Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[C:35](=[O:36])[CH:34]3[CH2:37][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([CH2:33]3)[C:31]2=[O:44])=CC=1.O>C(#N)C>[C:38]1([C:32]23[CH2:33][CH:34]([CH2:37]2)[C:35](=[O:36])[NH:30][C:31]3=[O:44])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(CN2C(=O)C3CC(c4ccccc4)(C3)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1NC(=O)C2(c3ccccc3)CC1C2
Reaction time: 1 h

Procedure:
A solution of 344 g of cerium(IV) ammonium nitrate in 1.1 1 of acetonitrile is added dropwise to a stirred solution of 53 g of 3-(4-methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 560 ml of acetonitrile at room temperature. After 1 hour, 515 ml of water are added and the mixture is stirred for 2 hours. It is concentrated to half the volume by distilling off the acetonitrile and is then diluted with 1 1 of water. The product which has precipitated is filtered off with suction, washed with water and dried in vacuo. The brown-yellowish crystalline substance is taken up in 800 ml of methylene chloride, 11 ml of n-propylamine are added and the mixture is left to stand overnight. The black solution is concentrated and 80 ml of methylene chloridediethyl ether (1:1) are added to the brown crystalline mass, and the crystals are filtered off with suction and dried under a high vacuum. The title compound is obtained as white crystals of m.p. 217-218° C.
Reaction SMILES: CN(C=O)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1
Reactant: ClCCCCBr
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: ClCCCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a DMF solution (110 ml) containing 2-pyridinol (10 g, 105 mmol) and 1-bromo-4-chlorobutane (36 ml, 315 mmol) was added potassium carbonate (16 g, 116 mmol), followed by stirring at room temperature for 8 hours. Water (300 ml) was added to the reaction solution, and extraction with ethyl acetate (300 ml) was then conducted. The organic layer was washed with water (300 ml) twice and dried over magnesium sulfate. The solvent was distilled off, under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The purified product was concentrated under reduced pressure to thereby obtain 3.32 g of oily colorless 2-(4-chlorobutoxy)pyridine.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:18])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14].[OH2:19]>[Cl-].C([N+]1C=CC=CC=1)CCCCCCCCCCC>[CH:17]1[C:9]([Cl:8])=[CH:10][C:11]2[NH:18][C:1]([O:14][C:13](=[O:15])[C:12]=2[CH:16]=1)=[O:19]
Reactant: O
Reactant: Cc1ccccc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Yield: 101.7 %

Procedure:
According to the sa manner as in Example 3, except that the flask was changed to 500 ml flask, 70 g of water, 280 g of toluene and 35 g of 4-chloroanthranilic acid were in place of 53 g of water and 2.8 g of laurylpyridinium chloride, and that the reaction temperature was maintained at 15°-25° C., 41.0 g of 7-chloroisatoic anhydride (purity: 94%) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH2:42]O)[CH:35]=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:54])=[O:53])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1>C1COCC1.C(OCC)C>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH2:42][CH2:41][CH2:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:53])=[O:54])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: OCCCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCCc2cccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.25 h

Procedure:
To 1.5 g of triphenylphosphine dissolved in 25 ml of THF is added 0.909 g of diisopropyl azodicarboxylate. After 15 minutes at room temperature, 0.61 g of 3-pyrid-3-ylpropan-1-ol is introduced and the mixture is left at 20° C. for 15 minutes. 1.36 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are introduced and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a toluene/ethyl acetate mixture passing from a ratio of 9/1 to 5/5 (v/v). 5 ml of 2M hydrochloric acid are added to the product obtained, dissolved in diethyl ether, and the solvents are then evaporated off. The residue is taken up in diisopropyl ether to give, after filtration, 0.55 g of the expected product.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ccc2cc3n(c2c1)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (50 mg, 0.19 mmol) in iPrOH (2 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (105 mg, 0.58 mmol) and DIEA (185 mg, 0.96 mmol). The mixture was stirred at 100° C. for 4 h. The mixture was concentrated under vacuum and the residue was purified by preparative TLC to afford 1-isopropyl-7-(methylthio)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (45 mg, 57.7% yield) as a yellow oil. LC-MS MS (ESI) m/z 407.1 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2.[N-:18]=[N+]=[N-].[Na+]>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[NH:18][CH2:12][CH2:11]2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 60 °C

Procedure:
Sulfuric acid (82.6 mL) was carefully added, at 0° C., to 5-methoxy-1-indanone (25 g, 154 mmol) in benzene (400 mL) followed by sodium azide (18 g, 277.4 mmol). The resulting mixture was heated at 60° C. for 24 h. After cooling at room temperature, the benzene was evaporated and the resulting mixture was diluted with water and extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation the product was obtained as a white solid after purification by chromatography (SiO2, ethyl acetate/n-hexane 1:1 to 4:1 v:v gradient) (13.2 g, 49%). MS: m/e=177.2 (M+)
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](N)(=[O:5])=[O:4].Cl.[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]2[C:18]2[CH:17]=[CH:16][C:15]([OH:34])=[CH:14][C:13]=2[N:12]=1.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]([F:8])([F:7])[S:3]([O:34][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[C:20](=[N:21][N:22]([CH2:32][CH3:33])[C:23]=3[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]([NH2:10])=[N:12][C:13]=2[CH:14]=1)(=[O:5])=[O:4]
Reactant: CCn1nc2c(N)nc3cc(O)ccc3c2c1CCc1ccccc1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1nc2c(N)nc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2c1CCc1ccccc1
Reaction time: 6 h
Yield: 91.9 %

Procedure:
N-Phenyl-bis(trifluoromethanesulfonamide (0.187 g, 0.447 mmol) was added to a stirred solution of 4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-ol hydrochloride (0.15 g, 0.41 mmol) and triethylamine (0.280 mL, 2.03 mmol) in DMF (5 mL). After 6 hours, water (25 mL) was added and a precipitate formed that was isolated by filtration, washed with water, and dried to yield 0.175 g of 4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-yl trifluoromethanesulfonate as a white powder, mp 178-179° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[O:7][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:13])([CH3:14])[O:7][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(O)c2c(c1)OC(C)(C)OC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)c2c(c1)OC(C)(C)OC2=O
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
A solution of 5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (30.00 g, 0.134 mol) in N,N-dimethylformamide (400 mL) was treated with powdered anhydrous potassium carbonate (19.41 g, 0.14 mol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with benzyl bromide (24.03 g, 0.14 mol) added dropwise over 15 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting material left by tlc). The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (500 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Crystallization form ethyl acetate (50 mL) and hexane (150 mL) gave 35.17 g of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as large colorless prisms. Chromatography of the mother liquors on silica gel (4×13 cm, elution toluene-ethyl acetate 0-5%) gave 6.64 g of additional material to afford a total yield of 41.81 g (99%). HRMS (ESI) calcd for C18H19O5 [M+H]+ m/z 315.1227. found 315.1386. 1H NMR (CDCl3, 600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04 (d, J=2.03 Hz, 1H), 6.15 (d, J=2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36 (broad t, 2H), 7.52 (broad d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[C:23]1([C:29]2[N:30]=[N:31][N:32]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:36]2[CH2:37][CH2:38][CH:34]([N:32]3[CH:33]=[C:29]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:30]=[N:31]3)[CH2:35]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CCC(n3cc(-c4ccccc4)nn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 9.8 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (100 mg, 0.33 mmol), 3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (160 mg, 0.42 mmol) and diazobicycloundecane (102 mg, 0.67 mmol) in pyridine (5 ml) was heated at 90° C. for 20 hrs. The reaction mixture was concentrated and the residue was diluted with water. The separated solid was filtered, washed with water, methanol and then with CHCl3, followed by acetonitrile to get 16 mg (10%) of title compound, m.p. 265° C. 1H NMR (TFA) δ: 0.92-1.43 (m, 4H), 2.51-2.80 (m, 2H), 3.57-4.59 (m, 5H), 5.43-5.62 (m, 1H), 7.44 (dd, 5H), 8.50 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:15])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Clc1ccc(Cc2ccccn2)cc1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 2-p-chlorobenzylpyridine (12.0 g, 0.059 moles) and hydrogen peroxide (33% w/v, 4.02 g, 12.2 ml, 0.118 moles) in glacial acetic acid (40 ml) was heated at 60° for 15 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (20 g) the chloroform was removed to give 2-p-chlorobenzylpyridine-N-oxide (11.02 g, 85%) as a viscous oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc(OCCN(C)C)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Potassium carbonate (0.46 g) was added to a solution of the product from step (i) (1.10 mmol) and 2-dimethylamino ethyl chloride hydrochloride (0.16 g) in DMF at RT. After 1 h no reaction was evident so the mixture was heated to 60° C. for 18 h. Water was added and the mixture extracted with ethyl acetate, washed (brine) and the organics dried (MgSO4) and concentrated to a green oil which was purified by flash column chromatography (eluent 1% triethylamine and 2% methanol in ethyl acetate) to give the subtitle compound as a coulourless oil (100 mg).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH:18]([OH:20])=O.[O:21]1CCC[CH2:22]1>>[OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:18]=[O:20])[C:6]3[C:11]([C:12]=2[CH:22]=[O:21])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Reactant: O=CO
Reactant: C1CCOC1
Product: O=Cc1c2ccccc2c(C=O)c2cc(O)ccc12
Reaction time: 2 h

Procedure:
In the same system as described for the 2,6-dihydroxy analog, a solution of 0.01 mole of the silated 2-hydroxy-anthraquinone in tetrahydrofuran is treated slowly with a solution of 0.01 mole of the same lithio anion. The reaction is allowed to proceed for two hours at room temperature. This solution of the enamine is hydrolyzed at room temperature by addition of 20 ml. of 90% formic acid solution. The reaction mixture is filtered, washed with water, dried and recrystallized from toluene giving 2-hydroxy-9,10-anthracene dicarboxaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH2:6][CH2:5][CH:4]=1)[CH3:2].C(=O)(O)[O-].[Na+].[NH2:13][C:14]1[C:19]2[N:20]([CH3:24])[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[H][H]>CO.[Pd]>[CH2:1]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4][N:13]1[C:14]1[C:19]2[N:20]([CH3:24])[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCC1=CCCC1
Reactant: [H][H]
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC1CCCCN1c1cccc2[nH]c(=O)n(C)c12
Reaction time: 12 h
Yield: 75 %

Procedure:
A mixture of 1-ethylcyclopentene (1.0 g, 10.4 mmol) and sodium bicarbonate (0.1 g, 1.19 mmol) in methanol (150 ml) was ozonized at −78° C. until TLC analysis indicated complete consumption of 1-ethylcyclopentene. The crude ozonide was transferred directly to a mixture of 7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.5 g, 3.07 mmol) and 10% palladium on carbon (0.05 g, Degussa type; 50% wet). The flask was fitted with a balloon of hydrogen and allowed to stir for 12 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with a 10% acetone/hexanes mixture to afford 597 mg (75%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:31](O)=[O:32])[N:29]=1)=[O:23].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:31]([NH:1][CH:2]2[C:12](=[O:13])[N:4]3[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1)=[O:23]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CCOCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 83.6 %

Procedure:
A solution of 7-amino-3-cephem-4-carboxylic acid (1.3 g.) and trimethylsilylacetamide (7.0 g.) in ethyl acetate (30 ml.) and a solution of 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetic acid (syn isomer, 1.72 g.), N,N-dimethylformamide (0.48 g.) and phosphoryl chloride (1.01 g.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.35 g.).
Reaction SMILES: [N:1]1([CH2:6][C@@:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[C@H:8]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:26][N:27]1[C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=[N:28]1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([CH2:6][C@@:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[C@H:8]([C:10]2[CH:15]=[CH:14][C:13](/[CH:33]=[CH:32]/[C:31]3[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](c1ccc(I)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=Cc1ccnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(/C=C/c2ccnn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 64.7 %

Procedure:
A stirred solution of (2R,3S)-1-(1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-iodophenyl)butan-2-ol (Preparation 12; 0.5 g, 1.1 mmol), 1-methyl-5-vinylpyrazole (Preparation 17; 0.14 g, 1.3 mmol), triethylamine (0.25 ml, 2 mmol), palladium acetate (130 mg, 0.6 mmol) and tri-o-tolylphosphine (340 mg, 1.2 mmol) in acetonitrile (25 ml) was heated under reflux for 1 hour and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml), then the organic phase separated, washed with saturated brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of hexane:propan-2-ol (90:10 to 75:25), to give the title compound (0.31 g) as a white solid, m.p. 81-83° C., after crystallisation from aqueous ethanol. [α]D25 −55° (c=0.1, CH3OH).
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])[CH:24]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Yield: 69 %

Procedure:
1-Nitronaphthalen-2-yl triflate (5.94 g, 18.5 mmol) and tert-butyl 3-aminophenylcarbamate were used in a process similar to Example 1(1) to give the titled compound (4.83 g, yield 69%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[N:6][C:5]=2[N:21]=1.[OH-:22].[K+].[CH3:24]O>Cl>[Cl:10][C:9]1[C:4]2[S:3][C:2]([O:22][CH3:24])=[N:21][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=1
Reactant: [OH-]
Reactant: CO
Reactant: Fc1cccc(CSc2nc(Cl)c3sc(Br)nc3n2)c1F
Agent: Cl
Agent: [K+]
Product: COc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of example 31 step a) (5.6 g) was suspended in methanol (150 ml) and potassium hydroxide powder (0.77 g) added. The whole was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with a few drops of concentrated hydrochloric acid before it was evaporated to dryness. Purified by column chromatography (silica-3:2 to 1:1 isohexane/dichloromethane) to give white solid (2.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH2:29][CH2:30][OH:31])=[CH:25][NH:26]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH2:29][CH2:30][OH:31])=[C:25]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]3[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=3[OH:1])[NH:26]2)=[CH:22][CH:21]=1
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: OCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1ccccc1
Product: CC(C)C1NC(=O)C(C(c2ccccc2)c2[nH]c3cc(F)ccc3c2CCO)=C1O

Procedure:
Using general procedure D, rac-4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and 2-(6-fluoro-1H-indol-3-yl)-ethanol to give the title compound as a pale yellow solid. MS: 409.1 ([M+H]+).