Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1([Li])C=CC=CC=1.[C:16]1([C@H:22]2[O:25][C@@H:23]2[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:23]([OH:25])[CH3:24])=[N:6][CH:7]=1
Reactant: Cc1ccc(Cl)cn1
Reactant: C[C@H]1O[C@@H]1c1ccccc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: C[C@@H](O)[C@@H](Cc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in 15 mL anhydrous ether was added phenyl lithium (1.8 M in cyclohexane/ether, 7.2 mL, 13 mmol) at 0° C., and the reaction was stirred at room temperature for 30 min. The resulting mixture was cooled back to 0° C., and was added (1R,2R)-1-phenylpropylene oxide (2.3 g, 17 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.28 (d, 1H), 7.59 (dd, 1H), 7.25-7.12 (m, 5H), 7.05 (d, 1H), 4.03 (m, 1H), 3.29 (dd, 1H), 3.19 (dd, 1H), 3.12 (m, 1H), 1.12 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:14][C:13]([CH:15]=[O:16])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H][H]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc(-c2ccc(CO)[se]2)c(F)c1F
Reaction time: 0.08 h

Procedure:
3.9 g (12.4 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a suspension in 100 ml of diethyl ether are added slowly to a suspension of 0.47 g (12.4 mmol) of lithium aluminium hydride in 20 ml of diethyl ether with ice-cooling. When the addition is complete, the mixture is stirred for 5 min, and water is added dropwise to the mixture until evolution of hydrogen no longer occurs. The mixture is filtered through Celite with MTBE. The filtrate is washed with water and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (yellowish crystals) is used directly for the subsequent reaction.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C.[OH-].[Na+].C(O)C.O.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 111.2 %

Procedure:
A mixture of 14.6 g (0.04 mole) of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester, 2.9 g (0.073 mole) of sodium hydroxide pellets, and 150 ml of ethanol/water (1:1) was refluxed for 45 min. The reaction mixture was poured into a 250-ml of water, acidified with concentrated hydrochloric acid; and filtered, giving 12.8 g (97%) of a white solid. A 2-g portion was recrystallized from methanol-water to give 1.2 g of white needles, mp 271°-273° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cccc(F)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(5-bromopyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.81 mmol, 1.00 equiv), (3-fluorophenyl)boronic acid (0.790 g, 5.65 mmol, 2.00 equiv), Tetrakis(triphenylphosphine)palladium (0.325 g, 0.280 mmol, 0.10 equiv), potassium carbonate (1.17 g, 8.47 mmol, 3.00 equiv), dioxane (24 mL), and water (4 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 0.955 g (92% yield) of tert-butyl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 372 [M+H]+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1cscn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-Arg(Tos)-Thiazole (300 mg, 0.6 mmol) in CH2Cl2 (10 mL) at 0° C. is added TFA (10 mL). The solution is stirred at 0° C. for 2 h. The solvent and excess TFA are evaporated to an oily residue which is used directly without further purification.
Reaction SMILES: [H-].[Na+].OC1C=CC(C2C3C=C(N(C)C)C=C[C:15]=3[S:14](=[O:25])(=[O:24])CCC2)=CC=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.CN(C=[O:37])C>>[S:14]([O:25][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:37])(=[O:24])[CH3:15]
Reactant: CN(C)C=O
Reactant: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of NaH in 22 mL of DMF was added 2.05 g (4.45 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the mixture was added 18.02 g (55.63 mmol) of 1,5-dibromopentane and the solution was stirred overnight at ambient temperature. DMF was removed by high vacuum and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO4, and the concentrated residue was purified by column chromatography to give the pentyl mesylate intermediate: 1H NMR (CDCl3) δ0.90(q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6h), 3.0 (q, 2H), 3.22 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).
Reaction SMILES: CN(C)C=O.[CH:6]([O:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:6]([O:9][N:10]=[C:11]([N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7]
Reactant: c1nc[nH]n1
Reactant: CC(C)CCc1cccc(C(Cl)=NOC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 100 ml of N,N-dimethylformamide was added 1.5 g (5.6 mmol) of O-isopropyl-3-isopentylbenzohydroximoyl chloride, 0.8 g (11.6 mmol) of 1,2,4-triazole, and 1.6 g (11.6 mmol) of potassium carbonate. The mixture was stirred at 120° C. for 3 hours to complete the reaction. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled reaction mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was then removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.2 g (yield: 71%) of the desired product having a refractive index of [nD20 ] 1.5317 at 20° C.
Reaction SMILES: CO.Cl.CO.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)[CH:7]=1>C(N(CC)CC)C>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][OH:18])[CH:7]=1
Reactant: c1cncc(CCN(CCCOC2CCCCO2)Cc2ccncc2)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: OCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A 2N-hydrogen chloride methanol solution (1.2 ml) was added to a methanol solution (4 ml) of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine (236 mg, 0.66 mmol), and stirred at room temperature overnight. A 2N-hydrogen chloride methanol solution (0.5 ml) was added to the mixture, and stirred at 50° C. for 3 hours. Triethylamine (0.64 ml) was then added to the reaction mixture, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane). The purified product was concentrated under reduced pressure to thereby obtain 186.3 mg (yield: quantitative) of 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol as an orange oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 73.7 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (130 mg, 0.84=mol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (91 μL, 1.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (220 mg, 75%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].Cl[CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH2:15][C:16]([OH:18])=[O:17])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1OCC(=O)O
Yield: 90.2 %

Procedure:
16.4 g of 2,6-diisopropylphenol, 10.0 g of chloroacetic acid, 10.0 g of sodium hydroxide and 300 ml of water were put into a round bottom flask and stirred under reflux for 6 hours. The reaction mixture was cooled and then the pH was adjusted to from 3 to 4 with a dilute hydrochloric acid. The precipitate thereby formed was collected by filtration, washed with water and dried to obtain 20.5 g of crude crystals. The crude crystals were recrystallized from diethyl ether-hexane to obtain 19.6 g (yield: 88.3%) of the desired compound as colorless prism crystals. Melting point: 84°-87° C.
Reaction SMILES: [O-]CC.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[O:23]=[C:15]1[NH:8][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1
Temperature: 20 °C

Procedure:
A 4-neck round bottomed flask (250 mL) was charged with sodium ethoxide (21 wt % in ethanol, 56 mL, 192 mmol). 3-Hydrazinopyridine-dihydrochloride (10.0 g, 55.0 mmol) was added, causing an exotherm from 20° C. to 32° C. The reaction was allowed to cool to 20° C. and diethyl maleate (13.4 mL, 82.0 mmol) was added, and the reaction was heated at 60° C. for 3 hours. The reaction was cooled to 20° C. and quenched with acetic acid. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were concentrated to dryness and the residue was purified by flash column chromatography using ethyl acetate as eluent to the title compound as a blue oil (6.60 g, 51%): 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.40-8.26 (m, 1H), 8.19 (dd, J=4.4, 1.6 Hz, 1H), 7.47-7.21 (m, 2H), 4.77 (dd, J=9.8, 2.1 Hz, 1H), 4.22 (qd, J=7.1, 1.7 Hz, 2H), 3.05 (dd, J=17.0, 9.8 Hz, 1H), 1.99 (s, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 170.37, 146.60, 142.60, 137.28, 123.54, 121.94, 65.49, 61.32, 32.15, 20.72, 13.94; ESIMS m/z 236 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[O:37][C:33]=2[CH:32]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:26][C:27]2[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]3[CH:45]=[CH:44][C:34]4[N:35]=[C:36]([NH:38][C:39]([CH:41]5[CH2:42][CH2:43]5)=[O:40])[O:37][C:33]=4[CH:32]=3)[CH:28]=2)=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)oc5c4)c3)c2)CC1
Yield: 66.5 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (224 mg, 1.19 mmol), thionyl chloride (1 mL, 13.7 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (131 mg, 424 μmol) produced in Example B1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (28.1 mg, 230 μmol) as starting materials, and in the same manner as in Example B1(viii), the title compound (135 mg, 66%) was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.O.[OH-].[K+].C(OP([C:22](Br)([F:24])[F:23])(=O)OCC)C>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH:22]([F:24])[F:23])=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: OCc1cc(Br)ccc1S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: OCc1cc(Br)ccc1SC(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in MeCN (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a −78° C. bath and when the mixture began to freeze diethyl[bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 7.76 (s, 1H), 7.47 (m, 2H), 6.80 (t, J=56.5 Hz, 1H), 4.87 (s, 2H), 1.96 (br s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].O>[Ni].CO.C(O)(C(F)(F)F)=O>[NH2:1][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 1 h
Yield: 35.1 %

Procedure:
An aqueous slurry of Raney nickel (10.2 g.) was added in one portion to a stirred solution of the azide (20.0 g.) in a mixture of MeOH (60 ml.) and TFA (60 ml.) at room temperature. A vigorous effervescence was observed. Stirring was continued for 1 hour and the Raney nickel was removed by filtration through diatomaceous earth. The filter pad was washed well with MeOH and the washings were combined with the filtrate. The solvents were evaporated under reduced pressure to give a pale green solid residue which was then stirred for 2 hours with a mixture of TFA (60 ml.) and water (15ml.). This mixture was evaporated to dryness and the residue was stirred vigorously with water (400 ml.) for 30 minutes. The resulting solution was filtered through diatomaceous earth to remove the undissolved triphenylmethanol and the filtrate was applied to a column of Diaion HP 20 resin (1 1.). The column was eluted with water (500 ml.) to remove inorganic material and then with aqueous MeOH 1:1 v/v. The fractions which were shown by HPLC to contain the product were evaporated under reduced pressure to yield 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (4.2 g.) as a pale yellow foam having the following n.m.r. in solvent A: 1.4 (s,6H); 3.1-3.8 (complex, 4H); 4.95 (d,1H); 5.7(d,1H); 6.72 (s,1H).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>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.C(Cl)Cl.O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:10]1[CH:11]=[C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)=O)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ncnc2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A mixture of N-{7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (200.0 mg, 0.3792 mmol), acetic acid (5 mL, 90 mmol) and DCM (25 mL) was degassed with vacuum and then the atmosphere was replaced with nitrogen. To the mixture, tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.00923 mmol) and phenylsilane (0.187 mL, 1.517 mmol) were added. The resulting mixture was stirred at 40° C. for 30 min. The mixture was allowed to cool to rt followed by adding water and DCM. After being stirred for 10 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (57.3 mg, 31%) as a pale yellow solid. LCMS: (AA) ES+ 487, 489. 1H NMR (400 MHz, d6-DMSO) δ: 12.74 (bs, 1H), 11.88 (bs, 1H), 8.95 (s, 1H), 8.52 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.53-7.45 (m, 2H), 7.16 (bs, 1H), 6.98 (bs, 1H), 2.24 (s, 3H).
Reaction SMILES: N[C@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[BrH:19].N([O-])=O.[Na+].[Cl-].[Na+]>O.C(O)C>[Br:19][C@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Yield: 50 %

Procedure:
To an ice-cooled mixture of t-butyl 7α-amino-3-methyl-3-cephem-4-carboxylate (1.3 g, 0.0048 mol), ethanol (30 ml), water (8.5 ml), hydrobromic acid (48%, 5.83 ml), sodium nitrite (0.48 g, 0.00696 mol) was added portionwise over 15 minutes and the mixture was stirred at ice-temperature (-5° C.) for 3 hours, saturated with sodium chloride, extracted with ethyl acetate (3 times). The combined ethyl acetate extract was washed with water, brine, dried and concentrated to give 800 mg (50%) of pure t-butyl 7α-bromo-3-methyl-3-cephem-4carboxylate.