Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.[Na+].[I-].C(N(CC)CC)C>S(Cl)(Cl)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@@H:13]1[CH3:12])[CH2:6][CH2:5]2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: OC1CCc2cc(Br)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-1-indanol (1.0 g, 4.7 mmol) of Step A was dissolved in thionyl chloride (10 mL). After stirring at room temperature for 2 hrs, the solution was concentrated under vacuum. The residue was taken up in DMF (10 mL). To the mixture were added tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.94 g, 4.7 mmol), NaI (2 g, 13 mmol) and triethylamine (1.5 mL, 10 mmol). The resulting solution was stirred at 70° C. overnight. After cooling to room temperature, water was added. The solution was extracted with EtOAc twice. The combined EtOAc layers were washed with brine, dried over MgSO4 and concentrated. Column chromatography on silica (50% EtOAc in hexane) provided two isomers. Isomer 1 (fast moving isomer): 0.36 g; MS calculated for C19H27BrN2O2 (M+H)+ 395; found 395.1, 397.0. Isomer 2 (slow moving isomer): 0.33 g; MS found 395.1, 397.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[NH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][NH:34][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: NCCO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using (S)-phenyl 4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenylcarbamate (intermediate 10) and 2-amino ethanol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[O:25]=[C:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
To a solution of oxalyl chloride (2.33 mL, 26.7 mmol) in methylene chloride (50 mL) cooled at −60° C. was added a solution of DMSO (4 mL, 56 mmol) in methylene chloride (5 mL) followed by a solution of trans-4-tert-butoxycarbonylaminocyclohexanol (5 g, 23 mmol) obtained above in methylene chloride (20 mL). After stirring at −60° C. for 20 minutes, triethylamine (16.1 mL, 116 mmol) was added. The mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Water was added. The organic phase was separated and the aqueous layer was extracted with methylene chloride twice. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 3% to 5% to 10% MeOH/CH2Cl2 provided 4.5 g (90%) of the title compound. MS (M+H)+ 214, found 236 (M+Na)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]1[C:14]2=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=[C:13]2[O:12][C:11]([CH3:36])([CH3:35])[C@@H:10]1[OH:37])[C:23](=[O:29])[C:22]1[C:17](=[CH:18][CH:19]=[C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]2=1)[N:16]3[CH3:34]>N1C=CC=CC=1>[C:1]([O:37][CH:10]1[C:11]([CH3:35])([CH3:36])[O:12][C:13]2[C:14](=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=2)[C:23](=[O:29])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]4[CH:33]=[CH:32][CH:31]=[CH:30][C:21]4=2)[N:16]3[CH3:34])[CH:9]1[OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(O)C(OC(C)=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.2 mmol of acetic anhydride are added to a solution, cooled to 0° C., of 2 mmol of the compound of Example 4 in 5 ml of anhydrous pyridine. After stirring at ambient temperature for 3 hours, the reaction mixture is concentrated under reduced pressure. Chromatography over silica gel (dichloromethane, and then dichloromethane/methanol: 99/1) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31](B1OC(C)(C)C(C)(C)O1)([CH3:33])=[CH2:32]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:31]([CH3:33])=[CH2:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
In a manner similar to that described in Scheme 1 (Step 3), 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a) was coupled with isopropenylboronic acid pinacol ester to provide 6-chloro-3-(prop-1-en-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C28H22ClIN3 [M+1]+ 436, found 436.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:22][CH2:23][C:24]([N:26]3[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]3[CH3:32])=[O:25])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17]C)[C:10]3=[N:19][CH:20]=[CH:21][N:9]23)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:22][CH2:23][C:24]([N:26]3[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]3[CH3:32])=[O:25])[C:16]3[C:15]([OH:17])=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3=[N:19][CH:20]=[CH:21][N:9]23)=[CH:4][CH:3]=1
Reactant: COc1cccc2c1C(CCC(=O)N1C(C)CCC1C)(c1ccc(Cl)cc1)n1ccnc1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2c(O)cccc2-c2nccn21

Procedure:
To a solution of 5-(4-chlorophenyl)-5-[3-(2,5-dimethylpyrrolidin-1-yl)-3-oxopropyl]-6-methoxy-5H-imidazo[2,1-a]isoindole (190 mg) in CH2Cl2 (2 mL) was added BBr3 (1.7 ml) slowly at 0° C. After 90 min the mixture was quenched with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to an off-white solid (179 mg) which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]3[O:22]C(=O)[CH:24]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[N:25]=3)[CH:12]=[N:13][C:14]=2[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:19])([F:20])[F:18])=[N:13][CH:12]=[C:11]([CH:10]=2)[C:21]([NH:25][CH2:24][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OC(c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)c(Cl)c3)c2)=NC1C(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(=O)C(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Yield: 56.3 %

Procedure:
A suspension of 3.00 g 2-[5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-4-(2,2,2-trifluoro-acetyl)-4H-oxazol-5-one in 15 ml water and 15 ml dioxan was heated to reflux for 1 h. The resulting slightly turbid solution was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 1:1. The product fractions were concentrated and the residue was taken up in dichloromethane whereby crystallization occurred. The solid was collected by filtration and washed with little dichloromethane to yield 1.60 g of the title compound as white solid. m.p.: 122-124° C. MS (EI): 474 (M+).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6](=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:8])[CH3:7]>C1COCC1.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]([CH:1]1[CH2:3][CH2:2]1)([CH3:7])[CH3:8])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of copper(I) iodide (7.61 g, 40.0 mmol) in THF (50 mL) at −50° C. was added cyclopropylmagnesium bromide (160 mL, 80.0 mmol, 0.5 M in THF) under nitrogen. After stirring for 15 minutes, the suspension was allowed to warm up and stirred at rt for 20 min before cooling back to −50° C. A solution of diethyl isopropylidenemalonate (4.0 g, 20.0 mmol) in THF (50 mL) was added, and the reaction was allowed to warm to rt over 3 h. The reaction mixture was then quenched with saturated sodium bicarbonate (200 mL), and filtered through Celite. The filtrate was extracted with ethyl acetate (3×250 mL). The combined extracts were dried over sodium sulfate and concentrated, and the resulting residue was purified by silica gel chromatography eluting with diethyl ether/hexanes (1:10) to afford 2-(1-cyclopropyl-1-methylethyl)malonic acid diethyl ester.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[C:1]1([N:7]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(N(c2ccccc2)c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1cccc(N(c2ccccc2)c2ccc3ccccc3c2)c1
Temperature: 0 °C

Procedure:
The thus-obtained phenyl-β-naphthyl-3-methoxyphenylamine was dissolved in 250 ml of toluene, and 25 g of anhydrous aluminum chloride was added thereto. The resulting mixture was heated under reflux for 2 hours. After being allowed to cool down, the reaction liquor was poured into ice water and then rendered acidic by adding hydrochloric acid. The organic phase thus-obtained was separated and the toluene was concentrated under reduced pressure. Crystals precipitated were collected by filtration to obtain 24 g of phenyl-β-naphthyl-3-hydroxyphenylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH2:44][CH3:45])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH2:44][CH3:45])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3CC)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K31) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (294 mg, 69%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]([S:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14].CI.Cl>O1CCCC1>[CH:13]([S:16][CH:17]([CH3:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CSC(C)C
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
A solution of diisopropylamine (15.4 mL, 0.11 mol) in tetrahydrofuran is cooled to 0° C., treated dropwise with a 2.04 M solution of n-butyllithium in tetrahydro-furan (51.4 mL, 0.105 mol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl (isopropylthio)acetate (16.3 g, 0.1 mol), stirred at 0° C. for 1 hour, treated with methyl iodide (15.6 g, 0.11 mol), stirred at room temperature for 20 hours, and poured into an ice-water mixture (100 g) containing 15 mL of 6 N hydrochloric acid. The resulting aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water, saturated sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown solution. Vacuum distillation of the brown solution gives the title product as a liquid (10.0 g) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>C(#N)C>[NH:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)Nc1ccccc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution/suspension of 2-(2-aminophenyl) benzimidazole (5.0 g, 23.0 mmol), potassium carbonate (9.5 g, 69.0 mmol) in acetonitrile (300 mL) at 0° C. was added propionyl chloride (2.3 g, 23.0 mmol). The reaction mixture was allowed to warm to room temperature, stir overnight, followed by filtration to remove the white solid. This was washed thoroughly with acetonitrile. The acetonitrile was concentrated in vacuo, the residue extracted into methylene chloride, washed with potassium carbonate (saturated solution) and the organic layer was dried over anhydrous magnesium sulfate. The methylene chloride was removed in vacuo and the resulting solid was recrystallized from methanol, m.p. >200° C. 1H NMR (300 MHz, DMSO-d6) δ13.14 (bs, 1H), 13.00 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.31-7.20 (m, 3H), 2.53 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 313C NMR (75 MHz, DMSO-d6) δ172.2, 150.9, 172.1, 138.4, 133.4, 130.7, 127.3, 123.5, 122.7, 122.3, 119.8, 118.6, 115.2, 111.5, 31.1, 9.6; IR (KBr)3262, 1662 cm-1 ; MS (DCI) m/e MH+ =266; Analysis calc'd for C16H15N3O1 /0.4H2O1 : C, 70.53; H, 5.64; N, 15.37; H2O1, 2.40; found: C, 70.52; H, 5.84; N, 15.42; H2O1, 2.64.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:18]=[C:19]([C:23]#[C:24][C:25]3[CH:26]=[C:27]([NH:31][C:32]([C:34]4[O:35][CH:36]=[CH:37][C:38]=4[CH3:39])=[O:33])[CH:28]=[CH:29][CH:30]=3)[CH:20]=[N:21][CH:22]=2)=[N:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:18]=[C:19]([C:23]#[C:24][C:25]3[CH:26]=[C:27]([NH:31][C:32]([C:34]4[O:35][CH:36]=[CH:37][C:38]=4[CH3:39])=[O:33])[CH:28]=[CH:29][CH:30]=3)[CH:20]=[N:21][CH:22]=2)=[N:13]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(-c3nnn(CCCO[Si](C)(C)C(C)(C)C)n3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(-c3nnn(CCCO)n3)c2)c1
Temperature: 0 °C

Procedure:
To the solution of N-(3-((5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-methylfuran-2-carboxamide (71 mg, 0.131 mmol, 1 eq) in anhydrous THF (2.6 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.393 mL, 3 eq). The clear reaction solution was stirred at 0° C. using an ice-bath for 3 hours. The solution was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was isolated, washed with aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper clear liquor was decanted, concentrated, and the oily residue was loaded onto silica and chromatographed (EtOAc-Hex 1:4 to 4:1) to yield N-[3-({5-[2-(3-hydroxypropyl)-2H-tetrazol-5-yl]pyridin-3-yl}ethynyl)phenyl]-3-methyl-2-furamide as a white solid in the amount of 28 mg.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCNCC2)Cc2ccccc21
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a suspension of 10% palladium on carbon (5 mg) in ethanol (5 mL) was added of 1'-benzylspiro[3H-2-benzopyran-3,4'-piperidine]-1(4H)-one (20 mg, 0.058 mmol). (Hashigaki et al Chem. Pharm. Bull. 32 pg 3561-3568 (1984)). Hydrogenation was performed at 1 atmosphere pressure at room temperature. The reaction was stirred for 2 hours under hydrogen atmosphere, until TLC analysis indicated that the reaction was complete. The catalyst was removed by vacuum filtration through celite 545 and the filtrate was concentrated to give the desired product (12.4 mg, 98.5%). FAB-MS calc. for C13H15NO2 217; found 218 (M+H, 100%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH:69]1[CH:70]=[C:66]([S:65][CH2:64][C:18]2[CH2:19][S:20][C@@H:21]3[CH2:24][C:23](=[O:63])[N:22]3[C:17]=2[C:15]([OH:14])=[S:16])[N:67]=[N:68]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=C1C[C@H]2SCC(CSc3c[nH]nn3)=C(C(O)=S)N12
Reaction time: 1 h
Yield: 148.1 %

Procedure:
To a suspension of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4- yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl) thiomethylthio-3- cephem-4-carboxylic acid diphenylmethyl ester (9.2 g: 9 mMol.) in a mixture of anisole (18 ml) and nitromethane (72 ml) is added dropwise a solution of aluminum chloride (9.6 g: 72 mMol.) in anisole (31 ml) at -30° C. After stirring for 1 hour at the same temperature, the reaction mixture is quenched with ethanol (25 ml), stirred for several minutes, diluted with 1N-hydrochloric acid (75 ml) and water (500 ml), and washed with ethyl acetate. The aqueous layer was separated, concentrated to remove the organic solvents, and passed through a column of styrene- divinylbenzene copolymer adsorbent. The product is eluted with a mixture of methanol and water (4:1) to give 7β-(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio -3-cephem-4-carboxylic acid as pale yellow powder (4.19 g). Yield: 90%.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:13]([CH:14]([CH3:16])[CH3:15])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC(C)Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Yield: 97 %

Procedure:
To 100 ml dry toluene 15.3 g (0.1 m) 4fluoro-N-isopropylaniline and 8.7 ml (0.11 m) pyridine were added and stirred. To this solution 12.4 g (0.11 m) chloroacetyl chloride was added dropwise below 25° C. It was allowed to stir overnight at room temperature and the mixture was washed with 2×100 ml water. The organic layer was dried on anhydrous magnesium sulfate and evaporated to give 22.2 g pale yellow liquid, yield 97%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20]>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[C:20][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: C#CCOCCCCCBr
Product: COC(=O)c1ccc(C#CCOCCCCCBr)o1
Yield: 40.6 %

Procedure:
Methyl 5-bromo-2-furancarboxylate (1.49 g) was treated with 3-[(5-bromopentyl)oxy]-1-propyne (1.49 g) according to the method of Intermediate 9 to give the title compound as a yellow oil (0.97 g), t.l.c. (cyclohexane-diethyl ether 10:1) Rf 0.18.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[F:28]>C(#N)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:7]=[C:8]([O:9][CH3:10])[C:3]2=[O:2])=[C:22]([F:28])[CH:23]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COc1ccc(-c2cnc(OC)c(OC)c2)cc1
Solvent: CC#N
Product: COc1ccc(-c2cc(OC)c(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 29.3 %

Procedure:
According to Scheme 4 Step 1: The title compound was prepared from 2,3-dimethoxy-5-(4-methoxyphenyl)pyridine (1 eq, 0.41 mol, 0.10 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (2 eq, 0.82 mmol, 0.18 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 14 hours at 80° C. in acetonitrile. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 10 g SiO2) using cyclohexane/AcOEt 70/30 to 50/50 as eluent to afford 1-(4-Chloro-2-fluorobenzyl)-3-methoxy-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.24 mmol, 0.09 g, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(Cc2ccccc2)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A mixture of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6.05 g, 39.24 mmol), benzyl bromide (5.14 mL, 43.17 mmol) in DMF (50 mL) was cooled with an ice-water bath, then the solids of NaH (1.89 g, 47.09 mmol) were added in one portion, the mixture was stirred at 0° C. for 1.5 h, then quenched with saturated ammonium chloride aqueous solution, diluted with EtOAc, the organic phase was washed with water and saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with column chromatography to give the desired title product (5.537 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=7.30 (m, 3H), 6.95 (m, 2H), 6.57 (d, 1H, J=3.0 Hz), 6.53 (d, 1H, J=3.0 Hz), 5.03 (s, 2H), 4.25 (q, 2H, J=7.0 Hz), 2.44 (s, 3H), 1.34 (t, 3H, J=7.0 Hz).