Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[C:23](OCC=C)(=O)[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:23]=[CH:24][CH2:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: C=CCOC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 80 °C

Procedure:
In one embodiment, allylation of noroxymorphone with allyl acetate is accomplished by combining noroxymorphone with triethylamine (3 equivalents), toluene (50 mL) and tetrakis(triphenylphosphine)palladium[0] (0.1 equivalent), and heating the mixture at 80° C. for 64 hours. The mixture is cooled to a temperature of about 20° C. and filtered through a plug of CELITE and the filtrate was concentrated under reduced pressure. Naloxone is isolated from the concentrated filtrate using normal extractive procedures.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:9][N:8]([CH:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[C:6]=2[N:7]=1.CC(C)([O-:31])C.[K+].Br[CH2:35][CH:36]([F:38])[F:37]>CC(N(C)C)=O.C1COCC1.CS(C)=O>[F:37][CH:36]([F:38])[CH2:35][NH:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:9](=[O:31])[N:8]([CH:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[C:6]=2[N:7]=1
Reactant: FC(F)CBr
Reactant: COc1ccc(C2=Cc3c(C)nc(N)nc3N(C3CCC(O)CC3)C2)cn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: COc1ccc(-c2cc3c(C)nc(NCC(F)F)nc3n(C3CCC(O)CC3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(4-hydroxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-[7(8H)-one (50 mg, 0.13 mmol) in anhydrous DMA (1.0 ml) at room temperature was added a 1M solution of potassium tert-butoxide in THF (0.14 ml). After stirring at R.T. for 1 hour, to the reaction mixture was added 1-bromo-2,2-difluoroethane (20.9 mg, 0.14 mmol). After stirring at room temperature for 16 h and 4.5 h at 80° C. the reaction mixture was cooled to room temperature, and 1M solution of potassium tert-butoxide in THF (0.16 ml) and 1-bromo-2,2-difluoroethane (41.8 mg, 0.28 mmol) were added. After stirring at 80° C. for 16 h, to the reaction mixture was added another 1M solution of potassium tert-butoxide in THF (0.1 ml) and 1-bromo-2,2-difluoroethane (62.7 mg, 0.42 mmol). After stirring at 80° C. for 16 h, to the reaction mixture another 3 eq of 1M solution of potassium tert-butoxide in THF and 3 eq of 1-bromo-2,2-difluoroethane were added. After heating in microwave for 20 mins at 120° C., the reaction mixture was cooled to room temperature and diluted with DMSO, the precipitate was removed by filtration. The filtrate was combined and purified using reversed phase column eluted with acetonitrile (0.1% acetic acid) and water (0.1% acetic acid) to give the titled compound as a solid weighted 14.6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:30]([CH3:31])([CH3:32])[CH2:29][OH:28])=[CH:41][C:40]=1[NH:42][C:25]([C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=3)=[N:13][C:14]=12)=[O:26]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:30])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:30]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1[C@H](O)CCN1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-3-(tert-butyldiphenylsilyloxy)-1-phenylpyrrolidin-2-one (2.88 g, 6.93 mmol) in THF (8.6 mL) at 0° C. was added TBAF (13.9 mL of 1 M in THF, 13.86 mmol) slowly and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and evaporated to dryness. Purification by silica gel chromatography (0-10% MeOH in DCM) gave (R)-3-hydroxy-1-phenylpyrrolidin-2-one as a white solid (0.9 g 73%). 1H-NMR (400 MHz, DMSO-d6) δ 7.69 (d, J=7.8 Hz, 2H), 7.40-7.36 (m, 2H), 7.14 (t, J=7.4 Hz, 1H), 5.75 (d, J=5.8 Hz, 1H), 4.33-4.27 (m, 1H), 3.77-3.66 (m, 2H), 2.44-2.36 (m, 1H) and 1.86-1.81 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[N:7][C:6]=2[CH:19]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C:11]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[S:28][N:27]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:30]=4)[CH2:32][CH2:33]3)=[O:18])=[N:7][C:6]=2[CH:19]=1
Reactant: O=C(Nc1nc2cc(Cl)ccc2o1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1nc2cc(Cl)ccc2o1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 24.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-chloro-1,3-benzoxazol-2-yl)carbamate (254 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 79.2 mg (24.3%) of the desired product as a solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])[CH2:10][CH2:11][CH3:12].C[O:20][C:21](=O)[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O)(=O)C>O1CCCC1.ClCCl>[C:27]([O:26][C:24]([NH:23][CH2:22][C:21](=[O:20])[CH2:18][P:13]([CH2:9][CH2:10][CH2:11][CH3:12])(=[O:17])[O:14][CH2:15][CH3:16])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCCP(C)(=O)OCC
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCP(=O)(CC(=O)CNC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.82 g of lithium diisopropylamide in 30 ml of anhydrous tetrahydrofuran is cooled to -78° C. under an inert atmosphere. Under constant stirring at -78° a solution of 9.84 g of ethyl n-butyl(methyl)phosphinate in 20 ml of anhydrous tetrahydrofuran is added over 15 minutes under a positive pressure of an inert atmosphere via a canula. The resulting pale yellow solution is stirred for 1 hour at -78° and a pre-cooled (-78° C.) solution of 1.89 g of N-tert.-butoxycarbonylglycine methyl ester in 10 ml of anhydrous tetrahydrofuran is added over 5 minutes via a canula. Thin layer chromatography indicates complete reaction after circa 10 minutes. At -78° 4.0 g of glacial acetic acid is added and the mixture is allowed to warm to room temperature. The reaction mixture is diluted with dichloromethane and washed with water. Drying over magnesium sulphate and removal of the solvent in vacuo affords a pale yellow oil. Removal of the excess starting material by distillation and chromatography of the resulting yellow oil on silica gel yields ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(n-butyl)phosphinate as a colourless viscous oil.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[OH:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[CH:10][CH:9]=1.C([O-])(=O)C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[OH:7][C:8]1[CH:16]=[CH:15][C:2]([C:1]([O:4][CH:5]=[CH2:6])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=COC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=COC(=O)c1ccc(O)cc1
Yield: 10 %

Procedure:
2000 g of dichloromethane, 24.9 g of vinyl acetate, 40.0 g of 4-hydroxybenzoic acid, 0.79 g of palladium acetate and 3.5 g of potassium acetate were charged into a separable flask of the same type as used in Reference Example 3 and subjected to reaction at 50° C. for 6 hours, while replacing the flask inside atomosphere with a nitrogen gas. After completion of the reaction, the reaction mixture was washed successively with an aqueous 0.5N sodium carbonate solution and water, and then treated in th same manner as in Reference Example 3, whereby 4.8 g of vinyl 4-hydroxybenzoate having the following chemical formula was obtained (yield: 10%): ##STR5##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17][CH2:18]Cl)[CH3:15]>CN(C)C=O.C(Cl)(Cl)Cl.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:15][CH2:14][O:16][CH2:17][CH3:18])=[N:7][C:6]=2[CH:11]=1
Reactant: CCOCCCl
Reactant: Sc1nc2cc(Cl)ccc2s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOCCSc1nc2cc(Cl)ccc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
5.00 g (24.8 mmol) of 5-chloro-2-mercaptobenzothiazole was dissolved in 25 ml of N,N-dimethylformamide. 710 mg (29.6 mmol) of sodium hydride was added to the above solution and the mixture was stirred for one hour. Then, 5.44 ml (49.6 mmol) of 2-chloroethyl ethyl ether was added to the resulting suspension. and the mixture was stirred for two hours while heating at 50° C. The reaction mixture was diluted with 500 ml of chloroform and 500 ml of 20% aqueous solution of sodium chloride was added thereto. After shaking and washing the mixture, the chloroform layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was separated and purified by silica gel chromatography using a solution of hexane/ethyl acetate (10/1 by volume) as a developing solvent. Thus, 5.40 g of the desired compound was obtained in the form of a colorless oily substance. Yield: 80%.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].BrC[CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1)[CH2:11][CH2:12][CH3:13]
Reactant: CC1COC(CCBr)OC1C
Reactant: CCCCOC(CN)OCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromoethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([Li])CCC.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:42])[CH:29]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:30][S:31]2)=[CH:26][CH:25]=1.O>O1CCCC1>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([C:28]2([OH:42])[C:27]3[C:32](=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:31][CH2:30][CH:29]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 0.83 h
Yield: 28.1 %

Procedure:
To a solution of (3-bromobenzyloxy)-t-butyldimethylsilane (2.207 g, 7.326 mmol) in dry tetrahydrofuran (20 ml) was added n-butyl lithium (4.18 ml, 6.66 mmol, 1.59M tetrahydrofuran solution) at −78° C. over 25 minutes and stirred for 50 minutes. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (1 g, 3.33 mmol) dissolved in tetrahydrofuran at the same temperature over 10 minutes. The reaction mixture was stirred for 20 minutes at −78° C., followed at −15° C. for 12 h and at 0° C. for 8 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2) to give 0.49 g (yield: 28%) of the title compound as a colorless oil. In this reaction 0.55 g (55%) of the unreacted starting compound was recovered.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1>C(O)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:16][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=CCCCCCl
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: ClCCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
5-Chloropentanal (ca. 70% pure, 8.0 g) was added to a suspension of 4-bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%, 300 ml). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml), dried (MgSO4), filtered and evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate:light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 200° C., 0.5 mm, which rapidly darkened on storage.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[OH:14].[CH2:15]([N:22]1[C:30]2[C:29](Cl)=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1.O>[CH2:15]([N:22]1[C:30]2[C:29]([O:14][C:5]3[C:4]([CH3:3])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=3[CH3:13])=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of NaH (61.9 mg, 2.6 mmol) in dry NMP (4.7 mL) was added 2,6-dimethyl-4-nitrophenol (258.9 mg, 1.55 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (431 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product as a white solid (598 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.C(O)C.N>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 48 %

Procedure:
5-Amino-3-phenyl-1H-indazole can be obtained as described in Example 4 from 5 g of 5-nitro-3-phenyl-1H-indazole, 75 ml of ethanol, 77.5 g of ferrous sulfate, 65 ml of water and 50 ml of 32% aqueous ammonia. 2.1 g of 5-amino-3-phenyl-1H-indazole are thus obtained in the form of a white powder melting at 62° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:43]([O:46][CH:47](Br)[CH3:48])(=[O:45])[CH3:44].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O:29][CH:47]([O:46][C:43](=[O:45])[CH3:44])[CH3:48])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (0.31 g). The mixture was stirred for 20 minutes at room temperature, and 1-bromoethyl acetate (0.96 g) was added dropwise thereto at 0°-3° C. After the mixture was stirred for 40 minutes, 1-bromoethyl acetate (0.3 g) was added thereto. After stirring for 1 hour, reaction mixture was poured into ethyl acetate (120 ml) and the insoluble material was filtered off. The filtrate was washed with water (120 ml×2), an aqueous solution of sodium bicarbonate (50 ml × 1) and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to give 1-acetoxyethyl 7-[2-(2-aminothiazol- 4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl) vinylthio]-3-cephem-4-carboxylate (syn isomer) (0.27 g).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:20][C@@:10]12[C:17]([CH3:19])([CH3:18])[C@@H:13]([C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:9]=31)[CH2:12][CH2:11]2
Reactant: BrCCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 14.4 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 150 mg, 0.56 mmol), tetrabutylammonium iodide (200 mg, 0.54 mmol) and (2-bromoethyl)benzene (500 μL, 3.7 mmol) in dimethylformamide (1.5 mL) was heated in a pressure tube in an oil-bath at 100° C. for 2 days. Dichloromethane (100 mL) was added and the solution was washed with water (4×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and co-evaporated successively with dichloromethane/petroleum ether and then methanol, and dried under high vacuum over the weekend at room temperature and then at 80° C. for 4 h. The residue was treated with petroleum ether to give a solid. The solvent was evaporated and the solid was dried overnight at 70° C. to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (30 mg, 14%) as a pale yellow solid. ES(+)-MS (M+H) 373.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[N:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: COc1cnc(Cl)nc1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Product: COc1cnc(N2CC[C@H](N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)C2)nc1
Reaction time: 0.33 h

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-chloro-5-methoxypyrimidine following a procedure analogous to that described in Example 1 heating at 150° C. for 20 min. LC-MS Method 1 tR=1.27 min. min, m/z=427(M+1); 1H NMR (CD3OD) 8.17(d, 2H), 7.37(m, 5H), 4.79(m, 1H), 3.82(s, 3H), 3.67(m, 2H), 3.49(m, 1H), 3.78(m, 1H), 2.52(m, 2H), 2.24(m, 2H), 2.18(s, 2H), 1.24(s, 3H), 0.94(s, 3H).