Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:29]=[CH:30][N:31]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:29]=[CH:30][N:31]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cccc(-c2cc(Nc3ccc(OC)c(OC)n3)c3nccn3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Ethyl 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (150 mg, 358 μmol) was dissolved in dioxane (18 mL). To this was added a solution of LiOH (85.6 mg, 3.58 mmol) in water (9 mL). The mixture was stirred for 4 h, acidified with 1N HCl, and concentrated in vacuo to give the crude acid which was recrystallized from isopropyl alcohol and methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (123 mg, 314 μmol, 88%) as a light brown powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.97 (s, 1H) 8.60 (s, 1H) 8.52 (s, 1H) 8.17-8.30 (m, 2H) 8.05 (d, J=7.55 Hz, 1H) 7.60-7.72 (m, 2H) 7.41 (d, J=8.31 Hz, 1H) 7.12 (d, J=8.31 Hz, 1H) 4.05 (s, 3H) 3.76 (s, 3H); LC/MS: 391.8 [MH]+.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[N:13]1([C:19](=[O:21])[CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:7]([Cl:10])=[O:6])[CH2:15][CH2:14]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (2.31 g, 7.80 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-piperazin-1-yl-ethanone (2.0 g, 15.6 mmol) and pyridine (1.38 ml, 17.2 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 1.12 g (38%) of the title compound as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O-:26][N+:1]1[CH:2]=[CH:3][C:4]([C:7]2([OH:17])[CH2:8][CH2:9][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:15][CH2:16]2)=[CH:5][CH:6]=1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
To a solution of 2.35 g (10 mmol) of 8-pyridin-4-yl-1,4-dioxaspiro[4.5]decan-8-ol (prepared following the procedure described in Example 7) in 20 mL of methylene chloride was added 2.6 g (15 mmol) of mCPBA. The reaction mixture was stirred at room temperature for 1.5 h. Direct chromatography on silica gel afforded the title compound (2.45 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl 5-chloroisophthalate (10.0 g, 43.7 mmol, Astatech) in methanol (50 mL) and methylene chloride (50 mL) at 0° C. was added sodium borohydride (5.5 g, 140 mmol, Aldrich). The reaction was allowed to gradually reach room temperature and stir for 1 hour. Additional portions of sodium borohydride (0.50 g, 13 mmol) were added at 2 hours and 3 hours. The reaction mixture was cooled to 0° C. and the reaction was quenched with water. The layers were separated and the aqueous layer was extracted with three portions of DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes. Yield: (4.51 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cc(F)ccc4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,5-difluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 555.3 ([M+H]+)
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])=[N:4][NH:3]1.[Li+].[OH-].O>C1COCC1>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])=[N:4][NH:3]1
Reactant: CCOC(=O)C(C)c1ccc(=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a solution of Ethyl (3-oxo-2,3,-dihydropyridazin-6-yl)-propionate (3.00 mmol, 589 mg) in THF was added LiOH (2M, aqueous) (7.50 mL). The solution was stirred at rt. for 15 minutes, additional water (25 mL) was added and the THF removed in vacuo. The pH of the aqueous phase was adjusted to 3.0 by addition of HCl (2M, aqueous) and the solid material filtered off and washed with water (2×3 mL). The solid was dried in vacuo to yield the desired product (461 mg, 91.4%) as a colorless powder. 1H NMR (CDCl3): δ 11.62 (s br, 1H, NH), 7.18 (d, J=9.7 Hz, 1H, arom.), 7.88 (d, J=9.7 Hz, 1H, arom.), 4.11 (q, J=7.1 Hz, 2H, CH2), 2.90 (t, J=7.0 Hz, 2H, CH2), 2.64 (t, J=7.0 Hz, 2H, CH2), 1.25 (t, J=7.1 Hz, 3H, CH3). FAB+ MS: 169.0611 (M+H+, calc. for C9H12N2O3+H+ 169.0613).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9][OH:10])[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9][O:10][CH3:27])[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1
Reactant: CI
Reactant: CON=C1C[C@@H](CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1CC(=NOC)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of alcohol (2) (EZ mixture, 20 mg, 0.06 mmol) and sodium hydride (3 mg, 0.12 mmol) in tetrahydrofuran (1 ml) under argon, was added methyl iodide (7.7 μl, 0.12 mmol). The reaction mixture was stirred overnight and quenched with water. The mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4) and concentrated in vacuo. The crude was purified on silica gel preparative chromatography using DCM: MeOH 100:0 then 95:5.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]1([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[C:11]1([O:21][CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: c1ccc2c(OCC3CCCN3)cccc2c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: c1ccc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc2c1

Procedure:
1.6 235 mg of 6-chloropurine, 400 mg of 2(-naphthalen-1-yloxymethyl)pyrrolidine and 0.8 ml of triethylamine are dissolved in 30 ml of 1-butanol and irradiated in the microwave at 120° C. for 6 h. After removal of the solvent in vacuo, the residue is taken up in 10 ml of methanol, the crystals which precipitate in the process are filtered off with suction and washed with methanol, giving 340 mg of colourless crystals 6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine (“A1”); Rt.: 1.806 min; [M+H]+346; m.p. 207-208°;
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CI
Product: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid are added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 mL of ethanol at 20° C. and stirred for 3 h. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide are added dropwise at 20° C. and the mixture is stirred for 24 h. It is worked up and purified analogously to compound 3b. Yield: 21.06 g of 11 (80% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14].B1C2CCCC1CCC2.[CH:24]([O:27][BH-](OC(C)C)OC(C)C)(C)C.[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:24]=[O:27])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: CC(C)O[BH-](OC(C)C)OC(C)C
Reactant: C=CCc1ccc(F)c(OC)c1OC
Agent: B1C2CCCC1CCC2
Agent: [K+]
Product: COc1c(F)ccc(CCCC=O)c1OC
Reaction time: 2 h

Procedure:
The product from Example 54 (7.2 g) was treated with 9-BBN (85 ml, 0.5M in THF) at room temperature with stirring for 2 hours. The stirring was stopped and the reaction mixture cooled to 0° then potassium triisopropoxyborohydride (43 ml, 1.0M in THF) was added. Carbon monoxide was bubbled through the reaction mixture for 3 hours, then pH 7 buffer (60 ml) and 30% H2O2 (16 ml) was added with stirring and the reaction was allowed to stir overnight. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was separated, dried and evaporated to afford the desired product as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:35]=1[CH2:36][CH2:37][C@H:38]2[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[NH:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:33]=[C:32]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C@H:38]4[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4-(N-(3-cyano-4-isopropoxybenzolyloxy) carbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate. The mixture was partitioned between EA and NaHCO3 and the organic layer was collected and dried over MgSO4. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95° C. for 12 hrs. The reaction was diluted with NaHCO3 (200 mL) and extracted with EA (3×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS-ESI (m/z) calculated for C26H28N4O4: 460.5; found 483.2 [M+Na]+, tR=4.25 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.1, 1H), 8.34 (dd, J=8.9, 2.2, 1H), 8.09 (d, J=7.6, 1H), 7.51 (d, J=7.5, 1H), 7.39 (t, J=7.6, 1H), 7.12 (d, J=9.0, 1H), 5.28 (d, J=8.2, 1H), 4.80 (hept, J=6.0, 1H), 3.47 (ddd, J=17.4, 8.9, 3.5, 1H), 3.27-3.03 (m, 1H), 2.68 (d, J=8.7, 1H), 1.87 (td, J=16.7, 8.5, 1H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.99, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate was eluted using 20% i-PrOH in hexanes: >99.9% ee, tR=13.33 min. The (S)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate using General Procedures 3 and 4 (tR for (S)-enantiomer=16.31 min).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C[CH:15]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(O)=O.[C:36](O)(=[O:38])C.O>ClCCl>[OH:38][CH2:36][CH:22]1[C:27]2[C:26]3[CH:25]=[CH:31][CH:30]=[CH:29][C:28]=3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:35]2[C:23]1=[CH:24][CH:32]=[CH:33][CH:34]=2
Reactant: CC(=O)O
Reactant: O=C(O)CC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 3 h
Yield: 10 %

Procedure:
Diisobutylaluminum hydride (4.6 ml, 4.62 mmol; 1M in CH2Cl2) was added at -65° C. to a solution of 13-carboxymethyl-dibenzo(a,c)fluorene (0.5 g, 1.54 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 3 h and the temperature maintained between -50° C. and -40° C. A white precipitate was obtained. The reaction mixture was treated with a mixture of acetic acid and water (1:1; 30 ml) and extracted with dichloromethane (3×60 ml). The organic layer was washed with saturated bicarbonate (50 ml), water (30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a crude solid. This crude solid was purified by flash chromatography using chloroform as the eluent. Compound (21) was obtained as a white solid which was washed with petrol (0.217 g, 48%); m.p. 167°-168° C.; (Found: C, 89.0; H, 5.39; C22H16O requires: C, 89.2; H, 5.41%); t.l.c. Rf (D) 0.26; Rf (E) 0.64; νmax (CH2Cl2) 3610 (free OH), 3490 (H bonded OH), 3060 (CH stretching), 2940, 2890 (CH stretching, alkyl), 1610, 1600, 1580 (aromatic rings) cm-1 ; λmax 366 (888), 338 (12728), 322 (14504), 266 (27232), 246 (31968) nm; δH (CDCl3, 200 MHz), 8.88-8.68 (3H, m, aromatic), 8.38 (1H, d, 3J=7.9 Hz, aromatic), 8.14-8.08 (1H, m, aromatic), 7.81-7.33 (7H, m, aromatic), 4.45 (2H, m, HaCH2 and Hc), 3.85 (1H, m, Hb, CH2), 1.64 (1H, S, OH), δC (CDCl3, 50 MHz), 146.7, 142.5, 139.4, 134.9, 130.9, 130.1, 128.7 (quaternary aromatic C's), 127.5, 126.8, 126.1, 125.9, 125.8, 124.7, 124.2, 124.1, 123.8, 123.4, 122.9 (aromatic CH's), 65.7 (CH), 50.0 (CH); m/z (EI) 296, 265.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[O:1]1[CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[N:21][C:22]=4[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc2c(c1)OCCO2
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3c(c2)OCCO3)c2c(N)ncnc21
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (26 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA54 (6 mg, 15% yield). ESI-MS (M+H)+ m/z calcd 312.1, found 312.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.C([Li])CCC.[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33](N(OC)C)=[O:34])=[CH:31][CH:30]=1>CCOCC>[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(C(=O)c3ccc(F)cc3)c2)cc1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (6.0 g, 16.6 mmole) in 100 mL of ether at −73° C., is added a solution of butyl lithium (7.3 mL, 18.3 mmole, 2.5 M in hexane) slowly (maintaining internal T<−70° C.). After stirring at −73° C. for 30 minutes, a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (4.56 g, 24.9 mmole) in 15 mL of ether is added slowly (maintaining internal T<−70° C.). After stirring at −70° C. for 1.5 hours, the reaction is quenched by addition of 20 mL of water and warmed to room temperature with stirring. The resulting mixture is diluted with 100 mL of EtOAc and washed with 2×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (CH2Cl2 95%, EtOAc 5%) to give (4-fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanone (4) (6.4 g, yield 86%) as a light brown viscose liquid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:15]([CH3:16])=[CH:14][S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:15]([CH3:16])=[CH:14][S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Cc1cscc1-c1ccccc1C(O)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Temperature: 110 °C
Yield: 75.8 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 100 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 76%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)noc2c1
Reaction time: 68 h
Yield: 103.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH--CH2Cl2 as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from EtOH provided 2.3 g (41%) of a white powder, m.p.=129°-131° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](Br)[CH:5]=1.B1([C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)OCCCO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1)[C:3]([OH:2])=[O:12]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COC(=O)c1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(F)cc(-c2cccnc2)c1
Temperature: 120 °C
Yield: 55.5 %

Procedure:
To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (O) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120° C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid.