Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:1]([O:5][CH2:6][C:7]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use butoxyacetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (40.8% yield). 1H NMR (300 MHz, CDCl3) δ 9.19, 8.35, 7.72, 7.55, 7.33, 7.03, 4.05, 3.94, 3.60, 3.31, 1.64, 1.43, 0.93. MS (ES+) m/z 465.6 (M+1).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34]O)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58]>C(#N)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34][Cl:58])[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CO)N2C[C@H]1Cc1c[nH]c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CCl)N2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 70 °C

Procedure:
A mixture of (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-hydroxymethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.30 g), triphenylphosphine (1.2 g), carbontetrachloride (4 mL), and acetonitrile (40 mL) was heated at 70° C. for 6 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was purified by ion-exchange chromatography on a strong cation exchange (SCX) column, to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-6-chloromethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.06 g) (Intermediate 5).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2-bromo-1-[4-(methyloxy)phenyl]ethanone (3.5 g, 15.28 mmol) and sodium azide (1.490 g, 22.92 mmol) in THF (40 mL) and water (13.33 mL) was stirred at 25° C. for 2 hours. The mixture was diluted with water (150 mL), and extracted with Et2O (3×100 mL), dried (Na2SO4), filtered, concentrated to afford the title compound (3.0 g) as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3H), 4.83 (s, 2H), 7.07 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH3:18][C:19](=O)[CH2:20][CH2:21][C:22](=O)[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:22]1[N:2]([S:1]([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4])[C:19]([CH3:18])=[CH:20][CH:21]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (200 mg) and 2,5-hexanedione (0.26 ml) in toluene (1 ml) was added p-toluenesulfonic acid monohydrate (28 mg), and the mixture was stirred under reflux with Dean-Stark Trap for 24 hours. Then 2,5-hexanedione (0.26 ml) and p-toluenesulfonic acid monohydrate (30 mg) was added to the mixture, and the mixture was stirred under the same condition for 24 hours. The mixture was evaporated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane (5:95–20:80)) to give 3-[(2,5-dimethylpyrrol-1-yl)-sulfonyl]-5-(trifluoromethyl)benzoic acid (280 mg) as a crude solid. The solid was dissolved in a mixture of 1N sodium hydroxide aqueous solution (10 ml) and water (20 ml), and then adjusted to pH 1–2 with 1N hydrochloric acid (20 ml). The resulting powder was collected by filtration and dried under reduced pressure to give pure product (191.1 mg).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[O:4][CH2:5][O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=2[O:4][CH2:5][O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:25]=[CH:24][C:23]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=1
Reactant: C[Si](C)(C)CCOCOc1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[Si](C)(C)CCOCOc1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-((2-bromo-5-(trifluoromethyl)phenoxy)methoxy)ethyl)trimethylsilane and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C23H25F4N3O2Si, 479.17; m/z found, 480.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55-8.48 (m, 2H), 7.60-7.51 (m, 3H), 7.48-7.36 (m, 3H), 5.33-5.29 (d, J=1.0, 2H), 3.73-3.66 (m, 2H), 0.93-0.84 (t, J=8.0, 2H), −0.03-−0.07 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1.Cl.[CH3:10][NH:11][O:12][CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: COC1(C(=O)Cl)CC1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C1(OC)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
10 g (74 mmol) of 1-methoxy-cyclopropane-carbonyl chloride are added at 20° C. with stirring to a mixture of 8 g (82 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 100 ml of absolute dichloromethane. 13 g (164 mmol) of absolute pyridine are then added dropwise at 0° C. The mixture is initially subsequently stirred at 20° C. for one hour and then at 40° C. for one hour, the precipitate is then filtered off and 100 ml of dichloromethane are added. The reaction mixture is washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The remaining residue is subjected to a vacuum distillation. 10 g (85% of theory) of N-methoxy-N-methyl-1-methoxy-cyclopropanecarboxamide are obtained in this manner in the form of an oil having a boiling point of b.p.=125° C. at 20 mbar. ##STR35##
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5](=[O:14])[NH:4]1.[CH3:15]I>C1COCC1>[CH3:15][N:4]1[C:5](=[O:14])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:3]1
Reactant: O=C1CCc2ccccc2CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2ccccc2CCC1=O
Reaction time: 0.17 h
Yield: 95 %

Procedure:
At 25° C., sodium hydride (150 mg, 6.3 mmol) was added to a solution of 1,2,4,5-tetrahydro-benzo[c]azepin-3-one (1 g, 6 mmol) in THF (50 mL). The suspension was stirred for 10 minutes and treated with methyl iodide (1 g, 7 mmol). The mixture was stirred for an additional 4 hours and then partitioned between ethyl acetate (100 ml) and water (50 ml). Washing once with brine (30 ml), drying over anhydrous magnesium sulfate and evaporation of solvent gave 2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (1 g, 5.7 mmol, 95%): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.52 (s, 2H), 3.18 (t, 2H), 3.09 (s, 3H), 3.00 (t, 2H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH3:23][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[CH:20]=2)[NH:4]1
Reactant: COC(=O)C1=Cc2cc(-c3nnn[nH]3)ccc2OCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
In DMF (6 ml) was dissolved methyl 7-(1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (400 mg, 1.47 mmol), and to the mixture was added at 0° C. sodium hydride (60%, 90 mg, 2.3 mmol). The mixture was stirred at the same temperature for 15 minutes, and to the mixture was added at 0° C. methyl iodide (0.28 ml, 4.4 mmol). While the temperature of the mixture was warmed from 0° C. to room temperature, the mixture was stirred for 3 hours. To the mixture was added at 0° C. water (30 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 40 g, ethyl acetate/hexane=1/8→1/2), and the first eluted desired fraction was concentrated under reduced pressure to give methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (334 mg, 1.17 mmol, 79%). The second eluted desired fraction was concentrated under reduced pressure to give methyl 7-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (76 mg, 0.27 mmol, 18%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:11])[NH:9][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22]OCC)[C:17](OCC)=[O:18])[CH3:13]>C(O)(=O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17](=[O:18])[N:9]2[N:10]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[C:8]2[NH:11][CH:22]=1)=[O:26])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C2CCCC2)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C3CCCC3)nn2c1=O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
To a solution of 5-cyclopentyl-2H-pyrazol-3-ylamine (510 mg, 3.4 mmol, 1 eq) in acetic acid (4.8 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (750 μL, 3.7 mmol, 1.1 eq). The mixture was heated at 120° C. for 3 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol and diethyl ether and recrystallised from methanol to afford the expected compound as white powder (657 mg, 71% yield).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[H-].[Na+].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>CN(C=O)C>[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:29][CH:28]=2)=[CH:50][CH:51]=1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.51 g (13.29 mmol) of (4-cyanobenzyl)triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol), of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and 3.5 g (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile. (M.P. 116° C. -118° C.)
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].O.O.O.[C:15]([O-])(=[O:17])[CH3:16].[Na+].C(OC(=O)C)(=O)C>>[C:15]([NH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)(=[O:17])[CH3:16]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
25 g. of 2-indanamine hydrochloride (0.15 mole), 20 g. of sodium acetate trihydrate (0.14 mole), and 40 g. of acetic anhydride (0.4 mole) were stirred at 25° C. for sixteen hours. The mixture was evaporated and the residue was partitioned between chloroform and water. The chloroform extracts were pooled, washed with 10% hydrochloric acid and then with 5% aqueous sodium carbonate, dried and evaporated to yield N-acetyl-2-indanamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11][NH2:12]>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][N:11]=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1F
Reactant: NN
Product: Brc1ccc2[nH]ncc2c1
Yield: 38 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol) and 98% hydrazine (20 mL) was heated to reflux for 5 hours, poured over ice, and filtered. The solid was recrystallized from H2O/methanol to provide the desired product (3.7 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4(O)[CH2:29][O:28][CH2:27]4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([F:39])[CH2:29][O:28][CH2:27]4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C1N(c2ccc(C3(O)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1N(c2ccc(C3(F)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of 8-(2-chloro-benzenesulfonyl)-2-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 229, 35 mg, 0.07 mmol) in DCM was added DAST (11 uL, 0.08 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 hr and then quenched with sat. NaHCO3. The reaction mixture was diluted with DCM and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 8-(2-chloro-benzenesulfonyl)-2-[4-(3-fluoro-oxetan-3-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (14 mg, 40%) as a white solid. MS (ESI): 479.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:20]3[CH:19]=[CH:15][C:14]([OH:13])=[CH:22][C:21]=3[OH:23])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: Oc1ccc(-c2nc3ccc(O)cc3o2)c(O)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 2,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. 293–296° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C(C)=O)C.[Br:17][CH2:18][CH2:19][OH:20]>N1C=CC=CC=1>[C:1]([O:20][CH2:19][CH2:18][Br:17])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OCCBr
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: O=C(C=Cc1ccccc1)OCCBr
Reaction time: 2 h
Yield: 94.9 %

Procedure:
83.3 g (0.5 mol) of cinnamic acid chloride and 200 mL of methyl ethyl ketone were placed in a reaction vessel. 62.5 g (0.5 mol) of 2-bromoethanol and 50 g of pyridine were added dropwise in the reaction vessel. The solution was refluxed with stirring for 2 hours under a nitrogen atmosphere and then concentrated. 100 mL of water was added to the concentrated solution. After extraction with chloroform, dehydration with anhydrous sodium sulfate, concentration, and drying, 121 g of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.Br[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:44]([C:41]1[CH:42]=[CH:43][C:38]([C:13]2[S:12][C:11]([C:9]3[S:10][C:6]([C:38]4[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=4)=[CH:7][CH:8]=3)=[CH:15][CH:14]=2)=[CH:39][CH:40]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2ccc(-c3ccc(-c4ccc(C(C)C)cc4)s3)s2)cc1
Yield: 61.6 %

Procedure:
A solution of 1.8 g of 5,5′-bis(tributylstannyl)-2,2′-bithiophene, 1.3 g of 1-bromo-4-isopropylbenzene, and 80 mg of Pd(PPh3)4 in 35 milliliters (“mL”) of N,N-dimethylformamide was heated at 70° C. for 2 days under nitrogen. After cooling, 0.6 g of yellow-green solid was obtained after washing with methanol and ether, verified pure by nuclear magnetic resonance spectroscopy (“NMR”), and used directly for film and crystal studies.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)c1
Reaction time: 8 h

Procedure:
The resulting ethereal solution from Example 4 containing 1-[4-(4-chlorophenyl)-2-(3-aminophenylthio)-n-butyl]imidazole was treated at room temperature with stirring with acetic anhydride (1.5 m.). After stirring overnight, the mixture was evaporated to dryness in vacuo and the residue chromatographed on silica gel eluting with methylene chloride followed by 2.2% water in ethyl acetate. The resulting pure product, 1-[4-(4-chlorophenyl)-2-(3-acetylaminophenylthio)-n-butyl]imidazole, obtained as a gum, was dissolved in a small volume of methanol and treated with excess ethereal hydrogen chloride. The solution was filtered, evaporated almost to dryness and evacuated in a warm water bath to give 1-[4-(4-chlorophenyl)-2-(3-acetylaminophenylthio)-n-butyl]imidazole hydrochloride 1.79 g as a brittle foam, dec 87°-92° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[C:48]([Cl:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1cccc(Cl)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cccc(Cl)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 3-chloro-benzylamine (Avocado) to give the title compound. HR-MS (ES, m/z) calculated for C43H49Cl3N5O3 [(M+H)+] 788.2896, observed 788.2890.
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37]C=O)[N:32]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]([S:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)[CH3:19])[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[N:32]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]([S:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)[CH3:19])[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Conc. hydrochloric acid (0.31 ml.) was added to a solution of 7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75 g.) in methanol (7 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was removed by distillation from the reaction mixture, and the remaining aqueous solution was diluted with water (80 ml.) and then adjusted to pH 2-3 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade Mark, manufactured by Mitsubishi Chemical Industries Ltd.) (50 ml.). After the column was washed with water (1 l.), elution was carried out with 50% aqueous methanol (1 l.) and fractions containing the desired compound were collected. The methanol was removed by distillation from the combined fractions under reduced pressure and the resultant aqueous solution was lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.13 g), mp. 149°-151° C. (dec.).