Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].ClCCl>CN(C)C=O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1cccc(CBr)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)c1cccc(CN=[N+]=[N-])n1

Procedure:
2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61 g, 33 mmol) was dissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7 mmol) added. After stirring the resultant mixture overnight at ambient temperature, the reaction was poured into dichloromethane and washed well with water. The organic layer was dried (magnesium sulphate), filtered and concentrated to dryness. The resulting yellow oil (5.88 g, 93%) was used without further purification; NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz), 4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06 min, (M+H)+ 193.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:20]=[C:12]3[N:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.[CH2:21]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(Cl)Cl.[Cl-].[NH4+].O.CO>[CH2:27]([N:26]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]([C:14]1[CH:15]=[CH:16][N:11]2[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:20]=[C:12]2[N:13]=1)=[O:19])[CH2:28][CH:29]([CH3:30])[CH3:31]
Reactant: COc1ccc(-c2cc3nc(C(=O)O)ccn3n2)cc1
Reactant: CC(C)CCNCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cc3nc(C(=O)N(CCC(C)C)CCC(C)C)ccn3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid in DMF (10 mL) and methylene chloride (5 mL) was added diisopentylamine (0.67 mL; 512 mg; 3.3 mmol) and hydroxybenzotriazole monohydrate (499 mg; 3.3 mmol). The mixture was stirred for 10 min. at room temperature and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (626 mg; 3.3 mmol) was added. The mixture was stirred overnight at room temperature. An additional amount of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride was then added (626 mg; 3.3 mmol) and the reaction mixture was heated to 50° C. for 30 min. The mixture was then cooled to room temperature, diluted with methylene chloride and saturated ammonium chloride was added. The aqueous layer was back extracted with methylene chloride and the combined organics were washed with water (3×10 mL) and brine. Concentration afforded a crude oil that was purified by flash-chromatography using first 100% methylene chloride then 5% methanol in methylene chloride to afford an oil that solidified under vacuum. This solid was taken into hot methanol (7 mL) and, upon cooling, a solid formed. Water (3 mL) was then added slowly and filtration afforded 590 mg (89%) of the title compound. LCMS m/z 409.3 (M+H)+, ret. time=3.08 min.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1OC>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(O)c1
Product: CCC(Cc1cccc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-ethylpropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:12])([F:13])[C@@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][OH:10])[CH2:7][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@@H](C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
cis-4-(Trifluoromethyl)cyclohexanecarboxylic acid (1.5 g, 7.65 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction solution was cooled to 0° C., and lithium aluminum hydride (435 mg, 11.5 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to 0° C., and water (0.4 mL), a 5 N aqueous solution of sodium hydroxide (0.4 mL), and water (1.2 mL) were added thereto, followed by filtration. To the filtrate, ethyl acetate was added, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained as a colorless oily substance (1.26 g).
Reaction SMILES: [CH:1]1([C@@H:7]([OH:35])[C:8]([N:10]2[CH2:34][CH2:33][CH2:32][C@H:11]2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[CH2:23][NH:24]C(OC(C)(C)C)=O)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O>[CH:1]1([C@@H:7]([OH:35])[C:8]([N:10]2[CH2:34][CH2:33][CH2:32][C@H:11]2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[CH2:23][NH2:24])=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-((2R)-2-Cyclohexyl-2-hydroxyethanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide from the previous step (1.87 g, 3.68 mmol, HPLC RT=3.45 min) was dissolved in EtOAc (150 mL) and cooled with stirring to 0° C. HCl gas was bubbled through the solution for 10 minutes. After 2 hours at 0° C., HPLC analysis indicated complete consumption of the starting material, and the solvent was removed under reduced pressure. The resulting solid was triturated in EtOAc, filtered, and dried in vacuo to give the hydrochloride salt of the title compound as a white solid (TLC Rf=0.4 (90:10:0.5 CH2Cl2:MeOH:NH4OH); HPLC RT=2.65 min, method A; LC-MS m/z=408).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([O:8][C:5]2[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)nc2)C1
Temperature: 90 °C
Yield: 29.5 %

Procedure:
In a 250 mL round bottom flask, added 6-Bromo-pyridin-3-ol (4.69 g, 26.95 mmol) and 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (7.63g, 26.95 mmol) and Cs2CO3 (12.26 g, 37.73 mmol) in DMF (10 mL) with stirring under argon. The reaction was heated at 90° C. overnight. Reaction was then poured onto water (200 mL). The crude product was extracted with EtOAc (3×50 mL). The organic extraction was concentrated and purified by flash chromatography with 10% EtOAc in Hexanes to afford product 2.62 g (yield 30%) of 3-(6-Bromo-pyridin-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as light brown solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=O)[CH3:2].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=[N:19][OH:20])[CH3:2]
Reactant: CCC1(CC)C(=O)CCc2ccc(OC)cc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCC1(CC)C(=NO)CCc2ccc(OC)cc21
Temperature: 25 °C

Procedure:
1,1-Diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one (4.40 g, 18.96 mmol) in dry pyridine (20 mL) with the hydroxylamine hydrochloride salt (10.54 g, 151.7 mmol) was heated to 80° C. for one day. The mixture was cooled down to r.t., then the pyridine was removed under vaccum. The green gum was dissolved with AcOEt, washed with H2O, HCl 10%, H2O, brine, dried over MgSO4 and filtered through a small silica pad. The crude compound was used without any other purification (4.69 g, 100%).
Reaction SMILES: N[C@H](C(O)=O)CO.[ClH:8].[CH3:9][O:10][C:11](=[O:16])[C@H:12]([CH2:14]O)[NH2:13].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[ClH:18].[CH3:9][O:10][C:11](=[O:16])[CH:12]([NH2:13])[CH2:14][Cl:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Product: COC(=O)C(N)CCl

Procedure:
The method which comprises derivatizing a β-hydroxy-α-aminocarboxylic acid into the corresponding β-hydroxy-α-aminocarboxylic acid ester, then halogenating the hydroxyl group thereof with a phosphorus halide to give the corresponding β-halogeno-α-aminocarboxylic acid ester, and hydrolyzing the ester group using a hydrohalogenic acid to give the objective β-halogeno-α-aminocarboxylic acid. Specifically, serine is derivatized into serine methyl ester hydrochloride, the ester salt is then treated with phosphorus pentachloride to give α-amino-β-chloropropionic acid methyl ester hydrochloride, which is further hydrolyzed with hydrochloric acid. The resulting α-amino-β-chloropropionic acid hydrochloride is isolated by concentrating the reaction mixture to dryness, followed by crystallization of the residue from a mixture of 1-propanol and hydrochloric acid [e.g. CHIRALITY, 8:197-200 (1996)]; and
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12].[NH2:22][C:23]1[N:32]=[CH:31][C:30]2[CH2:29][CH2:28][C:27]3[C:33]([C:37](OCC)=[O:38])=[N:34][N:35]([CH3:36])[C:26]=3[C:25]=2[N:24]=1>C1COCC1>[NH2:22][C:23]1[N:32]=[CH:31][C:30]2[CH2:29][CH2:28][C:27]3[C:33]([C:37]([NH:15][C:14]4[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=4[CH2:11][CH3:12])=[O:38])=[N:34][N:35]([CH3:36])[C:26]=3[C:25]=2[N:24]=1
Reactant: CCc1cccc(CC)c1N
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
Sodium hexamethyldisilazide (NaHMDS) in THF (1.0 M, 11.0 mL, 11.0 mmol) was added over 30 min to a solution of 2,6-diethylaniline (1.2 mL, 8.32 mmol) and ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (0.760 g, 2.77 mmol) in THF (30 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 10 min and allowed to warm to room temperature over a period of 30 min. After stirring at room temperature for 3 h, the reaction was quenched by the addiction of saturated acquesous NH4Cl (10 mL). The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The acqueos layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 0.830 g (80% yield) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[CH:32]=[C:33]([I:35])[S:34][C:27]=34)=[C:19]([F:24])[CH:18]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(NCc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: Clc1ccnc2cc(I)sc12
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(NCc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O

Procedure:
A mixture of 2-(benzylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (0.036 g, 0.112 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.030 g, 0.102 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.025 g, 0.20 mmol) in bromobenzene (1.5 mL) under nitrogen was stirred at 150° C. for 3 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible. MeOH was added to the residue and a brown solid precipitate was filtered and discarded. The filtrate was concentrated and then purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (15.7 mg; 27%) as a yellow solid. LRMS (APCI pos) m/e 585 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)(C)C)cn1
Yield: 76 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using tert-butylamine instead of 3-methoxypropylamine, to the title compound (89 mg, 76%) which was obtained as an off white solid. MS: m/e=366.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[Al].[Li].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3cccc(F)c3)c21
Agent: [Al]
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3cccc(F)c3)c21
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
In 100 ml of THF was dissolved 300 g of 3,4-dihydro-9-(3-fluorobenzylamino)acridin-1(2H)-one. The mechanically stirred solution was cooled in ice under nitrogen and 4.68 ml of 1M lithium aluminum hidride in THF was added dropwise over 15 minutes. After 0.5 hours, analysis by TLC indicated the reaction was complete, so it was neutralized with 1 ml of saturated ammonium chloride solution and the resulting salts were filtered. The filtrate was evaported to an oil which crystallized on trituration with pentane. The solid was filtered and recrystallized from 1:1 dichloromethane/pentane to yield 2.50 g of solid, mp 128° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[N:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH:39]1([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]O)[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([C:24]1[CH:29]=[N:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([O:36][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:35])=[CH:32][CH:31]=2)=[N:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: OCCCCCCC1CCCC1
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)OCCCCCCC3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g of N,N'-dicyclohexyl-carbodiimide in 6 ml of dichloromethane is added dropwise at 0° C. within 15 minutes to a solution of 0.201 g of 4-(5-octyl-pyrimidin-2-yl)-benzoic acid, 0.116 g of cyclopentane-hexanol and 0.02 g of 4-dimethylaminopyridine in 10 ml of dichloromethane. The suspension is stirred at 0° C. for a further 1 hour, filtered and concentrated. The residue is chromatographed on 10 g of silica gel with hexane/ethyl acetate 19:1 (v/v). Recrystallization of the product-containing fractions from ethanol gives pure 6-cyclopentyl-hexyl 4-(5-octyl-pyrimidin-2-yl)-benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12]C(F)(F)C(C(F)(F)F)OS(F)(F)OC(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][F:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: FC(F)(F)C(OS(F)(F)OC(C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CF)cc1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A solution of 770 mg (5 mmol) of 4-nitrobenzyl alcohol in 15 ml of methylene chloride was added dropwise to a stirred solution of 3.0 g (7.5 mmol) of bis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfur difluoride in 5 ml of methylene chloride at 25°. The reaction mixture was stirred for 18 hrs, and then evaporated to dryness under reduced pressure. The residue was recrystallized from pentane to give 490 mg (63%) of 4-nitrobenzyl fluoride as colorless needles, mp 33° to 34°. A second recrystallization raised the melting point to 36° to 37°. The 4-nitrobenzyl fluoride is a known compound useful as a chemical intermediate.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[N:17][CH:16]=[CH:15][N:14]=3)=[C:7]([O:20][CH3:21])[CH:6]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[N:17][CH:16]=[CH:15][N:14]=3)=[C:7]([O:20][CH3:21])[CH:6]=1
Reactant: COc1cc(OC(C)=O)ccc1-c1nc2nccnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(O)ccc1-c1nc2nccnc2[nH]1
Reaction time: 16 h

Procedure:
A mixture of 10 g of 2-(4-acetoxy-2-methoxyphenyl)-1,3,4,7-tetraazaindene (obtainable by condensing IIa with 4-acetoxy-2-methoxybenzoic acid), 100 ml of methanol and 100 ml of a 2N aqueous NaOH solution is left to stand at 20° for 16 hours. The customary working up gives 2-(4-hydroxy-2-methoxyphenyl)-1,3,4,7-tetraazaindene.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14](O)=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: O=c1c(-c2ccccc2)coc2ccccc12
Yield: 28.4 %

Procedure:
Prepared according to the general procedure using genistein (300 mg, 1.11 mmol), K2CO3 (307 mg, 2.22 mmol), acetone and MeI (0.139 mL). Purified by flash column chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 15 (70 mg, 22%) as an off-white solid. Analytical data for isoflavone 15: 1H NMR (500 MHz, DMSO) δ 12.96 (s, 1H), 9.62 (s, 1H), 8.41 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 6.41 (s, 1H), 3.86 (s, 3H); 13C NMR (125 MHz, DMSO) δ 181.1, 165.9, 162.4, 158.2, 158.1, 155.1, 130.9, 123.2, 121.7, 115.8, 106.1, 98.7, 93.1, 56.8; LCMS: Mass calculated for C16H12O5, [M+H]+, 285. Found 285.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH3:23])=[O:21])(=O)=O.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]1([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH3:23])=[O:21])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.95 g, 5 mmol) and phenylboronic acid (1.22 g, 10 mmol) in Dioxane (20 ml) was added Pd(dppf)Cl2 and a solution of Na2CO3 (3.18 g, 30 mmol) in water (6 mL), after degassed with N2 for 5 min, the reaction was heated at 100° C. for 15 h, the mixture was cooled to room temperature, diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:1) to give 1-tert-butyl 3-methyl 4-phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (740 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (22 μl, 3 eq) followed by addition of DIEA (94 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/brine. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (162) (13.9 mg, yield: 63.9%, purity>95%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51]>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]#[N:15])([NH:16][C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH3:44])[CH:53]=2)=[O:51])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cncc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.485 g, 2.15 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (11 mL) and N-ethyl diisopropylamine (0.44 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.047 g, 2.37 mmol, 1.1 equiv; BOP reagent) 5-methyl-nicotinic acid (0.295 g, 2.15 mmol, 1.0 equiv) and the reaction mixture stirred at 40° C. during a weekend. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.48 g (65%) of the title compound as off-white foam. MS (ISP): 345.3 [M+H]+