Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH:14]([CH3:16])[CH3:15])(O)[CH:4]([OH:17])[CH2:3]1.C1COCC1.[Si](OC1CC(F)(F)C2C(=CC=C(F)C=2)C1=O)(C(C)(C)C)(C)C.F>N1C=CC=CC=1>[F:18][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[CH2:3]1
Reactant: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Agent: CC(C)(C)[Si](C)(C)OC1CC(F)(F)c2cc(F)ccc2C1=O
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Temperature: 25 °C
Yield: 69 %

Procedure:
4,4,6-Trifluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalene-1,2-diol (62): A THF solution (8 mL) of 2-((tert-butyldimethylsilyl)oxy)-4,4,6-trifluoro-3,4-dihydronaphthalen-1(2H)-one 54 (0.585 g, 1.77 mmol) was cooled to 0° C. and a solution of hydrogen fluoride in pyridine (70%, 200 μL) was added dropwise. The reaction was allowed to warm to ambient temperature over 12 h at which point the reaction was quenched with an aqueous solution of saturated sodium bicarbonate, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product as a colorless oil (0.263 g, 1.22 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ: 8.14 (dd, J=8, 4 Hz, 1H), 7.48 (dt, J=8, 4 Hz, 1H), 7.36 (m, 1H), 4.67 (ddd, J=12, 8, 4 Hz, 1H), 3.66 (s, 1H), 3.17 (m, 1H), 2.54 (m, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11](N)[CH:10]=1)([O-:8])=[O:7].N([O-])=[O:26].[Na+]>O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11]([OH:26])[CH:10]=1)([O-:8])=[O:7]
Reactant: O=N[O-]
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 15.0 mL water and 11.0 mL concentrated sulfuric acid was added to 13.0 g of 4,4'-dinitro-2-aminobiphenyl, and the resulting mixture was stirred for 2 hours while heating, whereupon 26.5 g of crushed ice was added. On an ice bath, an aqueous solution of 3.51 g of sodium nitrite was added dropwise to the aforementioned mixture; the resulting system was mixed for 10 minutes and subsequently allowed to stand at quiescence for several minutes. The reaction mixture was then added dropwise to a boiling solution that had been prepared by adding 33.4 mL concentrated sulfuric acid to 25 mL of water. Boiling was continued for 5 minutes, after which the mixture was poured into a beaker on an ice bath. The filter cake afforded by suction filtration was purified by column chromatography to give 10.9 g of 4,4'-dinitro-2-hydroxybiphenyl as a yellowish brown powder.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[N:8][C:9]=1Cl)(=O)[CH3:2].[NH2:29][NH2:30]>CC(O)C.O>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[N:8]=[C:9]3[NH:29][N:30]=[C:1]([CH3:2])[C:4]3=[N:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: CC(=O)c1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Cc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)cnc12
Temperature: 120 °C

Procedure:
N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide (230 mg) was suspended in a mixture of 2 ml iPrOH and 2 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation (Biotage Initiator™ apparatus) for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by recrystallisation from an acetone-water mixture afforded the title compound as a pale yellow solid after drying under vacuum. Yield: 81.6 mg (38%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18].[OH-].[K+]>>[NH2:9][C:4]1[N:3]=[C:2]([O:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])[CH:7]=[C:6]([NH2:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(Oc2ccc(Cl)cc2Cl)nc(N)n1

Procedure:
First the substance of the formula (I) was synthetized from 4-chloro 2,6-diaminopyrimidine British patent specification No. 1,167,735; CA. 68, 21947h by heating the latter compound with 2,4-dichlorophenol at 150° C. in the presence of 85% aqueous potassium hydroxide solution to give 2,6-diamino-4-(2,4-dichlorophenoxy)pyrimidine. This substance was oxidized in a low yield to 6 amino 4-(2,4 dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, which was then transformed at 150° C. with piperidine to the target compound of the formula (I). The overall yield of this synthesis amounts to about 2.5% with a 45% yield in the last step. This is mainly caused by the fact that the replacement of the 2,4-dichlorophenoxy group by piperidine requires severe reaction conditions and long heating periods which favour unrequired side reactions, too.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]([C@@H:8]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([OH:30])[C@@H:19]([CH2:31][OH:32])[O:18][C@H:9]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+:6]=[N-:7].O.CCOC(C)=O>N1C(C)=CC(C)=CC=1C>[C:1]([O:32][CH2:31][C@H:19]1[O:18][C@@H:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12])[C@H:8]([N:5]=[N+:6]=[N-:7])[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:20]1[OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1N=[N+]=[N-]
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: -40 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Acetyl chloride (4.5 mL, 63.3 mmol) was added dropwise to a solution of tert-butyldimethylsilyl 2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranoside (25 g, 61 mmol) in 2,4,6-collidine (110 mL) under nitrogen at −40° C. After stirring at −40° C. overnight, water was added. The mixture was poured into EtOAc and extracted with 1 N HCl, brine and saturated NaHCO3. The organic phase was dried over Na2SO4, filtered and the solvents were removed in vacuo to afford 6 (26.5 g, 58.7 mmol, 96%) as a colorless solid. [α]24D: −27.1 (c 1.00, CH2Cl2); IR (thin film) 3482, 2110, 1743, 1255 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 4.96 (d, J=11.4 Hz, 1H), 4.73 (d, J=11.4 Hz, 1H), 4.55 (d, J=7.6 Hz, 1H), 4.34-4.27 (m, 2H), 3.50-3.38 (m, 2H), 3.33 (dd, J=7.6, 9.9 Hz, 1H), 3.21 (dd, J=8.3, 9.9 Hz, 1H), 2.59-2.46 (br s, 1H), 2.09 (s, 3H), 0.96 (s, 9H), 0.18 (s, 6H); 13C-NMR (75 MHz, CDCl3) δ 171.5, 138.1, 128.8, 128.31, 128.28, 97.4, 82.2, 75.3, 73.8, 70.3, 68.3, 63.5, 25.8, 21.1, 18.3, −4.1, −5.0; FAB MS (C21H33N3O6Si) m/z (M+) calcd 451.2138, obsd 451.2135.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:32][C:33]([NH:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)=[O:34]
Reactant: Cc1cccc2nc(N)c(-c3cccc(C(F)(F)F)c3)n12
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cccc2nc(NC(=O)CC(C)(C)C)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-ylamine (compound s, 0.05 g, 0.0002 mol) was dissolved in acetonitrile (0.9 mL) and pyridine (0.03 mL, 0.0003 mol). t-butylacetyl chloride (0.028 mL, 0.00020 mol) was added and the mixture was stirred at room temperature for 4 hours. Solvent was removed then ethyl acetate and saturated sodium bicarbonate was added. The layers were separated and the organic layer dried (magnesium sulfate) then removed. The crude product was chromatographed using 60% ethyl acetate/hexanes to give 39 mg of 3,3-Dimethyl-N-(5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl)-butyramide as a white solid. Rf 0.27, 100% ethyl acetate; MS m/z 390 (M+H). SH-SY5Y_EC50: 0.3399.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[C-:10]#[N:11].[Na+]>C(C#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1)#[N:11]
Reactant: [C-]#N
Reactant: OCc1ccc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1ccc(CO)nc1
Temperature: 110 °C
Yield: 47.8 %

Procedure:
(5-Bromo-pyridin-2-yl)-methanol (1.0 g), NaCN (521 mg), Pd(PPh3)4 (612 mg), and CuI (200 mg) were taken up in degassed EtCN and heated at 110° C. (4 h). The solution was partitioned between EtOAc and 10% NH4OH(aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/2 hexanes/EtOAc, SiO2) gave 341 mg (48%) of (5-cyano-pyridin-2-yl)-methanol as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:62])[NH:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][C@H:43]([CH3:45])[CH2:42][N:41]6[C:46](=[O:56])[C@@H:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[C:24]([O:57][C:58]([F:61])([F:60])[F:59])[CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:55][O:54][C:52](=[O:53])[NH:51][C@H:47]([C:46]([N:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([C:25]3[CH:26]=[C:27]([Cl:28])[C:22]([NH:21][C:20]([N:17]4[CH2:18][CH2:19][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH2:15][CH2:16]4)=[O:62])=[CH:23][C:24]=3[O:57][C:58]([F:61])([F:60])[F:59])=[CH:34][CH:33]=2)[N:36]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)N4CCN(C5CCN(C(=O)OC(C)(C)C)CC5)CC4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)N4CCN(C5CCNCC5)CC4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-(5-chloro-4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 2TFA (12.94 mg, 0.012 mmol; Preparation 14) in 4 M HCl in 1,4-dioxane (0.21 mL) was stirred at RT for 30 min to provide the intermediate product {(S)-1-[(2S,4S)-2-(4-{5′-Chloro-4′-[(4-piperidin-4-yl-piperazine-1-carbonyl)-amino]-2′-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[C:9](OC(=O)C)(=O)[CH3:10]>>[CH3:9][C:10]1[O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnccc1O
Product: Cc1nc2cnccc2o1

Procedure:
3-Amino-4-hydroxypyridine was reacted with acetic anhydride to afford 4.7 g of 2-methyloxazolo[4,5-c]pyridine; mp 56°-58° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]1[CH:19]=[C:18]([O:20]C)[C:17]2[C:12](=[C:13]([O:24][CH3:25])[CH:14]=[CH:15][C:16]=2[O:22][CH3:23])[C:11]=1[O:26]C)[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH2:1]([O:3][CH:4]([C:10]1[C:11](=[O:26])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:22][CH3:23])[CH:15]=[CH:14][C:13]=2[O:24][CH3:25])[CH2:5][CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(CCC(C)C)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(CCC(C)C)C1=CC(=O)c2c(OC)ccc(OC)c2C1=O
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
600 mg (3.4 mmole) of 2-(1-ethoxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene was dissolved in 25 ml of acetonitrile and then a solution of 8.6 g (17 mmole) of cerium (IV) ammonium nitrate dissolved in 25 ml of distilled water was added dropwise thereto over 30 minutes through a dropping funnel in a cooling bath (0°-5° C.). The reaction mixture was stirred at normal temperature for 2 hours. After adding 60 mg of distilled water thereto, the reaction mixture was extracted twice with dichloromethane solvent, dried over anhydrous magnesium sulfate and then filtered through filter paper. The resulting filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 4.0×15 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 10:1 to 1:1, to obtain 300 mg of the title compound as a yellow precipitate.
Reaction SMILES: [C:1]1([P:7](=[O:20])([C:14]2C=C[CH:17]=[CH:16][CH:15]=2)[C:8]2C=C[CH:11]=[CH:10][CH:9]=2)C=C[CH:4]=[CH:3][CH:2]=1.CC1C2C(=CC=CC=2)C=CC=1.[H][H].[C]=O.C(OC)(=O)C>C(O)(=O)C.C(O)C.CO>[CH2:1]([P:7](=[O:20])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: CO
Product: CCCCP(=O)(CCCC)CCCC
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A one gram quantity of Co(acetate)2. 4H2O and 9 grams triphenylphosphine oxide were charged to an autoclave with 100 cc methanol and 30 cc methylnaphthalene. The reactor was pressured to 3200 psi with an approximately equimolar mixture of hydrogen and carbon monoxide and heated to 180° C. with stirring. The reaction was allowed to proceed for 5 hours. The reactor was cooled and vented, and the reaction product was analyzed and shown to contain ethanol (21.3%), methyl acetate (9.8%), dimethylacetal (15.9%) and acetic acid (5.1%). The products were distilled and the cobalt remained in a soluble form in the distillation residue which consisted primarily of methylnaphthalene. The absence of a solid coating or precipitate on the distillation flask was noted. The distillation residue was returned to the reactor with additional methanol, and found to display high catalytic activity under carbonylation conditions as employed in this example. Thus it is demonstrated that the catalyst can be retained in soluble form by use of phosphine oxide stabilizer, and recycled in a form suitable for use upon application of carbonylation conditions. Similar results to the foregoing can be obtained if tributylphosphine oxide or other tertiary phosphine oxides are substituted for the triphenylphosphine oxide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.[I:22]CI.C(ON=O)(C)(C)C>CCOC(C)=O>[I:22][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: ICI
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A suspension of Example A9 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with t-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHCO3 (3×), 10% Na2S2O3 (2×), and brine (2×) and the combined aqueous washes were back-extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford 2-iodo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.51 g, 59%). MS (ESI) m/z: 393.0 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:27][CH3:28])[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@H:11]12)=[O:8].CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:27][CH3:28])[C:25](=[O:26])[N:12]2[CH:13]([C:22]([OH:24])=[O:23])[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(COC(C)=O)=CS[C@@H]21
Yield: 68.2 %

Procedure:
To a cooled (0°), stirred solution of 7.75 g. of 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl- 3-cephem-4-carboxylic acid [prepared from cephalothin in accordance with procedures described by G. A. Koppel and and R. E. Koehler, J. Amer. Chem. Soc., 95, 2403 (1973 )]in 46 ml. of dry pyridine was added 5.02 ml. of acetic anhydride. The reaction mixture was allowed to stir with cooling for 2 hours, after which time the mixture was evaporated in vacuo to near dryness. The residue was dissolved in ethyl acetate, and the resulting solution was extracted 3 times with aqueous sodium bicarbonate. The aqueous extracts were combined, layered with ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 5.29 g. (68.2 percent) of the title product as a browh froth. Thin layer chromatography of the methyl ester derived from diazomethane exhibited a single spot. For identification purposes a small portion of the product acid was also converted to the corresponding benzhydryl ester using diphenyldiazomethane. Chromatography on a small silica gel column provided pure benzhydryl 7-(2-thienylacetamido)-7 -methoxy-3-acetoxymethyl-2-cephem-4-carboxylate: ir (CHCl3) 1780 cm-1 (β-lactam); nmr (CDCl3) δ1.92 (s, 3, OAc), 3.42 (s, 3, OCH3), 3.85 (s, 2, side chain CH2), 4.55 (s, 2, --CH2OAc), 5.01 (m, 1, C4 --H), 5.35 (s, 1, C6 --H) and 6.35 (m, 6, C2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:21]=[CH:22][C:23]2[N:28]([CH3:29])[N:27]=[CH:26][C:24]=2[N:25]=1.CN(C(C)C)C(C)C>C(O)CCC>[CH3:29][N:28]1[C:23]2[CH:22]=[N:21][C:20]([NH:18][C@H:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH3:17])=[N:25][C:24]=2[CH:26]=[N:27]1
Reactant: Cn1ncc2nc(Cl)ncc21
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Agent: CC(C)N(C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc2c(cnn2C)n1)c1nc2ccccc2n1-c1ccccc1
Yield: 35.9 %

Procedure:
A solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (200 mg, 0.83 mmol, 1.00 equiv, 98%), 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (180 mg, 1.07 mmol, 1.29 equiv) and methylbis(propan-2-yl)amine (0.3 mL, 98%) in n-butanol (8 mL) was stirred at 130° C. for 96 h. The resulting mixture was concentrated under vacuum and the residue was purified on a C18 column eluted with water/acetonitrile to give 110 mg (31%) of 159 as a light yellow solid. LC-MS: (ES, m/z) 370 [M+H]+, 221, 115. H-NMR: (CD3OD, 300 Hz, ppm) δ 8.86 (s, 1H), 7.70 (s, 1H), 7.65-7.54 (m, 6H), 7.61 (d, 2H), 7.09 (s, 1H), 5.30 (m, 1H), 4.04 (s, 3H), 1.64 (d, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[C-:14]#[N:15].[K+]>CC(C)=O.CCO.O>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:14]#[N:15])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: COc1cc(CCCBr)ccc1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(CCCC#N)ccc1C
Yield: 99.9 %

Procedure:
A solution of 8.68 g (35.7 mmol) of 4-(3-bromopropyl)-2-methoxy-1-methylbenzene in 50 mL of acetone and 50 mL of EtOH was treated with a solution of 2.8 g (42.8 mmol) of KCN in 20 mL of H2O and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with H2O, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 6.75 g (100% yield) of the product as an oil. The structure was confirmed by NMR and IR spectroscopy.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:67])([F:66])[F:65])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][NH:61][CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:65])([F:66])[F:67])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][N:61]([C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]
Reactant: CCCC(=O)O
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc(C4(F)CNC4)cc3)=NO2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of butyric acid (50 mg) in DMF (5 mL) was added HATU (200 mg) then triethyl amine (150 μL). The resulting solution was stirred at ambient temperature for 15 minutes then 5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole hydrochloride (Preparation 16 100 mg) was added in one portion. Reaction stirred at ambient temperature for 16 hours. Solvent was removed in vacuo and the residue partitioned between water (10 mL) and CH2Cl2 (10 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 86 mg (80%). 1H NMR (CDCl3) δ 7.75 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.68-4.33 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.19 (m, 2H), 1.73 (m, 2H), 1.01 (m, 3H). LC/MS retention time=3.688 minutes, MS calculated for (C23H19Cl2F5N2O2), 520.07; found 521.0 M+H.