Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2]C(C)([O-])C.[K+].[CH3:8][C:9]([CH3:19])(/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17])[C:10]([O:12][CH3:13])=[O:11]>CS(C)=O.O1CCCC1>[C:16]([CH:15]1[CH2:2][CH:14]1[C:9]([CH3:19])([CH3:8])[C:10]([O:12][CH3:13])=[O:11])(=[O:18])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)(C)/C=C/C(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C1CC1C(C)=O
Reaction time: 14 h

Procedure:
A solution of trimethylsulfoxium iodide (506 mg, 2.297 mmol) and potassium tert-butoxide (258 mg, 2.297 mmol) in dimethylsulfoxide (6 mL) was stirred for 1.5 hours and then transferred via syringe to a solution of methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate (340 mg, 1.998 mmol) in tetrahydrofuran (6 mL). The reaction mixture was stirred for 14 hours and then partitioned between diethyl ether (25 mL) and a 5:1 v:v mixture of water:saturated aqueous sodium bicarbonate solution (12 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (20 mL, 10 mL). The combined organics were washed with water (3×10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-(2-acetylcyclopropyl)-2-methylpropanoate which was carried on without further purification. MS ESI calc'd. for C10H17O3 [M+H]+ 185. found 185.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1.O.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.C(OCC)(=O)C>[CH:25]([C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1)=[CH2:26]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)cnc21
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: CCOC(C)=O
Solvent: O
Product: C=Cc1cnc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a mixture of 1100 mg of tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 1062 mg of a 2,4,6-trivinylboroxine/pyridine complex, 1020 mg of potassium carbonate, 3 mL of 1,4-dioxane/water (4/1) was added 215 mg of tetrakis(triphenylphosphine)palladium. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture were added water and ethyl acetate and the aqueous layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 783 mg of tert-butyl 5-vinyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a yellow oil.
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](OB(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][N:26]=1)[C:20]([O:22][CH3:23])=[O:21]>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.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][N:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: N#Cc1cc(OB(O)O)ccc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boric acid and methyl 2-chloroisonicotinate, and the mixture was heated under reflux in an argon atmosphere to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl:8][C:9]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]>O>[Cl:8][C:9]1[C:17]([S:18](=[O:19])(=[O:20])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: CCCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred solution 7.3 gof n-butylamine, 8 g of sodium hydroxide in 200 ml of water, 30 g of 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid are added portionwise while keeping the temperature between 0° and 5°. After 1/2 hour the mixture is allowed to warm to room temperature for 2 hours. The supernatant solution is filtered, the filtrate combined with 25 ml of 2N of hydrochloric acid, the precipitate formed collected and recrystallized from aqueous ethanol, to yield the 4-chloro-3-nitro-5-n-butylsulfamoylbenzoic acid melting at 199°-201°.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[OH:17])=[O:15])=[CH:10][CH:9]=1>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[O:17])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(O)C(=O)c2ccc(Br)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)C(=O)c2ccc(Br)cc2)cc1

Procedure:
Cupric sulfate, 90 g. (0.36 mole), is stirred and heated on the steam-bath with 110 ml. of pyridine and 45 ml. of water until complete solution is obtained. 4-Bromo-4'-methylbenzoin, 55 g. (0.18 mole), is added and the mixture is stirred and heated on the steam-bath for 3 hours. During this period, the yellow crystalline product separates. After cooling and dilution with water, the product is collected, washed with water, 1 N hydrochloric acid, and water, and dried; m.p. 132°-135° C. The analytical sample is obtained as yellow needles, m.p. 136°-137° C, after repeated recrystallizations from 95% ethanol.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[C:15](#[N:18])[CH2:16][CH3:17]>CCO>[C:15]([C:16]([CH3:17])=[C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])[O-:8])#[N:18].[K+:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC#N
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C([O-])=C(C)C#N

Procedure:
Placed potassium ethoxide (1.0 eq.) in a sealed tube with EtOH and shook until dissolved. A mixture of diethyl oxalate (1.0 eq.) and propionitrile (1.0 eq.) was added to the sealed tube and the mixture was capped and stirred at reflux. After a time sufficient for reaction completion, the reaction was cooled and the precipitate collected and washed with diethyl ether to afford 47.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[CH:9]=[C:10]([O:11][CH:12]([CH3:13])[CH3:14])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-isopropoxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (96 mg, 0.26 mmol) in EtOH (4 mL) was added an aqueous solution of lithium hydroxide (21.8 mg, 0.52 mmol) in water (1 mL). The reaction mixture stirred at room temperature overnight and acidified with 1 N HCl to pH=4. The resulting mixture was extracted with EtOAc (15 mL) and combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (41 mg. Yield: 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.41-12.12 (m, 1H), 9.25 (s, 1H), 8.55 (d, J=0.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.23 (t, J=1.2 Hz, 1H), 6.99 (s, 1H), 5.42 (m, 1H), 4.67 (m, 1H), 3.18 (m, 1H), 2.19 (m, 1H), 1.27 (m, 6H). MS (ESI) m/z=345 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.027 g, 23%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.152 g, 0.31 mmol) and methylamine (0.086 g, 3.1 mmol). mp 185-187° C.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C@H:10]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=C(C)O[N:30]=4)=[CH:25][CH:24]=3)[N:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[C:5]([F:37])[CH:4]=1)#[N:2].C(C1C=CC(C(O)=[O:45])=C(F)C=1)#N>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[N:22]=[C:18]([C@@H:10]([NH:9][C:7](=[O:8])[C:6]3[CH:35]=[CH:36][C:3]([C:1]([NH2:2])=[O:45])=[CH:4][C:5]=3[F:37])[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[NH:30])[NH2:33]
Reactant: Cc1nc(-c2ccc(-c3c[nH]c([C@H](Cc4ccccc4)NC(=O)c4ccc(C#N)cc4F)n3)cc2)no1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Product: N=C(N)c1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccc(C(N)=O)cc3F)n2)cc1
Yield: 90 %

Procedure:
Part C: 4-Cyano-2-fluoro-N—((S)-1-{4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethyl)-benzamide: The compound of Example 183 Part B was coupled to 4-cyano-2-fluorobenzoic acid using the procedure of Example 176 Part B to provide the amide in 90% yield. 1H NMR (500 MHz, CDCl3) δ ppm 2.64 (s, 3 H) 3.43 (dd, J=13.75, 7.15 Hz, 1 H) 3.58 (dd, J=13.75, 7.70 Hz, 1 H) 5.38 (q, J=7.15 Hz, 1 H) 7.20-7.33 (m, 7 H) 7.42 (d, J=9.90 Hz, 1 H) 7.54 (d, J=8.25 Hz, 2 H) 7.86 (s, 1 H) 8.05 (d, J=8.25 Hz, 2 H) 8.14 (t, J=7.70 Hz, 1 H) 9.43 (s, 1 H). m/z 493.1 (M+H)+.
Reaction SMILES: [O-:1][O-:2].[Na+].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]([O:1][OH:2])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: [O-][O-]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(C)(N=NC(C)(C)C)OO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.56g (.02 moles) of sodium peroxide in 30 ml. of 75% aqueous methanol in a 50 ml. erlenmeyer flask immersed in a cold water bath, was added 4.1g (.02 moles) of 2-t-butylazo-2-chloro-4-methylpentane dropwise. After the addition was complete, the reaction mixture was stirred for an additional 45 minutes and poured into ice water containing 0.02 moles of HaSO4. The product was extracted with pentane and washed with cold solutions of ammonium sulfate and sodium bicarbonate, washed with water, dried over anhydrous sodium sulfate, filtered and the pentane stripped off under reduced pressure while the flask was immersed in an ice bath. The yield was 2.7 grams (67% of theory) and the product began to decompose when allowed to warm to room temperature. The infrared spectrum showed the characteristic hydroperoxide absorption at 3300-3400 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 110 °C
Yield: 12.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methy1-8H-pyrido[2,3-d]pyrimidin-7-one (0.2 g, 0.54 mmol, prepared according to Example 5 in WO 01/70741) and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 2.16 mmol) were combined in toluene (3 mL) and heated to 110° C. overnight. The reaction was quenched by the addition of succinic anhydride (0.2 g) and allowed to cool giving a solid. This solid was suspended in CH2Cl2 and filtered to give a white solid. The filtrate was washed with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel chromatography eluting with 75% ethyl acetate:25% hexanes to provide 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 13%). MS (APCI) M++1: Calc'd, 584.19, Found, 584.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:44]3[CH2:43][CH2:42][N:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:47])([F:48])[F:33])[CH:36]=4)[CH2:46][CH2:45]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.3 g, 0.014 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through the mixture for 21/2 hrs. A solution of N-(α, α, α-trifluoro-m-tolyl)-piperazine (3.2 g, 0.014 mole) in dry tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature for 41/2 hrs. The tetrahydrofuran was evaporated and the residue dissolved in methylene chloride (75 ml). The methylene chloride solution was extracted with 5% potassium hydroxide solution (2×30 ml), water (30 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (6.6 g) was twice recrystallized from isopropyl alcohol-isopropyl ether to give 3.3 g (47%) of white needles, mp 185°-186.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](OS(OCC)(=O)=O)[CH3:19].N>CC(=O)CC>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH3:19]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
3-Methyl-4-nitrophenol 403 (500 mg, 3.0 mmol) was dissolved in 2-butanone (10 mL). Potassium carbonate (903 mg, 6.5 mmol) was added to the solution followed by diethylsulfate (0.45 mL, 3.2 mmol). The reaction mixture was heated at 70° C. for 2 h. Upon completion, the mixture was cooled to rt and aqueous ammonia (30%, 1 mL) was added and stirred for 18 h at rt. The reaction mixture was filtered and washed with 2-butanone (30 mL). The filtrate was collected and evaporated in vacuo to yield a white solid (580 mg, 97%). mp 50-52° C. (lit.53 mp 51° C.). TLC Rf 0.65 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.11-8.09 (d, 1H, J=8.88 Hz), 6.82-6.78 (m, 2H), 4.14-4.10 (q, 2H, J=6.96 Hz), 2.65 (s, 3H), 1.48-1.46 (t, 3H, J=6.95 Hz). 13C NMR (150 MHz, CDCl3) δ 162.5, 142.0, 137.1, 127.6, 117.9, 112.2, 64.2, 21.8, 14.6.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=3)[C:10](=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 300 mg (0.85 mmol) 4-(4-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 7.1a) in 5.0 mL of DCM is added 120 μL (1.27 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:30]1(C)C=CC=CC=1N1CCNCC1>>[C:4]1([CH3:30])[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:13][CH2:14]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: Cc1ccccc1N1CCN(CCn2cnc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-o-tolylpiperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 3-chloro-6-phenylpyridazine (Aldrich, 1.4 g, 7.5 mmol) in conc. sulfuric acid (30 mL) was added 90% nitric acid (0.6 mL, 15 mmol). After 15 min. the mixture was poured over ice (200 mL) and neutralized with 25% aq. NaOH. The resulting precipitate was collected by filtration and dried under vacuum. The crude product (1.84 g) was a 1:1:0.5 mixture of ortho:meta para isomers.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#N>CCOCC>[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cn1cccc1
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)Cc1cccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A 28 ml solution of ethereal hydrogen chloride (0.049 mole of HCl) is added dropwise over a 3 hr period to a solution of 2.1 g of N-methylpyrrole and 2.9 g of ethyl cyanoformate in 3 ml ether. The ether supernatant is decanted off, and the precipitate taken up in 11 mls of dry pyridine and the mixture transferred to a pressure bottle. Hydrogen sulfide (13 g) is added to the mixture at -78° C., the bottle sealed, and the mixture is stirred at ambient temperature overnight (about 16 hours). Gas chromatographic analysis with internal standards shows 57% yield of ethyl N-methylpyrrole-2-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[CH3:24]I.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:24])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1nccnc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1nccnc1N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.1 g 3-(4-chloro-2-nitrophenylamino)-pyrazine-2-carboxylic acid methyl ester in 15 ml absolute hexamethylphosphorotriamide is treated portionwise with 0.3 g sodium hydride. The reaction mixture is stirred at room temperature for 1 hour and then treated dropwise with 2.8 g methyl iodide, and the temperature is maintained under 20° C. After the reaction mixture has been stirred for 1 hour at room temperature 10 ml water are added dropwise. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallised from ethyl acetate to give the heading compound, m.p. 111°-112°.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ncccc2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2ncccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 377.15 g/mol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>O1CCCC1>[OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([O:11][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:10]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12

Procedure:
3-Hydroxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (500 mg.) was dissolved in dry tetrahydrofuran and treated with a solution of diphenyldiazomethane (300 mg., 1.1 equiv.) in petrol. Nitrogen was evolved slowly, and after 21/2 hours the solution was evaporated, the residue dissolved in ethyl acetate, and the solution was washed with bicarbonate solution and re-evaporated. This gave a gum which solidified on trituration with ether (0.5 g.). A sample was recrystallised from methanol, m.p. 164°, [α]D23 = + 25° (c, 1.0, dioxan), +22° (c 1.0, tetrahydrofuran). λλmax. ethanol 234 nm. E1 cm1% = 255, (ε = 13,300), 259 nm. E1cm1% = 151 (ε 7,850), νmax. (bromoform) 3420 (OH), 3280 (NH), 1750 (β-lactam), 1722 cm-1 (COOR). (Found, C, 62.2; H, 4.5; N, 5.4; S, 12.1. C27H24N2O5S2 requires C, 62.3; H, 4.7; N, 5.4; S, 12.3%) RF = 0.83 (Kieselgel G plates; ethyl acetate:benzene=1:2).