Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](O)(O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:4]1[CH2:5][CH2:6][CH:7]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([F:17])([F:1])[CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1
Reactant: N#CCN1CCC(O)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#CCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
DAST (4.36 mL, 33 mmol) was added to a solution of (4-hydroxy-piperidin-1-yl)-acetonitrile (4.25 g, 30 mmol) in DCM (80 mL) at −30° C., the mixture was then stirred at rt for overnight. The reaction was cooled to −30° C. and quenched with methanol (10 mL) for 30 mins. The organic layer was then washed with NaHCO3 and dried. The residue was purified on a silica gel column to give 3 g (71%) of (4-fluoro-piperidin-1-yl)-acetonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: ClCCCCCCCCCCOCc1ccccc1
Product: COc1cc(C(O)CCCCCCCCCCOCc2ccccc2)ccc1OCc1ccccc1

Procedure:
By following the procedure as in Reference Example 17(c) using 4-benzyloxy-3-methoxybenzaldehyde and 10-benzyloxy-1-chlorodecane, 11-benzyloxy-1-(4-benzyloxy-3-methoxyphenyl)-1-undecanol was obtained.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH3:12])[CH:6]=1
Reactant: COc1cccc(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(SC)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl iodide (14.67 ml, 0.235 mol) was added dropwise to a solution of 3-methoxy-benzenethiol (30 g, 0.214 mol) and potassium carbonate (29.6 g, 0.214 mol) in acetone (400 ml) under nitrogen at 3° C. The reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (300 ml) and the aqueous layer was extracted with diethylether (3×200 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87 g) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[N:10]3[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=[C:9]3[C:6]2=[N:7][CH:8]=1)[CH3:2].Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[NH:10][C:13](=[O:20])[C:14]([CH:17]([CH3:18])[CH3:19])([CH3:16])[N:15]=2)=[C:5]([CH:4]=1)[C:11]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:12])[CH3:2]
Reactant: COC(=O)CCCCCN
Reactant: CCc1cnc2c(c1)C(=O)N1C(=O)C(C)(C(C)C)N=C21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 7-ethyl-2-isopropyl-2-methyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione (7.25 g, 26.75 mmol) in anhydrous N,N-dimethylformamide is treated successively with methyl 6-aminocaproate hydrochloride (5.10 g, 28.1 mmol) and triethylamine (3.00 g, 29.6 mmol). The resulting mixture is stirred at room temperature under nitrogen for 20.5 hours. After this period, the reaction mixture is partitioned between water and ethyl acetate. The layers are separated, and the organic layer is washed with water, dried over magnesium sulfate and vacuum filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a white solid. The solid is triturated with 1:1 ether/petroleum ether to give the title product as a white solid (7.40 g, 69%, mp 101°-103° C.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH:12]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCCC1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=CCc1ccc(C2OCCO2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(NCCc2ccc(C3OCCO3)o2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.3 %

Procedure:
Next, the resulting (5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57 g), aniline (0.94 mL, 10.3 mmol) and triacetoxy sodium borohydride (3.76 g, 17.2 mmol) were suspended in a mixture solution of tetrahydrofuran (30 mL) and acetic acid (1 mL) at 0° C., and the mixture was stirred at room temperature for 19 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (453 mg, 1.75 mmol, 14%) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:38]3[CH:39]=[CH:40][N:41]=[C:37]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCc1ncc[nH]1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-undecylimidazole (500 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from diethyl ether-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-undecyl-1-imidazolyl)oxazole as pale yellow prisms (100 mg, 13%). Melting point 53-54° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([O:20][C:8]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=3)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3cc(Cl)ccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4,7-dichloroquinoline (139 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (77 mg, yield 94%).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[CH:6]=1)[CH3:3].[CH2:17]([OH:19])[CH3:18]>>[ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[NH:10])[O:19][CH2:17][CH3:18])=[C:7]([O:13][CH:14]([CH3:15])[CH3:16])[CH:6]=1)[CH3:3]
Reactant: CCO
Reactant: CCOc1ccc(C#N)c(OC(C)C)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OCC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Hydrogen chloride gas was passed through a solution of 4-ethoxy-2-isopropoxy-benzonitrile (0.30 g, 1.46 mmol) in absolute ethanol (100 mL) in a pressure tube for 45 min at 0° C. The tube was sealed and stirred at room temperature for 4 d. The pressure was released only after the tube is cooled to 0° C. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99 %

Procedure:
A mixture of trans 3-bromocinnamic acid (m.p. 177°-179° C.; 11.4 g), thionyl chloride (11.9 g) and dry benzene (150 ml) was heated at reflux for 2 hours. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3-bromocinnamoyl chloride (12.2 g), b.p. 100°-100.5° C./0.2 mm Hg.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][CH3:44])[CH:34]=1)=[O:32]>O>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[N:11]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][C:35]=3[O:43][CH3:44])(=[O:41])=[O:40])[C:10]2=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: COCCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3-cyclohexyl-1,3-dihydro-5-(2-methoxyethoxy)-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for two hours at RT. The reaction mixture is poured into a mixture of water and ice, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.8 g of the expected product, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:33])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 1-fluoro-4-isocyanatobenzene (13 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 90 minutes before it was concentrated and directly purified by column chromatography on silica, eluting with 3:1 EtOAc/hexanes to yield the final product as a solid (30 mg, 84% yield). MS (apci) m/z=453.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.C(N(C(C)C)CC)(C)C.Cl[CH2:22][CH2:23][C:24]1[CH:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([N:11]1[CH2:22][CH2:23][C:24]3[C:25](=[CH:29][CH:30]=[C:31]([O:33][CH2:34][C@@H:35]4[CH2:39][CH2:38][CH2:37][O:36]4)[CH:32]=3)[C:26]1=[O:27])[CH2:5]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)c1ccc(OC[C@@H]2CCCO2)cc1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 0.08 h

Procedure:
A mixture of (R)-5-bromoindan-2-ylamine (hydrochloride, 1.05 g), THF (20 ml) and diisopropylethylamine (1.0 g) was admixed with 2-(2-chloroethyl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzoyl chloride (1.28 g; from 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-isochroman-1-one by boiling with thionyl chloride). After 5 minutes, potassium tert-butoxide (1.42 g) was added. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 ethyl acetate/heptane). This afforded the product with the molecular weight of 442.36 (C23H24BrNO3); MS (ESI): 442 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12.[Na+:28].Cl.C(O[CH:33]=[NH:34])C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:33]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[NH:34].[Na+:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCN)c4s3)[C@H](C)[C@H]12
Reactant: CCOC=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCNC=N)c4s3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
Sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (45.7 mg) was suspended in 3 ml of water under ice cooling. Ethylformimidate hydrochloride (46 mg) was added to the suspension. While adjusting the mixture to pH 8 to 9 by the addition of an aqueous sodium carbonate solution, the mixture was stirred at that temperature for one hr, and then at room temperature for 1.5 hr. The reaction product was then purified by column chromatography on Cosmosil 40C18-PREP (a 20% aqueous methanol solution) to prepare 5.4 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=5)[CH:14]=4)=[CH:5][CH:4]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(Cc3ccc(NC(=O)/C=C/c4cccc(-c5ccc(C)cc5)c4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.3 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 1-(4-methoxyphenyl)piperazine dihydrochloride (190 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1-(4-methoxyphenyl)-4-piperazinylmethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 62) (224 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34].[CH2:35]=O>[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:35])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34]
Reactant: C=O
Reactant: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Agent: [Pd]
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Reaction time: 2 h
Yield: 17 %

Procedure:
A mixture of the title compound of Example 87 (0.4 g, 0.82 mmol), formaldehyde (0.14 mL, 37% in water, 1.63 mmol) and palladium 10% on activated carbon (40 mg) was hydrogenated for 2 h. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica-gel (dichloromethane-ethanol-ammonium hydroxide 180:8:1) to yield the title compound (0.07 g, 17%) as an off-white solid.
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][CH2:22][CH:23]=[CH2:24])[CH:15]=2)(=O)=O)=CC=1>CCO.O>[CH2:22]([O:21][C:16]1[CH:15]=[C:14]([OH:13])[CH:19]=[CH:18][C:17]=1[Br:20])[CH:23]=[CH2:24]
Reactant: C=CCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(O)ccc1Br
Temperature: 90 °C
Yield: 84.1 %

Procedure:
Potassium Hydroxide (11.2 g, 200 mmoles) was added to a solution of the product from Example 63A (3.5 g, 9.14 mmoles) in EtOH (180 mL) and H2O (180 mL). The reaction was heated to 90° C. for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (1.76 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.Cl>CO>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(OC)cc2)CC(C(=O)OC)=C(Nc2ccc(OC)cc2)C1
Yield: 96.9 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (9.12 gm; 40 mmol) and methanol (200 ml) were heated to boiling, then 4-methoxyaniline (10.84 gm; 88 mmol) was added followed by conc. hydrochloric acid (400 μl). The mixture was refluxed for 2.5 hours under a nitrogen atmosphere. On cooling, an orange solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 17.0 gm (97%) of dimethyl 2,5-bis{(4-methoxyphenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]CO)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:2][Br:5])=[CH:9][CH:8]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A solution of tetrabromomethane (1.125 eq.) in dichloromethane (0.5 ml/mole) was added dropwise to the solution of the commercially available 3-(4-hydroxyphenyl)-1-propanol 1B (1 eq.) and triphenylphosphine (1.125 eq.) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 2 days, extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. the crude reaction mixture was filtered through silica gel, eluting with 10% ethyl acetate in hexane, to give 3-(4-hydroxyphenyl)-1-bromopropane 2 as a brown oil in 62% yield.