:37]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1nsc(N)n1
Reactant: Cn1ncc2c1CCC2
Agent: Cl
Agent: O=P(O)(O)O
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc4c(n3C)CCC4)CS[C@H]12)c1nsc(N)n1
Reaction time: 2 h
Yield: 18.7 %

Procedure:
A mixture of sodium 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (syn isomer)(6.43 g), 1-methyl-5,6-dihydro-1H,4H-cyclopenta[c]pyrazole (3.2 g), sodium iodide (20.54 g), phosphoric acid (0.67 g), water (2.8 ml) and acetonitrile (8.5 ml) was stirred at 70° to 75° C. for 2 hours. The reaction mixture was poured into water (100 ml) and the aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid. After removal of precipitates by filtration, the aqueous solution was washed with ethyl acetate four times. The aqueous layer was adjusted to pH 2.5 with 5% aqueous solution of sodium bicarbonate and subjected to column chromatography on macroporous non-ionic adsorption resin Diaion HP-20 (Trademark : prepared by Mitsubishi Chemical Industries). The column was washed with water and eluted with 50% aqueous methanol. The fractions containing the object compound were combined and methanol was evaporated under reduced pressure. The resultant aqueous solution was lyophilized to give 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-[1-methyl-5,6-dihydro-2(1H,4H)-cyclopenta[c]pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer)(1.3 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[F:16][C:17]([F:21])([F:20])[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[F:16][C:17]([F:21])([F:20])[CH2:18][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 46.4 %

Procedure:
tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g, 1.393 mmol), 2,2,2-trifluoroethan-1-ol (1.00 mL, 13.935 mmol), triphenylphosphine (0.440 g, 1.672 mmol) and N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (0.390 g, 1.672 mmol) were combined in THF (10 mL) and stirred at room temperature for 36 h before being heated to 75 C for 18 h. The reaction mixture was concentrated under reduced pressure and purified by FCC (EtOAc: heptane, 1:1) to afford the title compound (0.192 g, 50%). Method B HPLC-MS: MH+ requires m/z=297 Found: m/z=242 (MH+-tBu), Rt=2.25 min (100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:3]=1.[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[NH:35][CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[N:35]([C:2]4[CH:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:3]=4)[CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)CN(C)c1nccc(F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N(C)CC(=O)OC)n2)c(=O)[nH]c1=O

Procedure:
A mixture of the product of step (i) (0.68 g), and the product of example 15 step (vii) (2.35 g) was stirred with cesium carbonate (2.22 g) in 1-methyl-2-pyrrolidinone (20 ml) at 70-80° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography eluting with ethyl acetate in toluene. Yield 0.57 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[CH2:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:16]2[S:15][C:14]([CH2:11][CH2:12][CH3:13])=[CH:18][CH:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCc1cccs1
Reactant: O=C(O)c1cccc(Br)c1
Product: CCCc1ccc(Cc2cccc(Br)c2)s1

Procedure:
3-Bromobenzoic acid and 2-n-propylthiophene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19]>>[C:3]([C:7]1[CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: OCCCCO
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(CCCCO)cc(C(C)(C)C)c1O
Temperature: 235 °C

Procedure:
50 g of potassium hydroxide, 316 g of 2-tert-butyl-6-methylphenol and 866 g of 1,4-butanediol are initially introduced into an autoclave. After introducing nitrogen gas, the autoclave is closed and the mixture is heated at 235° C. (4 bar) for 6 hours, with stirring; a further rise in pressure as a consequence of the reaction is prevented by blowing of gas. When the reaction is complete, the reaction mixture is cooled to 80° C. and the autoclave is emptied. Excess butanediol is removed by distillation. The distillation residue is poured into 11 of water and 500 ml of toluene. The organic phase is then washed with water until neutral and the toluene is stripped off by applying a vacuum. The remaining residue (310 g) contains 68-70% of the title product of the formula ##STR25##