Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=O)C(Cl)=O.[Li].C[Cu]C.CO>C1C=CC=CC=1.CCOCC.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[CH3:20])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CC(=O)Cl)c1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: C[Cu]C
Agent: [Li]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: CC(=O)CC(C)c1cccc(Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(m-phenoxyphenyl)-butyryl chloride (1 g.) (from the corresponding acid (1 g.) using excess oxalyl chloride in benzene) in ether (20 ml) was added dropwise to a solution of dimethyl copper lithium at -70° C. under nitrogen (from methyl lithium (0.2 g.) and cuprous iodide (1 g.)) in ether (50 ml) and the mixture stirred a further 15 minutes at -70° C. Methanol was added to quench the reaction and the mixture was diluted with water, acidified and filtered through a pad of Kieselguhr. The ether layer was washed with sodium carbonate solution and with water, dried over anhydrous magnesium sulphate and evaporated to give a colourless oil. The product was purified by column chromatography to give 4-(m-phenoxyphenyl)-2-pentanone as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.I[C:12]1[C:13]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:14][C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:16][C:17]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>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.[Cu]I>[Cl:1][C:2]1[C:10]2[S:9][C:8]([C:12]3[C:13]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]4)=[N:14][C:15]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[N:16][C:17]=3[O:18][CH3:19])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2ncsc12
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cccc(Cl)c2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 7-chloro-1,3-benzothiazole (58.8 mg, 0.35 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100.0 mg, 0.19 mmol, 1.00 equiv), cesium carbonate (371.4 mg, 6.00 equiv), tetrakis(triphenylphosphine)palladium (40.4 mg, 0.03 mmol, 0.18 equiv) and copper (I) iodide (6.7 mg, 0.04 mmol, 0.18 equiv) in N,N-dimethylformamide (4.0 mL). The crude product was purified through a silica gel column, eluting with ethyl acetate/petroleum ether (1:10-1:3) to provide the title compound as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:5][NH:4]1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[O:29]=[C:30]1[N:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH:6]2[CH2:5][N:4]1[NH:3][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: C=CCOC(=O)CONC1CNNc2ccccc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CON1C(=O)N2CC1c1ccccc1N2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
5.63 g of the product obtained in stage D are dissolved in 2 l of acetonitrile. 8.45 g of triethylamine are slowly added, followed, at 0° C., by 1.658 g of diphosgene and 2.25 g of dimethylaminopyridine. The temperature is allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with AcOEt, and the organic phase is washed with water. It is dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica (eluent: heptane/AcOEt (4:1)). The compound obtained is crystallized from ether at 0° C. and 1.96 g of the expected product (41%) are isolated.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O-:6])=O)C.[C:11](OC(C)C)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC>>[CH2:4]([OH:6])[CH2:3][CH2:7][CH2:8][CH2:9][CH2:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CCCCC(CC)C(=O)[O-]
Product: CCCCCCCCCCCCCCCCCCO

Procedure:
10 Mixture of cetostearyl 2-ethylhexanoate and isopropyl myristate "CERAMOLL" (Creations Aromatiques) 2.0 g
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:14][C:15]1[N:20]=[C:19](I)[C:18]([NH2:22])=[CH:17][CH:16]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[Cl:14][C:15]1[N:20]=[C:19]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[C:18]([NH2:22])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: Fc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A 3-neck 1000 mL RBF was dried under vacuum, then charged with isopropylmagnesium chloride (78 mL, 156 mmol) and cooled with a water bath. 2-bromo-3-fluoropyridine (14.37 mL, 142 mmol) was added dropwise making sure temperature did not exceed 30° C. The reaction was stirred at room temperature overnight, then treated dropwise with zinc(II) chloride (341 mL, 170 mmol) over 3 hrs and stirred at room temperature overnight. This suspension was then added dropwise via canula to a degassed, 65° C. solution of Pd(PPh3)4 (8.21 g, 7.10 mmol) and 6-chloro-2-iodopyridin-3-amine (39.8 g, 156 mmol) in tetrahydrofuran (THF) (Volume: 474 mL) and heated at reflux overnight. After cooled to room temperature, the reaction was quenched with sat. aq. NaHCO3 and water. The precipitate was filtered out and washed with EtOAc. The filtrate was extracted with EtOAc. The crude product was purified by column chromatography in 40-50% EtOAc/hexanes with column conditioned in 20% TEA/hexanes to give 6-chloro-3′-fluoro-[2,2′-bipyridin]-3-amine (21.8 g, 69% yield).
Reaction SMILES: C([NH:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][C:17]1([CH3:18])[CH3:19])[CH3:10]
Reactant: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether, and the organic layer is dried over Na2SO4 and evaporated to yield 2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[Br:21][C:11]1[O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2ccco2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(Br)o2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Referring now to Scheme 5 above, to a chilled (ice/water bath) solution of 2-(4-cyanophenyl)furan (28.25 g, 0.167 mol) in DMF (100 ml) was added portionwise NBS (31.20 g, 1.05 eq., freshly recrystallized from nitromethane) with stirring (approximately 1 g portions over course of approximately 40 minutes). The resulting solution was stirred for 2 h at room-temperature, at which point TLC showed consumption of starting material. During the course of the reaction, the color went from yellow to orange and then finally to red. The solution was then diluted with water (approximately 300 ml) to give a pink/red solid, which was collected, washed with water, and air dried. Yield: 39.0 g, 94%. A small sample was recrystallized from MeOH/water to give a pale red crystalline solid, mp 96.5-97° C. 1H NMR (DMSO-d6): 6.80 (d, J=3.6 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.87 (m, 4H). IR (cm−1): 3142, 3128, 3060, 2226, 1613, 1515, 1475, 1015, 929, 833, 787, 545.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:34])CC)C.C(=O)([O-])O.[Na+]>COCCOC>[C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
The compound (257 mg, 0.69 mmol) synthesized in Example 1 (1h) was dissolved in 1,2-dimethoxyethane (5 mL) and diethylaminosulfur trifluoride (0.11 mL, 0.83 mmol) was added thereto at −20° C. The temperature of the mixture was gradually raised and the mixture was stirred at 60° C. for 1 hour. After saturated aqueous sodium hydrogencarbonate solution was added thereto at 0° C. until foaming did not occur, the mixture was extracted with ethyl acetate (15 mL) and the organic layer was washed with saturated brine (15 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain a colorless oil (113 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[CH:3]=1.[N:17]([O-])=[O:18].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[O:16])[C:3]=1[N:17]=[O:18]
Reactant: Nc1cc(=O)n(Cc2ccccc2)c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N=O

Procedure:
Slurry 6-amino-3-(phenylmethyl)-pyrimidine-2,4-dione (1.1 g=5 mmol) in 50 ml water. Add NaNO2 (0.63 g=9.1 mmol), warm to 75° C. and add acetic acid (2.6 ml=45 mmol) in 30 ml water over two hours. Collect the product, water wash and dry over P2O5 to give title compound as an orange solid. EI MS: M+=246.
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[S:41][C:40]([NH2:42])=[N:39][C:38]=2[CH3:43])=[CH:33][C:32]=1[S:44]([CH3:47])(=[O:46])=[O:45].[CH2:48]([O:50][C:51](=[O:57])[CH2:52][CH2:53][N:54]=[C:55]=[O:56])[CH3:49]>>[CH2:48]([O:50][C:51](=[O:57])[CH2:52][CH2:53][NH:54][C:55]([NH:42][C:40]1[S:41][C:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[C:32]([S:44]([CH3:47])(=[O:45])=[O:46])[CH:33]=2)=[C:38]([CH3:43])[N:39]=1)=[O:56])[CH3:49]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(C)(=O)=O)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:11][C:10]1[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][C:5]=1[N:4]([CH3:24])[C:1](=[O:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(NC(C)=O)c(C)nc1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N(C)C(C)=O)c(C)nc1C(=O)OCC
Reaction time: 1 h

Procedure:
A stirred mixture of 2.94 g of 5-acetamido-6-methylpyridine-2,3-dicarboxylic acid, diethyl ester, and 0.44 g of 60% sodium hydride in 200 mL dry tetrahydrofuran is kept at room temperature for 1 hour, then 0.93 mL of methyl iodide is added, and the reaction is stirred for an additional 4 hours. The reaction is concentrated in vacuo, and the residue is slurried in water, the pH is adjusted to 3 with hydrochloric acid, and the mixture is extracted with methylenechloride. The organic phase is dried, concentrated in vacuo to afford the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][CH2:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]([NH:29][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH2:25][CH3:24]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 72 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using S-(+)-2-amino-1-butanol instead of isopropylamine, to the title compound (89 mg, 72%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=S)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:18][NH2:19])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Product: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (1.50 g, 0.00485 mol) and a 1M solution of hydrazine in tetrahydrofuran (6.3 mL, 0.0063 mol) were heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. Additional 3 mL of a 1M solution of hydrazine in tetrahydrofuran was added and the stirring at reflux was continued for another 6 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.54 g, 0.0050 mol) as a tan solid. TLC (ethyl acetate/heptane 1:3) Rf 0.10
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=3Br)[CH:7]=[CH:6][C:5]=12.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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]>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=3[C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)=[CH:43][CH:44]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nsnc3c2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc3nsnc3c2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 9.3 %

Procedure:
A solution of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 1.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.634 g, 1.759 mmol), and Cs2CO3 (2.3 g, 7.329 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.24 g, 0.293 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 12 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (65 mg) as a yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1 H), 8.35 (s, 14 H), 8.12 (d, J=8.2 Hz, 1 H), 8.02 (t, J=7.4 Hz, 2 H), 7.79 (t, J=8.4 Hz, 1 H), 7.73-7.69 (m, 2 H), 7.63 (t, J=8.2 Hz, 1 H), 7.2 (d, J=8.3 Hz, 2 H), 7.12 (d, J=8.4 Hz, 2 H), 5.39 (s, 2 H), 1.49 (s, 6 H). MS: [M+Na]: m/z=502.2, [M+H]: m/z=480.1. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:37])=[N-]>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[C:16]([O:19][CH3:37])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
The 3-hydroxy-3-cephem ester can then be converted to a 3-alkoxy-3-cephem ester or to a 3-halo-3-cephem ester. For example, 4-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate is allowed to react in an inert solvent with diazomethane to form 4-nitrobenzyl 7-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylate. The 4-nitrobenzyl group is removed by catalytic hydrogenolysis over palladium on carbon catalyst to provide the antibiotic compound 7-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid. These 3-methoxy-3-cephem compounds are highly active antibiotics and are fully disclosed in my copending applications Ser. Nos. 310,190 and 310,191, filed Nov. 28. 1972 now U.S. Pat. Nos. 3,917,588 and 3,917,587, respectively, both issued Nov. 4, 1975.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH:18]([CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=3)[CH3:30])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17][CH:18]2[CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)[CH3:30])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-[(3RS,4SR)-3-[(SR)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.50 mmol) in 24 mL of CH2Cl2 was added 6 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH 1M (until ph=10) and the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to yield 0.237 g (99%) of the title compound as a white foam. ES-MS m/e: 473.0 (M+H+). Pyrrolidine VIII-B-2
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[NH3:21]>CO>[CH:17]1([C:3]2[C:2]([NH2:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: N
Solvent: CO
Product: Nc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Temperature: 50 °C

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (200 mg, 0.70 mmol) was suspended in methanol (8 ml). The mixture was saturated with ammonia and heated in a sealed tube at 50° C. overnight. The mixture was evaporated in vacuo, triturated (diethyl ether/hexane) and dried to give the title compound 1H NMR (360 MHz, d6-DMSO) δ 1.82-1.87 (1H, m), 1.99-2.35 (5H, m), 3.54-3.64 (1H, m), 7.34 (2H, vbs), 7.48-7.62 (3H, m), 8.08 (1H, s), 8.41 (2H, d, J=7.1 Hz); MS (ES+) m/e 266 [MH]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11]2.[Br:16]Br.Cl>ClC(Cl)C>[Br:16][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C1CCc2cccc(F)c21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C1CCc2c(Br)ccc(F)c21
Temperature: 65 °C
Yield: 64.3 %

Procedure:
To a room temperature solution of aluminum chloride (11.77 g, 88 mmol) in dichloroethane (100 mL) was added 7-fluoro-2,3-dihydro-1H-inden-1-one (5.3 g, 35.3 mmol) followed with bromine (1.91 mL, 37.1 mmol). The mixture was heated at 65° C. for 16 hours, then cooled to ambient temperature and poured into a mixture of ice and HCl (1N aqueous). The mixture was extracted twice with ether (200 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel column eluting with 0-10% EtOAc/hexanes) to provide the title compound (5.2 g, 64%). MS (DCI/NH3) m/z 246 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.C(=O)=O.[F:17][S:18](O)(=[O:20])=[O:19]>O>[Cl:1][C:2]1[CH:11]=[C:10]([S:18]([F:17])(=[O:20])=[O:19])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Reactant: O=S(=O)(O)F
Agent: O=C=O
Solvent: O
Product: Cc1ccc2c(Cl)cc(S(=O)(=O)F)c(O)c2n1
Temperature: -78 °C

Procedure:
A solution of 5-chloro-8-hydroxy-2-methylquinoline (9.2 g) in 55 mL of fluorosulfonic acid is stirred at 120° C. for 18 h in a tightly stoppered flask. The mixture is then cooled to −78° C. and poured onto an intimate mixture of 250 mL of crushed ice and 250 mL of powdered dry ice. The mixture is allowed to warm to 25° C., and then diluted with distilled water until further addition causes no additional solid to precipitate (ca. 100 mL). The mixture is filtered, and the solid obtained is washed with four 50 mL-portions of 0° C. distilled water and then dried in a stream of air to give 10.7 g of the title compound as an orange powder.