Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=2)[N:7]=1.[CH3:18][NH:19][CH3:20].C(O)(C)(C)C.Cl>O>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=2)[N:7]=1
Reactant: CNC
Reactant: CCCc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1nc2ccc(N(C)C)nn2c1S(N)(=O)=O
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-2-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.50 g, 1.81 mmol), 50% aqueous dimethylamine (1.0 ml) and t-butanol (5.0 ml) was heated at 100° C. for 8 hours with stirring in a sealed tube reactor. The reaction solution was left and cooled to room temperature, poured into water (50.0 ml) and adjusted to pH 6 with dilute hydrochloric acid, to precipitate crystals which were then filtered and washed with water, to give the title compound as pale yellow crystals. The yield was 0.38 g (74.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=2)[C:7]1=[O:18].BrCC1C=C([N+]([O-])=O)C=CC=1C(OC)=O.COC1C=C(OC)C=CC=1CN.C(N(CC)CC)C>CO.C(OCC)(=O)C.CCCCCC>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:18])[N:6]([CH2:5][C:4]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=1[O:2][CH3:1])[CH2:14]2
Reactant: COc1ccc(CN2Cc3cc([N+](=O)[O-])ccc3C2=O)c(OC)c1
Agent: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Agent: COc1ccc(CN)c(OC)c1
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3cc(N)ccc3C2=O)c(OC)c1
Yield: 84 %

Procedure:
2-(2,4-Dimethoxybenzyl)-5-nitroisoindolin-1-one. A mixture of methyl 2-(bromomethyl)-4-nitrobenzoate (2.5 g, 9.12 mmol), (2,4-dimethoxyphenyl)methanamine (1.525 g, 9.12 mmol), triethylamine (3.81 mL, 27.4 mmol) in methanol (25 mL) was refluxed for 16 h. The mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator to dryness. Flash chromatography (30-50% ethyl acetate in hexane) gave the desired product as a yellow solid (2.5 g, 7.68 mmol, 84% yield). MS (ESI) m/z 329.9 [M+1]+.
Reaction SMILES: [NH2:1][C@:2]1([C:11]([O:13]C)=[O:12])[CH2:4][C@@H:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:15]>O>[ClH:15].[NH2:1][C@:2]1([C:11]([OH:13])=[O:12])[CH2:4][C@@H:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccccc1
Agent: Cl
Solvent: O
Product: N[C@]1(C(=O)O)C[C@@H]1c1ccccc1

Procedure:
A mixture of (1R,2R)-methyl 1-amino-2-phenylcyclopropanecarboxylate (14 mg), water (4 mL) and hydrochloric acid (37% w/v, 6 mL) was heated under reflux for 6 h. The mixture was evaporated to dryness, triturated with diethyl ether and the solid collected and dried to give the subtitle compound (14 mg) as a colourless solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C1(C)C=CC(S(O[CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:22][C:21]=3[CH2:20]2)(=O)=O)=CC=1>CN(C)C=O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:22][C:21]=2[CH2:20]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
0.56 g of 50% sodium hydride was suspended in 60 ml of anhydrous dimethylformamide, and 0.79 g of imidazole was added thereto. The mixture was stirred at room temperature for 20 minutes and 4.5 g of ethyl 6-(p-toluenesulfonyloxymethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was added portionwise thereto. The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the residue was extracted with chloroform. The extract was washed with water and dried over sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of methanol and chloroform (2:98 by volume) for elution to give 2.31 g of ethyl 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as a colorless oil.
Reaction SMILES: C1(C(O)=O)CC1.[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:11])[CH:8]([CH3:10])[CH3:9]>>[CH:8]1([C:7]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)=[O:20])[CH2:16][CH2:17]2)=[O:11])[CH2:10][CH2:9]1
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C(O)C1CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(C(=O)C2CC2)CC1
Yield: 89 %

Procedure:
Cyclopropanecarboxylic acid (36 mg, 0.418 mmol) was reacted with PTU (100 mg, 0.348 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (110 mg, 0.310 mmol, 89% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.80 (s, 1H), 7.57 (s, 4H), 6.37 (d, J=7.2 Hz, 1H), 4.16 (br, 2H), 3.74 (m, 1H), 3.25 (t, J=11.7 Hz, 1H), 2.81 (t, J=10.8 Hz, 1H), 1.98 (m, 1H), 1.85 (m, 2H), 1.30 (m, 2H), 0.7 (s, 4H).
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.[CH:40](C1N=CNC=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-]>ClCCl.O.C(O)(=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:40][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of Compound B (5.3 g, 11.7 mmol) in dichloromethane (100 mL) were added acetic acid (15 mL) and 4-formylimidazole (1.15 g, 12 mmol). After 10 min, sodium triacetoxyborohydride (2.54 g, 12 mmol) was added. After 3 hr, 4-formylimidazole (0.5 g, 5.8 mmol) and borohydride (1.2 g, 5.5 mmol) were added. After 18 hr, aldehyde (0.5 g) and borohydride (1.2 g) were added. After 5 hr, the mixture was concentrated. Aqueous ammonia (100 mL) and chloroform (100 mL) were added to the residue and the mixture was stirred vigorously for 0.5 hr. The two layers were separated and the organic layer was washed again with aqueous ammonia (100 mL). The combined aqueous layer was extracted with chloroform (100 mL), the two organic extracts were combined, dried (K2CO3), and concentrated. The residue was purified by flash silica gel column chromatography (step gradient of 5% and 10% MeOH in chloroform) to afford a solid which was dissolved in dichloromethane (50 mL) and HCl gas was bubbled through the solution. The mixture was concentrated in vacuo to afford a solid which was dissolved in water and lyophilized to afford Compound C (5.2 g, 73%). MS: (M+H)+ 532
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[Cl-].[NH4+]>CCOCC>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(C(O)CCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
19.1 ml (0.14 mole) of 2-phenylethyl bromide were dissolved in 100 ml of ether and added dropwise to a suspension of 3.4 g (0.14 mole) of magnesium in 300 ml of ether. The reaction solution was next stirred for one hour at 40° C. and then cooled to 0° C. 20.4 g (0.15 mole) of 3-methoxybenzaldehyde in 100 ml of ether were added while cooling with ice and the reaction solution was stirred overnight at 20° C. 150 ml of a 20% ammonium chloride solution was then added at 0° C. to the reaction solution. The reaction solution was extracted three times with 200 ml of ether each time and the combined ether extracts were dried over sodium sulfate. The solvent was removed in vacuo. After drying, 28.5 g (98%) of 1-(3-methoxyphenyl)-3-phenylpropan-1-ol were obtained as a grey oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH2:20][Cl:21])=[O:19])[CH3:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:13]([O:15][C:16](=[O:22])[C:17](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:18](=[O:19])[CH2:20][Cl:21])[CH3:14]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)CCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=Cc1ccccc1C(F)(F)F)C(=O)CCl
Reaction time: 8 h

Procedure:
226.2 g of 2-trifluoromethylbenzaldehyde, 235 g of 4-chloroacetoacetic acid ethyl ester, 4.2 ml of glacial acetic acid and 2.1 ml of piperidine were dissolved in 500 ml of benzene and the solution was boiled for 8 hours using a water separator. 1 liter of ethyl acetate was added and the mixture was extracted twice with sodium bicarbonate, once with citric acid and once more with water, dried and evaporated. The crude product was subjected to incipient distillation up to 130° under a high vacuum and the product remained as the residue in the form of a chromatographically pure 2:1 isomer mixture.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.O>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CC#N
Product: CSc1nc(Cl)c(C=O)c(NC2CCCCC2)n1
Reaction time: 16 h
Yield: 99 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxaldehyde (4.0 g, 0.018 mol) in acetonitrile (65 mL) was treated with rapid stirring with cyclohexylamine (3.76 g, 4.3 mL, 0.038 mol) over 1 min. Reaction stirred 16 h then diluted with 3 volumes of H2O. The precipitated solid was collected, washed with H2O and dried in vacuo to afford 5.1 g. (99%) of the title compound as a white solid. LC MS (m/e)=286 (MH+). Rt=2.85 min.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[NH:5]=[C:6]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N1C=CC=N1.Cl.Cl.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O>[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([N:5]=[CH:6][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Reactant: NCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCC1CCN(N=CNC(=O)OCc2ccccc2)CC1
Yield: 95 %

Procedure:
Sodium hydroxide (4.45 g, 111.25 mmole) was dissolved in 150 mL of deionized water. The mixture of [imino(1H-pyrazol-1-yl)methyl]carbamic acid, phenylmethyl ester, dihydrochloride salt and 4-aminomethyl piperidine, dihydrochloride salt (prepared above, 16.18 g, 44.54 mmole) was added (pH of the cloudy solution was 13) and the mixture was extracted with dichloromethane (1×200 mL and 2×100 mL). The organic layers were combined and washed with brine (1×200 mL), dried (MgSO4), filtered and concentrated in vacuo to provide the title compound as a white foam (12.29 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17](O)=[O:18].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Solvent: O
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Reaction time: 0.5 h

Procedure:
Reaction of 500 mg (1.59 mmol) of the compound from Example V and 163 mg (1.75 mmol) of aniline as described for Example VI. The reaction time is about 30 min. For work-up, the reaction mixture is poured into 100 ml of water and extracted with dichloromethane (4×50 ml), and the combined organic phases are dried over sodium sulphate and concentrated. Yield: 610 mg (98% of theory). For characterization, a sample of the resulting product is recrystallized from ethanol, the main quantity is directly used further.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:19][CH2:18]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[CH:20]1([N:23]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[N:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O1CCOCC1>[CH:17]1([O:16][C:3]2[C:2]([C:26]3[CH:25]=[N:24][N:23]([CH:20]4[CH2:22][CH2:21]4)[CH:27]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:15])[N:8]3[C:12](=[O:14])[CH3:13])[CH2:19][CH2:18]1
Reactant: CC(=O)N1c2ccc(Br)c(OC3CC3)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CC3)c2CC[C@@H]1C
Temperature: 80 °C
Yield: 18.5 %

Procedure:
A 1.5 mL reaction vial was charged with (S)-1-(6-bromo-5-cyclopropoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.019 g, 0.06 mmol) and 1,4-dioxane (50 μL). 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 540 μL, 0.108 mmol) and potassium carbonate (1 M solution in water, 180 μL, 0.18 mmol) were added, and the reaction mixture was purged with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 300 μL, 0.006 mmol) was added, and the reaction was purged with nitrogen and heated to 80° C. on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and washed with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-1-(5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)ethanone (0.0039 g, 19%). MS (ESI, pos. ion) m/z 352 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52](N(OC)C)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:29])[CH3:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][CH:7]=2)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CON(C)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl N-[2-(4-bromophenyl)-ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithium in hexane (1.59M, 1.07 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N-methylbenzamide (480 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give tert-butyl N-[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]benzoyl]phenyl]ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (710 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.Cl>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(OC(F)(F)F)cc23)CC1

Procedure:
(19.2 mg, 59%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and 4-fluorobenzoyl chloride (17.0 mg, 0.107 mmol), HRMS-FAB+ for C22H18N2O2F4.HCl, calculated MH (-HCl): 419.13828; found: 419.13870.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[O:24]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25]1.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:25][CH:26]([OH:24])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Reactant: C1=C(c2ccccc2)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC(O)c1ccccc1)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1

Procedure:
A solution of 26.6 g of 4'-(6-hydroxyhexyloxy)(1,1')-biphenyl-4-carboxylic acid, 16 g of epoxystyrene and 16 g of triethylamine in 300 ml of tetrahydrofuran is heated at the boiling point for 140 hours. It is diluted with 1000 ml of methylene chloride, washed twice with 2N hydrochloric acid and dried over sodium sulfate. After concentration under reduced pressure, the residue is crystallized from ethanol. 2-Hydroxy-2-phenylethyl 4'-(6-hydroxyhexyloxy)-(1,1')-biphenyl-4-carboxylate is obtained; melting point: 148°-150°.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[O:30])=[C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[NH2:53][C:54]1[S:58][N:57]=[C:56]([C:59](=[N:63][O:64][CH2:65][CH3:66])[C:60](Cl)=[O:61])[N:55]=1>C(Cl)Cl.O.N1C=CC=CC=1.CO>[NH2:53][C:54]1[S:58][N:57]=[C:56]([C:59](=[N:63][O:64][CH2:65][CH3:66])[C:60]([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])=[C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:22][S:23][C@H:18]23)=[O:61])[N:55]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(C)(=O)=O)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h

Procedure:
To a solution of phosphorus pentachloride (57 g) in methylene chloride (1 l) was added to pyridine (22 ml) at -20° C. and the mixture was stirred for 30 minutes at -20° C. p-Nitrobenzyl 7-(2-phenylacetamido)-3-mesyloxy-3-cephem-4-carboxylate (50 g) was added to the solution at 5° C. and stirred at the same temperature for 1 hour. Methanol (56 ml) was added to the solution at -30° C. and stirred at -15° C. for 30 minutes. To the solution were added pyridine (80 ml) and diisopropylethylamine (31.4 ml) at -30° C. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride hrydrochloride (syn isomer) (26.7 g) was added to the solution at -30° C. by portions and stirred at -15° C. for 1 hour. Water (1 l) was added to the solution and stirred for 30 minutes. A resultant precipitate was collected by filtration and washed with diisopropyl ether and air-dried to give p-nitrobenzyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (40 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].C(N=C=NC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:15]2([OH:16])[CH:17]=[CH:18][CH:19]=[CH:20][CH:14]2[C:13]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: O=C(O)CCCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)C1C=CC=CC1(O)C(=O)CCCc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 1.00 g of 4-phenylbutyric acid and 60 mg of N,N-dimethylaminopyridine in 20 ml of dichloromethane is added 0.75 ml of ethyl salicylate, followed by 0.95 ml of diisopropyl carbodiimide. After 18 hours, the mixture is concentrated under reduced pressure, and the residue triturated with ether. The organic phase is washed with aq. sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated under reduced pressure. Flash chromatography on silica with 10% ethyl acetate in hexane affords 1.61 g of the title product as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si](C(C)(C)C)(C)C)[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine (1.9 g, 3.6 mmol) was dissolved in solvent mixture of N,N-dimethylformamide/H2O (10/1) (5.0 mL). Subsequently, cesium carbonate (1.2 g, 3.6 mmol) was added thereto. The mixture was stirred for 3 hours at room temperature, followed by concentration under reduced pressure. Hydrochloric acid (1.0 mol/L) was added thereto. The resultant mixture was extracted with ethyl acetate, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The resultant mixture was subjected to purification by silica gel chromatography (n-hexane/ethyl acetate=5/1), whereby the target compound was obtained (1.3 g, 89%).