Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:4][C@@H:5]([CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][C:7]([O-:9])=[O:8])=O.[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19]>C(O)C>[CH3:12][N+:11]([CH2:10][C@H:5]([OH:4])[CH2:6][C:7]([OH:9])=[O:8])([CH3:13])[CH3:14].[CH:16](/[C:15]([O-:22])=[O:21])=[CH:17]\[C:18]([O-:20])=[O:19]
Reactant: CC(=O)O[C@H](CC(=O)[O-])C[N+](C)(C)C
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: C[N+](C)(C)C[C@H](O)CC(=O)O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
To 10 mL of 95% v/v of ethanol at about 70° C., 2.28 g (0.01 moles) of acetyl L-carnitine inner salt (titre: 89.3%) and 1.16 g (0.01 moles) of fumaric acid were added under vigorous stirring. The resulting solution (“mother solution”) was cooled to room temperature while constantly keeping it under stirring. To the solution, a few milligrams of L-carnitine acid fumarate as precipitating agent were added. In few minutes a white, heavy precipitate formed which was filtered off one hour later.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([O-:13])=[O:12]
Reactant: CCOP(=O)(CS)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (569 mg, 1.57 mmol), potassium carbonate (303 mg, 2.36 mmol), diethyl sulfhydrylmethylphosphonate (405 mg, 2.20 mmol) and 2-butanone (5 ml) is heated under reflux for 5 hours. The reaction mixture is then filtered, and the filtrate is concentrated to dryness and purified by prep. TLC to give diethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate. NMR (CDCl3)δ5.87 (m, 4H, OCH2CH3), 6.90 (d, 2H, 14 Hz, SCH2 --P) and 8.63 ppm (t, 6H, OCH2CH3).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CC1C=CN=C(N)C=1C.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: Cc1ccnc(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXlII, EXAMPLE 88, 0.492 g), 2-chlorobenzoyl chloride (0.268 ml), dimethyl-aminopyridine (0.0538 g), diisopropylethylamine (0.368 g), and THF (9 ml) is stirred at 20°-25° for 1.5 hr. The mixture is then partitioned between ethyl acetate, aqueous sodium bicarbonate, and saline. The product is poorly soluble in both the organic and aqueous phases, filtration of the extraction solvents gives additional material. The crude product is then triturated with ethyl ether and dried to give the title compound, mp 254°-256°; MS (m/z) at 417, 419; IR (mineral oil) 1659, 1576, 1508, 765 and 1394; NMR (CDCl3) 8.16 δ.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-:6].[Al+3:7].[OH-].[OH-].Cl.Cl[O-].[Al+3].Cl[O-].Cl[O-]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[OH:6][Al+2:7].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: [OH-]
Reactant: NCC(=O)O
Reactant: [Al+3]
Agent: Cl
Agent: [O-]Cl
Solvent: O
Product: NCC(=O)[O-]
Product: O[Al+2]
Temperature: 80 °C

Procedure:
Monohydroxyaluminum glycinate [Al(OH)(glycinate)2 ] was prepared by reacting 4 grams of glycine with 2.5 grams of aluminum hydroxide powder (28.8% Al) in 30 grams of water. The mixture was heated at 80° C. for one half hour with agitation. The slurry was allowed to cool before adding 200 grams of 331/3 % zirconyl hydrochloride, ZrO(OH)Cl (14.1% Zr). The mixture was heated at 75° C. for 30 minutes. The resultant clear solution was then mixed with 4.14 grams of 50% aluminum chlorhydroxide (basic aluminum chloride), (12.5%). The product was oven dried at 45° C. under a vacuum of 175 mm of Hg, and found to contain 1.9% Al, 43.9% Zr, 5.1% glycine and 17.6% Cl.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].CC(C)=O>CO>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
4′-((tert-Butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde 3e (2.60 g, 38.10 mmol) was dissolved in 80 mL of methanol, followed by addition of sodium borohydride (1.66 g, 43.95 mmol). The reaction mixture was stirred for 3 hours. The resulting mixture was mixed with 50 mL of acetone and concentrated under reduced pressure. The residue was mixed with 200 mL of ethyl acetate, washed with water (60 mL×2), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methanol 3f (9.80 g, yield 98.0%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]1[C:33]([CH2:34]O)=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=[N:30]1.N(C(N1CCCCC1)=O)=N[C:41](N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCCCCC.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:34][C:33]3[N:29]([C:23]4[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:28])[N:30]=[CH:31][C:32]=3[CH:36]([CH3:38])[CH3:37])=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)[CH3:41]
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(O)cc2C)cc1
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of (108 mg, 0.403 mmol) 3-(4′-hydroxy-2′-methyl-biphenyl-4-yl)-acrylic acid methyl ester, [2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol (126 mg, 0.443 mmol) and toluene (2.1 mL) is added 1,1′-(azodicarbonyl)dipiperidine (112 mg, 0.443 mmol) followed by tri-n-butylphosphine (109 μL, 0.443 mmol). The reaction is kept overnight at room temperature. The reaction mixture is diluted with hexane and the solid is filtered. The concentrated filtrate is purified via flash chromatography eluting with 15% ethyl acetate/heptane) to give 183 mg (85%) of the ester.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)#[CH:33]>ClCCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#Cc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O

Procedure:
In the presence of copper(I) iodide (5 mg) and dichlorobis(triphenylphosphine)palladium(II) (18 mg), triethylamine (0.0794 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg) and ethynylbenzene (0.0626 ml) in 1,2-dichloroethane (2 ml) at 60° C. The mixture was refluxed for 2 hours. The mixture was cooled to give a precipitate. The precipitate was collected by filtration and suspended in MeOH to give 6-[5-amino-3-phenyl-6-(phenylethynyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (104 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH2:43][O:44][C:45](=[O:47])[CH3:46]>CN(C=O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH:10]2[C:9]3[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:2](=[O:1])[N:11]2[CH2:42][CH2:43][O:44][C:45](=[O:47])[CH3:46])=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: CC(=O)OCCBr
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methanesulfonyl-benzonitrile (INTERMEDIATE 18, 200 mg, 0.41 mmol) in DMF (4 mL) is added cesium carbonate (266 mg, 0.82 mmol) and 2-bromoethylacetate (91.0 μL, 0.82 mmol) and the mixture is stirred at 60° C. for 3 days. The mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 60.0 mg; ESI mass spectrum [M+H]+=576; Retention time HPLC: 1.07 min (Z018_S04).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.[NH:15]([CH2:19][CH2:20]O)[CH2:16][CH2:17]O>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]2[O:12][CH2:20][CH2:19][NH:15][CH2:16][CH2:17][O:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: OCCNCCO
Product: FC(F)(F)Oc1cccc(B2OCCNCCO2)c1
Yield: 86 %

Procedure:
The title compound (86%, crystals) was prepared from 3-trifluoromethoxyphenylboronic acid and diethanolamin.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:37](=O)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2)=O>ClCCl>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][CH2:37][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O=C([O-])c1ncccc1-c1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CCCc1ccc(-c2cccnc2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-[4-(3-hydroxypropyl)phenyl]pyridine-2-carboxylate (245 mg, 0.704 mmol) in dichloromethane (3 ml) and pyridine (357 uL, 3.52 mmol) was added a solution of Dess-Martin periodinane (358 mg, 0.845 mmol) in dichloromethane (3 mL). After stirring at rt for 30 min, the reaction was quenched by addition of a mixture of 15% Na2S2O3 (2 mL) and saturated NaHCO3 (3 mL). The organic layer was separated and the aqueous layer was extracted by ethyl acetate (3×). The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluting 10-50% ethyl acetate in hexanes) to afford the title compound. LC-MS: m/e 346 (M+H)+. 1HNMR (CDCl3, 500 MHz): δ 9.86 (1H, t, J=1.5 Hz), 8.68 (1H, dd, J=4.5, 1.7 Hz), 7.76 (1H, dd, J=8.0, 1.7 Hz), 7.48 (1H, dd, J=8.0, 4.5 Hz), 7.30 (3H, m), 7.26 (2H, d, J=8.0 Hz), 7.19 (2H, d, J=8.0 Hz), 7.14 (2H, dd, J=7.5, 2.0 Hz), 5.22 (2H, s), 3.00 (2H, t, J=7.5 Hz), 2.82 (2H, t, 7.5 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[Cl:3][C:2]1[C:1](=[O:9])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[CH:6][C:4]=1[Cl:5]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mucochloric acid (9.3 g, 0.055 moles) was dissolved in ethanol (60 ml) and phenyl hydrazine (5.4 g, 0.05 moles) was added. The reaction mixture was stirred at room temperature for 2 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (60 ml). Refluxed with stirring for 3 hours. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (11.0 g, 91%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33]OS(C)(=O)=O)[CH2:28]3)=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.O1C2C=CC(OCC3CCCN(C(C4(C5C=CC(Cl)=CC=5)CCC4)=O)C3)=CC=2OC1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:28]3)=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2cccnc2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 52 %

Procedure:
Compound 85 was synthesized from 3-hydroxypyridine (0.25 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.52 g of the desired product 85. C22H25ClN2O2, LRMS (m/z)=385 MH+).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)ncc1C#N
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyridine (5.0 g, 22.48 mmol) in DMF (80 mL) was purged with nitrogen for 15 min. At this point, Zn(CN)2 (3.96 g, 33.7 mmol) and Pd(Ph3P)4 (2.60 g, 2.25 mmol) were added, successively. The resulting suspension was stirred at 95° C. for 12 h under nitrogen atm. The reaction mixture was cooled to ambient temperature, filtered to remove inorganic solid. The solvent (DMF) was evaporated to provide the crude residue as an oil, which was purified on silica gel and eluted with 0-30% ethyl acetate/hexanes to afford the product. 1H NMR (500 MHz, DMSO-d6), δ 8.69 (s, 1H), 7.50 (s, 1H), 4.04 (s, 3H);
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:15]1[O:16][N:17]=[C:18]2[CH:23]=[C:22]([C:24](Cl)=[O:25])[CH:21]=[CH:20][C:19]=12>ClCCl>[CH:1]1([NH:7][C:24]([C:22]2[CH:21]=[CH:20][C:19]3=[N:15][O:16][N:17]=[C:18]3[CH:23]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc2nonc2c1
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of cyclohexylamine (1 ml) and triethylamine (1.7 ml) in dichloromethane (20 ml) was added a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (730 mg, 4 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was triturated with ether to give a white solid (265 mg, yield=27%). Mp=172-173° C., 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (d, 1H, J=9.0 Hz); 7.82 (d, J=9.0 Hz, 1H); 6.09 (“s”, NH, 1H), 4.05-3.97 (m, 1H) and 2.09-1.18 ppm (m, 10H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1C=O)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1[OH:27])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCOc1ccc(C=O)c(OCOCC)c1
Solvent: ClCCl
Product: CCOCOc1ccc(O)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 282.4 %

Procedure:
A solution of 2a (3.78 g, 12.0 mmol) in anhydrous CH2Cl2 (4.0 mL) was slowly added to mCPBA (70%) (3.26 g, 13.2 mmol) in anhydrous CH2Cl2 (16.3 mL) at 0° C. The resulting solution was warmed to room temperature, then refluxed for 12 hours. After cooling to room temperature, the resulting solution was washed with saturated aqueous NaHCO3 solution (3×20 mL) and 10% aqueous Na2S2O3 (30 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was re-dissolved in MeOH (5 mL) and stirred with excess 10% aqueous NaOH for three hours at room temperature. The pH was adjusted to 2 with 6 M HCl and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated to give 3a as an orange oil (8.21 g, 94%): 1H NMR (CDCl3, 500 MHz) 6.89-6.85 (m, 2H), 6.67 (dd, J=8.8, 2.7 Hz, 1H), 5.81 (d, J=6.6 Hz, 1H), 5.23 (s, 2H), 5.15 (s, 2H), 3.80-3.73 (m, 4H), 1.29-1.24 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 151.0, 145.0, 141.5, 115.2, 110.6, 106.0, 94.9, 94.2, 64.8, 64.1, 15.1, 15.1; IR (film) νmax 3362, 2887, 1460, 1286, 1162, 735 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C12H18O5, 265.1052; found, 265.1045.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: COc1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
The 4′-methoxy-salicylanilide was prepared by condensing phenyl salicylate with 4-aminoanisole then purified as described in Example 2a. The mixture of ligands was then prepared from 4′-methoxy-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 116-118 ppm.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1O)C(O)=O.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22](Cl)[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: Nc1ccc(OCc2ccccc2)cc1Cl
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
The 4-benzyloxy-3-chloroaniline was prepared from 3-chloro-4hydroxybenzoic acid using the same procedure described for the preparation of 4-benzyloxy-2-chloroaniline (Scheme 3). 1H NMR (300 MHz, CDCl3) δ:7.35 (m, 5 H), 6.77 (d, J=8.9 Hz, 1 H), 6.72 (d, J=2.1 Hz, 1 H), 6.49 (dd, J=8.9, 2.1 Hz, 1 H), 5.2 (s, 2 H), 3.55 (br s, 2 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][O:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: OCCCl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(OCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.9 %

Procedure:
2-Chloroethanol (1168 g, 975 mol) and benzene sulfonyl chloride (2780 g, 2015 mol) were stirred together at −5° C. and pyridine (2158 g, 2200 mol) was added over a 3 hours period, maintaining the temperature below 0° C. The reaction was stirred for a further 3 hours at −5° C. to 0° C. and was then allowed to warm to room temperature over 18 hours. After pouring into a mixture of ice (10 liters) and water (10 liters) the reaction was stirred for 15 minutes, extracted with ether (10 liters) and the organic phase was washed with 5N HCl (2×2 liters) and water (2×4 liters). It was then dried over MgSO4 and concentrated under reduced pressure to give benzene sulfonic acid 2-chloro-ethyl ester (1921 g) as an orange oil. 1H NMR (250 MHz, CDCl3): δ=7.78-8.02 (2H, m), 7.58-7.78 (3H, m), 420-4.45 (2H, t), 3.60-3.81 (2H, t) ppm.
Reaction SMILES: BrC1C=CC(O)=CC=1C.[Br:10][C:11]1[C:25]([CH3:26])=[CH:24][C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:13](OC)[CH:12]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])=[CH:24][C:25]=1[CH3:26]
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Agent: Cc1cc(O)ccc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)ccc1Br
Yield: 86 %

Procedure:
[2-(4-Bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane was prepared in 86% yield from 4-bromo-3-methyl-phenol according to the procedure for [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H, J=8.7 Hz), 6.93 (d, 1H, J=2.7 Hz), 6.75 (dd, 1H, J=8.7, 2.7 Hz), 5.16 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 2.36 (s, 3H), 0.95 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H21BrO2Si) C, H. Calculated: C, 49.21; H, 6.67. Found: C, 49.33; H, 6.67.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:25]([O-])=O)=[CH:4][C:5]([O:21][CH:22]([F:24])[F:23])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)=[O:8]>[Pd].CO.C1COCC1>[NH2:25][C:3]1[C:2]([NH2:1])=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)=[O:8])=[C:5]([O:21][CH:22]([F:23])[F:24])[CH:4]=1
Reactant: Nc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)c(OC(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(OC(F)F)c(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1N

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (702a) using palladium on charcoal in methanol and THF.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14](NC(C)(C)C)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22]>O1CCOCC1.O>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:15])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1occc1C(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccoc1C(=O)O
Temperature: 120 °C

Procedure:
To slurry of 3-benzoyl-N-tert-butylfuran-2-carboxamide (0.863 g, 3.18 mmol) in 4 mL dioxane and 3 mL water was added sulfuric acid (1.02 ml, 19.1 mmol). The mixture was sealed and heated to 120° C. for a total of 48 h. Additional 3.0 equiv H2SO4 was added, and the reaction was heated for 8 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (4×), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-benzoylfuran-2-carboxylic acid as a brown semi-solid. This material was carried on without further purification. MS m/z=217 [M+H]+. Calc'd for C12H8O4: 216.2.