Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH2:5][Br:6])[CH3:2].C1([P:18](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br-:6].[CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH2:5][PH3+:18])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1cccc(C)c1CBr
Solvent: Cc1ccccc1
Product: CCc1cccc(C)c1C[PH3+]
Product: [Br-]
Temperature: 100 °C

Procedure:
To a solution of 2-ethyl-6-methylbenzylbromide (0.432 g, 2.03 mmol) in toluene (10 mL) was added triphenylphosphine (0.6018 g, 2.29 mmol). The mixture was heated at 100° C. for 4 h. After cooling to room temperature, the precipitate was collected by filtration and washed with toluene to give 2-ethyl-6-methylbenzylphosphonium bromide as a solid. Yield (0.958 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.92 (m, 3H), 7.69 (ddd, J=8.4, 8.4, 3.6 Hz, 6H), 7.49-7.55 (m, 6H), 7.20 (ddd, J=7.6, 7.6, 2.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.91 (d, J=14.7 Hz, 2H), 2.05 (q, J=6.7 Hz, 2H), 1.75 (s, 3H), 0.78 (t, J=6.7 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24](O)[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:3])[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)CCc1cc(O)n2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1

Procedure:
Phosphorus oxychloride (6.4 ml) and triethylamine (3.5 ml) were added to 40 ml of a toluene suspension containing 4.2 g of the crystals obtained in step (4), and the mixture was refluxed with heating for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The mixture was neutralized with sodium acetate and extracted with ethyl acetate. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=4:1) to provide 4.3 g of 5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine as a light yellow oily compound.
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:37](=O)(OC)OC>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[CH3:37][P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)OC
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 321.8 g (1.1 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added afterwards. After one hour of reaction and mixing, the reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 4 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 584.8 g of methyl triphenyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after recrystallization and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]C(=O)C(C)(C)C.[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(Cl)Cl>C(Cl)Cl.CO>[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19]([C:3]2[C:2]([NH2:7])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH2:17]1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=C1CCC(C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: Nc1ncccc1C1=CCC(C(F)(F)F)CC1
Yield: 26 %

Procedure:
Prepared in analogy to example 262 step a-b), starting from N-(pyridin-2-yl)pivalamide and 4-(trifluoromethyl)cyclohexanone. 3-(4-Trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine was obtained after column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent as a white solid (yield: 26% over 2 steps).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O.CCOCC>[C:15]1(=[O:25])[N:19]([CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1cccc(OCC(O)CCl)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1

Procedure:
The distilled product from Example 1 (21.1 g, 0.098 mol) and potassium phthalimide (37 g, 0.20 mol) are dissolved in 100 ml of N,N-dimethylformamide and the mixture is heated 22 hours on a steam bath under N2. The mixture is cooled, diluted with 200 ml of ether and filtered. The filtrate is concentrated to remove ether and diluted to 500 ml with water to give the crystalline title product, 30.8 g, mp 122°-126°.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)[NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:8].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:25]([O:35][CH3:36])[CH:24]=3)[N:10]3[CH2:4][CH2:5][NH:6][C:7](=[O:8])[C:9]=23)=[CH:15][CH:16]=1
Reactant: COc1cc(/C=C/c2nc(C(=O)NCCCl)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCNC3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Sodium hydride (containing mineral oil at 60%, 3 mg) was added to a solution of 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylic acid (2-chloroethyl)amide (15 mg) in DMF (2 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 10 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C:10]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1C=O

Procedure:
To 10% palladium on carbon (2.1 g) in ethanol (50 mL) add (S)-5-benzyloxymethyl-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (3.29 g, 7.16 mmol) in ethanol (75 mL) and stir under 1 atmosphere of hydrogen gas at room temperature for 4 hours. Filter and concentrate to give the desired compound as a white solid. Dissolve the solid in dimethylsulfoxide (20 mL) and add triethylamine (1.30 g, 12.82 mmol), then pyridine sulfur trioxide complex (1.84 g, 11.55 mmol). Stir at room temperature 3 hours and dilute with 10% ethyl acetate/hexanes (˜150 mL). Wash with water, 1 N aqueous citric acid and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1
Reactant: OCCCC1CCCOC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC1CCCOC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To the solution of 3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (10.35 g, 0.0719 mol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (61.24 g, 0.1438 mol). The mixture was stirred at rt. When the reaction was over, the solution was poured into Et2O (300 mL) and anhydrous K2CO3 (19.84 g, 0.1438 mol) was added. The mixture was filtered and the filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[C:4](C(OCC)=O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]2.C(O)=O.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:10][CH:9]([CH3:11])[C:6]([CH3:12])([CH2:5][CH2:4][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]1[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)CCC1(C)C(C)CCN(C)C1C
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate (121 g, 389 mmol) at 0° C. was added formic acid (121 mL, 3.2 mol), followed by triethylamine (179 mL, 1.3 mol). The mixture was slowly heated to 160° C. over a period of 2 hours and was stirred at 160° C. for 20 minutes. The mixture was cooled to room temperature, and allowed to stand under nitrogen for 24 hours. The mixture was basified by the addition of saturated NaHCO3 and was extracted with ether (3X). The organic layers were combined, washed with saturated NaHCO3 then brine and were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was taken up in 0.5N HCl (500 mL) and washed with hexane (3X). The aqueous layer was basified with concentrated NH4OH and extracted with ether (3X). The ether layer was dried over MgSO4 and concentrated in vacuo to afford 34 g (36%) of ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate as a yellow oil. The combined aqueous phases were concentrated in vacuo and the residue was triturated with hot ethanol (800 mL at 70° C.). The solution was filtered, triturated with additional hot ethanol (300 mL) and filtered once again. The ethanol filtrates were combined, acidified with concentrated H2SO4 and refluxed for 24 hours under nitrogen. The solution was basified with concentrated NH4OH and extracted with ether (3X). The ether layers were combined, washed with saturated NaHCO3 (2X) and dried over MgSO4. The solvent was removed in vacuo to afford 28.5 g of additional product for a total yield of 62.5 g (67%). The product was treated with p-toluenesulfonic acid to afford ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate-4-methylbenzenesulfonate as a white powder, m.p. 171-171.5.C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:32]1[CH:36]([CH3:37])[CH2:35][NH:34][C:33]1=[O:38])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[CH:36]([CH3:37])[CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:33]1=[O:38])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1CNC(=O)N1C(=O)c1ccccc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)N(C(=O)c5ccccc5)C4=O)cc3)CC2)c(C)c1
Yield: 16 %

Procedure:
Using (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-benzoyl-5-methylimidazolidin-2-one (98 mg) described in Preparation Example 56 and by the reaction and treatment in the same manner as in Example 1, the title compound (32 mg) was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]([OH:54])CO)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC(O)CO)CCCCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC=O)CCCCC1
Reaction time: 4 h

Procedure:
A solution of EXAMPLE 167E (600 mg) in acetone (30 mL) was treated with a solution of sodium periodate (852 mg) in water (5 mL). After about 4 hours, the solvent was removed by distillation and the residue was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product which was purified by flash column chromatography (20% ethyl acetate in hexane) to give the pure product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].CC([N-]C(C)C)C.[I:28]I.O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:28])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: II
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Reaction time: 3 h

Procedure:
To a stirred solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]-pyrimidine (5.0 g, 0.017 mol) in THF (200 mL) under inert atmosphere, at −78° C., was added 2.0 M LDA solution (9.8 mL, 0.0195 mol) over a period of 15 min. After 1 h a solution of iodine (4.97 g, 0.0196 mol) in THF (50 mL) was added dropwise over a period of 15 min. The resulting solution was stirred for a further 3 h. Water (10 mL) was then added and the mixture allowed to reach r.t. The mixture was diluted with DCM (1 l), washed with brine (2×100 mL), dried and concentrated under reduced pressure. The resulting solid was triturated with MeCN to afford the 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (CDCl3, 400 MHz) 7.05 (1H, s), 7.50 (2H, t), 7.60 (1H, t), 8.20 (2H, d) and 8.65 (1H, br s).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:28])=O>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([Cl:28])=[N:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc2c(-c3ccc(-c4ccccc4)cc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(-c4ccccc4)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(biphenyl-4-yl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[C:16]1([O:15][C:13](=[O:14])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Reaction time: 24 h

Procedure:
Dissolve 2-amino-5-trifluoromethylpyridine (162 mg, 1.0 mmole) in pyridine (2.0 mL) under nitrogen at room temperature. Add drop wise phenyl chloroformate (0.125 mL, 1.0 mmole) to the reaction mixture at room temperature. Stir the mixture for 24 hours and new spot is noticed in TLC (30% EtOAc/hexane). Evaporate the reaction mixture under vacuo and purify the crude by flash column chromatography on a silica gel using CHCl3 to afford (5-Trifluoromethyl-pyridin-2-yl)-carbamic acid phenyl ester as a white solid. B. 1′-(5-Trifluoromethyl-pyridin-2-yl-carbamoyl)spiroisobenzofuran-1,4′-piperidine
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([F:40])[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:37][C:36]1[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][C:35]=1[F:40])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1sc2ccncc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc2ccncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
A degassed solution of 3-(nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (422 mg, 0.83 mmol), 4bromo -2-fluoroaniline (206 mg, 1.08 mmol), Pd2 dba3 (38 mg, 0.04 mmol), Xantphos (48 mg, 0.08 mmol) and DBU (316 μl, 2.08 mmol) in toluene (1 ml) was subjected to microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (30 ml). The resultant solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to give a solid residue. The solid residue was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 70:30) to afford the title compound as a white solid (210 mg, 64%). LCMS (method B): RT=3.78 min, M+H+=395/397.
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([OH:19])=O.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C=O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([NH:7][C:5]1[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=1)=[O:19]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Solid HOBT (552 mg, 3.60 mmol) was added in one charge to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 38; 800 mg, 3.28 mmol), 3-pyridinamine (339 mg, 3.60 mmol) and EDC (691 mg, 3.60 mmol) in DMF (30 mL) at room temp. The reaction mixture was stirred at room temperature for 4 h. After 4 h, water was added to the reaction mixture. The reaction mixture was filtered and the residue was washed with ethyl acetate to yield the title compound as a white solid. 500 mg.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[S:23][C:22]2[C:21]([NH:24]C3C=C4C(=CC=3)NC=C4)=[N:20][CH:19]=[N:18][C:17]=2[CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:15]2[S:23][C:22]3[C:21]([NH2:24])=[N:20][CH:19]=[N:18][C:17]=3[CH:16]=2)=[CH:7][CH:8]=1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Nc1ncnc2cc(-c3ccc(C(F)(F)F)cc3)sc12

Procedure:
The title compound was prepared from 3-trifluoromethylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 181-194° C.; LC-MS: 411 (MH+); HPLC RT: 4.88 minutes.
Reaction SMILES: C1(OC)C=CC=CC=1.[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:33][O:34][C:35]([CH3:53])([C:37]([O:39]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:38])[CH3:36])[C:16]([NH:18][C@H:19]2[C@@H:22]([CH2:23][O:24][C:25](=[O:27])[NH2:26])[N:21]([S:28]([O-:31])(=[O:30])=[O:29])[C:20]2=[O:32])=[O:17])[N:14]=1.[Na+].FC(F)(F)C(O)=O>CCOCC>[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:33][O:34][C:35]([CH3:53])([C:37]([OH:39])=[O:38])[CH3:36])[C:16]([NH:18][C@H:19]2[C@@H:22]([CH2:23][O:24][C:25](=[O:27])[NH2:26])[N:21]([S:28]([OH:31])(=[O:30])=[O:29])[C:20]2=[O:32])=[O:17])[N:14]=1
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(N)=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1)C(=O)O
Temperature: -20 °C

Procedure:
To 1 ml of anisole is added 250 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer) and under stirring at -20° C., 5 ml of trifluoroacetic acid is added dropwise. The mixture is stirred at -15° C. for 30 minutes, after which 10 ml of ether and 10 ml of petroleum ether are added. The resultant powder is recovered by centrifugation and dissolved in water. To the solution is Dowex 50W (H-form) resin, followed by stirring. The resin is filtered off and the filtrate is concentrated and purified by chromatography using an Amberlite XAD-2 (eluent: water, 100 ml; 10% ethanol, 100 ml; 30% ethanol, 100 ml and then 40% ethanol, 50 ml) and the fractions of 30% ethanol and 40% ethanol are lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1 -methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).