Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.C1(C)C=CC=CC=1.[CH2:29]=[O:30]>C1COCC1.C(N(CC)CC)C.C(OCC)(=O)C.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:29]=[O:30])=[C:13]([OH:17])[CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(O)c1
Agent: CC[Mg]Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of (1) (538 mg, 2.13 mmol) in THF (20 ml) and triethylamine (3 ml) cooled in an ice bath was added ethyl magnesium bromide (2.13 mL of a 1M solution, 2.13 mmol). The reaction was allowed to warm to room temperature and stirred for a total duration of 1 h. Solvent was removed under reduced pressure then toluene (50 ml) was added which was subsequently removed under reduced pressure. This procedure was repeated two times. After the third addition of toluene, paraformaldehyde (160 mg, 5.32 mmol) was added and the reaction was heated to reflux for 18 h. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL) were added; the organic layer was separated and washed with water (2×100 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the crude product as a yellow oil. This crude product was purified by silcagel column chromatography, eluting with a gradient from 10%-50% ethyl acetate in hexane producing the final product as a yellow oil (100 mg, 17%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12](Cl)[CH:13]=1)[C:8]([OH:10])=[O:9].Cl>CN1C(=O)N(C)CCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:2][CH3:1])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COc1cc(Cl)cc(C(=O)O)c1
Temperature: 170 °C

Procedure:
Sodium methoxide (25% wt., 7 ml) was added to a stirred solution of 3,5-dichlorobenzoic acid (2 g) in DMPU (10 ml) and heated at 170° C. for 5 days. The reaction was poured onto 1M HCl (50 ml). The resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (0.8 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]=[C:48]([CH3:50])[O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]=[C:48]([CH3:50])[O:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1nc(CCl)no1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)no1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole and isolated as yellow gum. MS(m/e): 379.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:36]([O:40][CH:41]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])[C@H:42]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])[NH2:43])[CH2:37][CH2:38][CH3:39]>CN(C)C=O.C(N(CC)CC)C>[CH2:52]([O:51][CH:41]([O:40][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:42]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])[NH:43][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:53][CH2:54][CH3:55]
Reactant: CCCCOC(OCCCC)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
In 25 ml of dimethylformamide was dissolved 2.65 g of N-benzyloxycarbonyl-L-leucine. After cooling to -15° C., 1.10 ml of N-methylmorpholine and then 1.37 ml of isobutyl chloroformate were added to the solution while stirring the solution at the same temperature. The mixture was sitrred at -15° C. for 5 minutes. On the other hand, 3.25 g of L-argininal dibutyl acetal hydrochloride (Example 2) was dissolved in 30 ml of dimethylformamide and 1.40 ml of triethylamine was added to the solution. The resulting solution was dropwise added at -10° C. to the mixed acid anhydride suspension which had been previously prepared. Stirring was continued at the same temperature for an hour and then at 0° C. for an hour. The resulting reaction solution was concentrated under reduced pressure and the residue was dissolved in 100 ml of chloroform. The solution was washed successively with 10% citric acid aqueous solution (30 ml×2), saturated sodium chloride aqueous solution (30 ml×1), saturated sodium hydrogencarbonate aqueous solution (30 ml×2) and saturated sodium chloride aqueous solution (30 ml×2). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel as a carrier and developed with chloroform: methanol=20:1 (v/v). The fraction showing Rf: 0.48 (under the same conditions as in Example 1 (A) 4) which was positive in the Sakaguchi reaction, was concentrated under reduced pressure to give 3.73 g of N-benzyloxycarbonyl-L-leucyl-L-argininal dibutyl acetal.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](=[O:34])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26]C(OC(C)(C)C)=O)=[CH:12]2)(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCC(O)=O)=CC=2C=1)=O>>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:18]([C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:35])=[O:5])=[CH:17][CH:16]=2)=[O:34]
Reactant: CC(C)(C)OC(=O)COc1ccc2[nH]c(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: Nc1ccccc1NC(=O)c1cc2cc(OCC(=O)O)ccc2s1
Product: Nc1ccccc1NC(=O)c1cc2cc(OCC(=O)O)ccc2[nH]1

Procedure:
was prepared from [2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-1H-indol-5-yloxy]-acetic acid tert-butyl ester (50) in an analogous manner to that described for the preparation of (45) example 19, step 2; mp.: >250° C. (decomposition).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C1C(=O)N([Br:24])C(=O)C1>CC(C)=O>[Br:24][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([CH3:1])[C:3]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1c2ccccc2CNc2ccccc21
Solvent: CC(C)=O
Product: CC1c2ccccc2CNc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,11-dihydro-11-methyl-5H-dibenzo[b,e]azepine (4) (8 g, 38.3 mmol) in aceton (1500 mL) was cooled to 0° C. and NBS (N-bromosuccinamide; 6.81 g, 38.3 mmol) was added. The reaction mixture was stirred for 20 min at 0° C., quenched by addition of aqueous NaHCO3 (300 mL) and concentrated under reduced pressure. The product was extracted into ethyl acetate which was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=8:2) to give 2-bromo-6,11-dihydro-11-methyl-5H-dibenzo[b,e]azepine (4, R8═Br; 32 g, 97%) Data: (m/z)=288/290 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isatin (2.5 g, 0.017 mol) in anhydrous DMF (50 mL) was cooled to 0° C. in an ice-bath and treated with sodium hydride (0.5 g, 1.2 equivalents). A purple solution was formed which was stirred at 0° C. for 30 minutes and then warmed to room temperature. To this solution was added 4-bromoanisole (2.13 mL, 1 equivalent) followed by copper iodide (6.46 g, 2 equivalents). The reaction was heated in an oil-bath at 145° C. for 6-7 hours. The reaction was then cooled to room temperature, diluted with an equal volume of ethyl acetate and filtered. The filtrate was evaporated to dryness. The crude product, which was obtained as a dark brown solid was used as such for the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:16][CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC3CC(C2)CN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CN2CC3CNCC(C3)C2)cc1

Procedure:
3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonane (1.97 g; 6.4 mmol; from step (a) above) was dissolved in EtOH (95%) and hydrogenated over 5% Pd/C at 1 atm. until tlc indicated that the reaction was complete. The catalyst was removed by filtration through a pad of celite and the residue was concentrated under reduced pressure to give the title compound in a quantitative yield.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])=[CH:22][CH:21]=2)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N#N>ClCCCl>[CH:1]1([CH2:6][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]3[CH:22]=[CH:21][C:20]([N:17]4[CH2:18][CH2:19][C@H:15]([N:11]5[CH2:12][CH2:13][CH2:14][C@@H:10]5[CH3:9])[CH2:16]4)=[CH:25][CH:24]=3)[CH2:31][CH2:32]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(CC(=O)NC3CCNCC3)cc2)C1
Reactant: O=CC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: N#N
Solvent: ClCCCl
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(CC(=O)NC3CCN(CC4CCCC4)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of cyclopentane-carboxaldehyde (138 mg, 1.4 mmol) and 2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-N-piperidin-4-yl-acetamide hydrochloride (0.52 g, 1.18 mmol) in DCE (10 mL) was added powder sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS showed a major peak at 2.300 min with MS of 453. The reaction was quenched with NaHCO3 aq. (15 mL) and NaOH (1N, 5 mL). The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (5 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 0.30 g (56%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13]O.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCBr)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-methoxy-1H-indol-3-yl)ethanol (4.0 g, 20.92 mmol) in DCM (30 mL), CBr4 (7.98 g, 24.06 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (6.3 g, 24.0 mmol) was added. After stirring at rt for 2 h, the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hex 3:1, Rf=0.31) to yield the title compound as a brown oil which turned into a solid during storage in the freezer. LC-MS conditions B: tR=0.78 min, [M+H]+=254.06.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([Mg]Br)#[CH:16]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]#[CH:16])([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.56 mmol) in THF (1 mL) was added dropwise to a solution of ethynylmagnesium bromide (0.5 M, 2.2 mL) in THF (1 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 4 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated to afford 3-ethynyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (119 mg, 94%) as yellow oil. MS: m/z=226 amu (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CC#N>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1cccc(CBr)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Yield: 77.9 %

Procedure:
Using General Procedure E, (R)-{3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (0.681 g, 1.81 mmol), 6-bromomethyl-pyridine-2-carbonitrile (0.535 g, 2.71 mmol) and DIPEA (630 μL, 3.62 mmol) in CH3CN (20 mL) at 55° C. for 16 h gave the crude product as a pale brown oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:, 95:5, v/v) afforded (R)-(3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.696 g, 78%) as a yellow crystalline solid. 1H NMR (CDCl3) δ 0.95 (d, 3H, J=6.0 Hz), 1.40 (s+m, 11H), 1.65 (m, 4H), 1.86 (m, 2H), 2.13 (br t, 1H), 2.54 (br t, 1H), 2.73-2.86 (m, 3H), 3.06 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 3.73 (s, 3H), 4.50 (s, 2H), 6.06 (br s, 1H), 6.68 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.52 (d, 1H, J=6.0 Hz), 7.54 (d, 1H, J=6.0 Hz), 7.70 (t, 1H, J=6.0 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]1
Reactant: Fc1ccccc1Br
Reactant: C[C@@H]1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccccc2F)CCN1
Yield: 54.2 %

Procedure:
To a mixture of 1-bromo-2-fluorobenzene (5.0 g, 28.5 mmol), (R)-2-methylpiperazine (3.15 g, 31.3 mmol) and sodium-tert-butoxide (4.0 g, 42 mmol) in dry toluene (100 mL) under nitrogen was added Pd(OAc)2 (250 mg, 1.1 mmol) followed by BINAP (750 mg, 1.2 mmol). The reaction mixture was then refluxed for 16 h and cooled. The reaction mixture was washed with water, dried and evaporated to a residue. The residue was purified by chromatography using chloroform/methanol (8/2) as eluent to afford the title compound as a liquid (3.0 g, 55%). TLC-Chloroform/Methanol (9/1); Rf: 0.25. HPLC purity: 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[B-]C#N.[Na+]>CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
2-Amino-6-fluorobenzoic acid (2.01 g, 12.93 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5.15 g, 25.9 mmol) were combined and dissolved in methanol (50 mL). Sodium cyanotrihydroborate (1.625 g, 25.9 mmol) was added in one portion at room temperature. Reaction stirred at room temperature for 1 hour. The solvent was removed in vacuo. The resulting foam was partitioned between dichloromethane (170 mL) and 1N sodium hydroxide (65 mL). Layers were separated. The dichloromethane layer was extracted with water (2×65 mL). The aqueous layers were combined and acidified with citric acid to pH around 3. The aqueous layer was extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were combined, dried (Na2SO4), filtered and concentrated to dryness. Title compound was obtained as off-white solid in 92% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.18-7.28 (m, 1 H) 6.57 (d, J=8.56 Hz, 1 H) 6.27 (dd, J=11.58, 8.06 Hz, 1 H) 3.83-3.95 (m, 2 H) 3.56-3.67 (m, 1 H) 3.00-3.15 (m, 2 H) 1.93-2.04 (m, 2 H) 1.44 (s, 9 H) 1.31-1.43 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C1COCC1.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)c(F)c1

Procedure:
Prepared analogously to example 1b by hydrogenation of 2-fluoro-4-nitro-benzoic acid using palladium/charcoal 10% in THF.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[C:39]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=3)=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:7](=[O:14])[O:8]2)=[CH:3][C:2]=1[CH3:39]
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1Br
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1C
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(6-bromo-7-methoxy-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester (100 mg, 0.17 mmol), K2CO3 (70 mg, 0.51 mmol), trimethylboroxine (24 μL, 0.17 mmol) and Pd(Ph3P)4 (20 mg, 0.017 mmol) in anhydrous dioxane (2 mL) was stirred at reflux temperature for 2 h. After cooling to room temperature, the resultant suspension was filtered over Celite, and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2/hexane to afford the desired compound as a beige solid (72 mg, 82%) displaying. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.22 (d, J=0.9 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (s, 1H), 4.02 (s, 2H), 3.91 (s, 3H), 2.16 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z 524.9 (M+H)+, HPLC tR 7.81 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15](I)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(Cl)Cl.Cl>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].O1CCOCC1>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
To stirred solution of K2CO3 (2 M in H2O) (1.9 mL, 3.6 mmol) at rt was added dioxane (14.3 mL), 3-bromo-4-(2-hydroxyethoxy)-5-iodo-benzoic acid ethyl ester (0.503 g, 1.21 mmol) and 3-trifluoromethyl-phenyl boronic acid (0.299 g, 1.57 mmol). The reaction mixture was purged with N2 for a few minutes and then [1,1′ bis (diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (0.030 g 0.036 mmol) was added. The reaction was stirred at rt for 1.5 h and then heated at reflux for 2 h. After cooling to rt, it was poured into a 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After concentration in vacuo, the residue was first purified by flash chromatography (25% EtOAc:hexane) and then HPLC [60% CH2Cl2 (6% MTBE):40% hexane to afford 5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester (0.215 g, 36%) as a white solid 1H NMR (CDCl3) δ8.09 (s, 2H); 7.94 (m, 2H); 7.86-7.80 (m, 2H); 7.71-7.58 (m, 4H); 4.42 (q, 2H) 3.63 (m, 4H); 1.42 (t, 3H) and 3-Bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester (0.173 g, 33%) as a white solid 1H NMR (CDCl3) δ8.29 (d, 1H); 8.00 (d, 1H); 7.86 (m, 1H); 7.80-7.55 (m, 3H); 4.40 (q, 2H); 3.74-3.60 (in, 4H); 1.92 (t, 1H); 1.40 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([OH:7])[CH3:6].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([CH3:6])[O:7][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: CC(O)c1cccc(Br)c1
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(OC1CCCCO1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 20 parts of m-bromo-α-methylbenzylalcohol and 16.8 parts of 3,4-dihydropyran is cooled in an ice-bath and there are added 2 drops of hydrochloric acid solution. The whole is stirred overnight at 0° C and then allowed to come to room temperature. The mixture is poured onto ether and shaken successively with a sodium hydrogen carbonate solution and twice with water. The organic layer is separated, dried, filtered and evaporated. The residue is distilled, yielding 2-(m-bromo-α-methylbenzyloxy)tetrahydropyran; bp. 168°-169° C at 12 mm. pressure.