Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][O:26][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14])=[CH:19][C:18]=1[CH3:27]
Reactant: Cc1cc(NCCO)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NCCO[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol), dimethylaminopyridine (13 mg, 0.11 mmol) and tert-butyl-dimethyl-chloro-silane (319 mg, 2.11 mmol) were added to a solution of 2-(4-bromo-3-methyl-phenylamino)-ethanol (430 mg, 1.87 mmol) in dichloromethane (3.8 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3-methyl-phenyl)-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amine (629 mg, 98%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>O>[O:20]=[C:14]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Phenol (1.88 g, 20.0 mmol) was dissolved in a solution of sodium carbonate (anhydrous) (1.06 g, 10.0 mmol) in water (20 ml) and cooled to 0° C. Succinic anhydride (2.00 g, 20.0 mmol) was added and the suspension was allowed to stir at 0° C. for 1 h. The reaction mixture was gradually warmed to room temperature and stirred over night. The clear solution was cooled to 0° C. and acidified to pH 0 (addition of 1M aqueous HCl). The reaction mixture was extracted with chloroform (3×25 ml), dried over Na2SO4, filtered and the solvent removed under reduced pressure to obtain a white solid (1.63 g, 8.4 mmol, 42%). The product was used without any further purification.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH3:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][CH:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:22][CH2:23]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCc1ccccc1B(O)O
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Product: COCc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3OC)nn12
Yield: 52.3 %

Procedure:
Following the procedure of example 532 (D), (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.062 g, 0.00012 mol) and 2-Methoxymethyl phenylboronic acid (0.0226 g, 0.000132 mol) were reacted. Purification by prep plate chromatography gave [7-(2-Methoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.034 g, 51%) as a tan solid MP: 96-101 C; 1H-NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 7.65-7.62 (m, 2H), 7.55 (m, 2H), 7.47-7.45 (t, 2H, J=3.56 Hz), 6.94-6.87 (q, 2H, J=4.56 Hz), 6.61-6.60 (d, 1H, J=2.28 Hz), 6.42-6.38 (d, 1H), 6.30-6.27 (d, 1H), 4.33 (s, 2H), 3.81 (s, 3H), 3.64-3.61 (d, 2H) 3.17 (s, 3H), 2.67-2.57 (m, 6H), 2.33 (br, 5H), 2.16 (s, 3H), 1.84-1.81 (m, 2H), 1.50-1.48 (m, 2H), 1.23-1.17 (br, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2O1
Agent: NN
Solvent: CO
Solvent: ClCCl
Product: NCC1Cc2ccccc2O1
Reaction time: 20 h

Procedure:
To a solution of 2-(2,3-dihydro-benzofuran-2-ylmethyl)-isoindole-1,3-dione (0.97 g, 3.47 mmol) in MeOH (15 mL) and CH2Cl2 (5 mL) is added hydrazine (0.55 mL, 17.4 mmol). After 20 h at rt, the mixture is filtered off and the filtrate is concentrated. The residue is diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The extracts are dried (MgSO4), filtered, and concentrated to afford C-(2,3-dihydro-benzofuran-2-yl)-methylamine, which is used for a next step without further purification. LCMS: RT=1.25 minutes; MS: 150 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:32](=[O:34])[CH3:33])[CH2:18][CH2:17]3)=[O:13])[CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc2c(c1)CCN2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21
Yield: 84 %

Procedure:
A solution of 2,3-dihydro-1H-indole-5-carboxylic acid quinolin-3-ylamide (77 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.060 mL, 0.345 mmol) in 1,2-dichloroethane (2 mL) was treated with acetyl chloride (0.020 mL, 0.292 mmol). The resultant solution was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated in water (1 mL) and saturated aqueous sodium bicarbonate (1 mL). The product was collected by filtration, to give the product 74 mg (84%). MS: m/z 332 (MH+). 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.24 (t, 2 H), 4.18 (t, 2 H), 7.59 (t, 1 H), 7.67 (t, 1 H), 7.89-7.98 (m, 4 H), 8.15 (d, 1 H), 8.84 (s, 1 H), 9.14 (s, 1 H) and 10.566 (s, 1 H).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.C[Si](C)(C)Cl.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].Cl>ClCCl.C(N(CC)CC)C>[CH:27]([S:28]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:11][CH:12]=1)(=[O:30])=[O:29])=[CH2:26]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
276 mg of triethylamine was added to a dichloromethane suspension (4 ml) containing 100 mg of 6-[4-(3-aminopropoxy)phenyl]pyridazin-3(2H)-one hydrobromide and 37 mg of dimethylanitine, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 86 mg of trimethylchlorosilane was added thereto, and the mixture was stirred at room temperature for 2 hours. Again, under ice cooling, a dichloromethane solution (1 ml) containing 65 mg of chloroethylsulfonyl chloride was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. 5 ml of 1M hydrochloric acid was added to the mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (30: 1)) to obtain 73 mg of 6-[4-(3-vinylsulfonylaminopropoxy)phenyl]pyridazin-3 (2H) -one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(Cl)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (52 mg, 0.158 mmol) (from Example 3 supra) in THF (3 mL) were added diisopropylethylamine (44 mg, 0.35 mmol) and then 4-chlorobenzoyl chloride (30.8 mg, 0.174 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (50 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[3-(4-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 41.4 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:23]([O:25][C:26](=[O:29])[C:27]#[N:28])[CH3:24].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:28]=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:29])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: CCOC(=O)C#N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)nc2ccccc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-N-phenylbenzamide (6 g, 28.40 mmol, 1.00 equiv) in toluene (60 mL) and PCl5 (7.13 g, 34.24 mmol, 1.20 equiv). The mixture was stirred for 2 h at 65° C. The mixture was concentrated under vacuum. The residue was diluted with 30 mL of PhCl. To the mixture was added 2-ethoxy-2-oxoacetonitrile (3.37 g, 34.01 mmol, 1.20 equiv), SnCl4 (12.5 g, 1.70 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 125° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 2.64 g (32%) of ethyl 2-(4-methylphenyl)quinazoline-4-carboxylate as a light green solid. MS (ESI) m/z 293 ([M+H]+).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:11]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOP(=O)(Cc1cccc(Oc2cc(C)ccn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
[3-(4-Methyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.9 g, 8.6 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.03 mL, 0.17 mmol) were combined in THF (10 mL). Sodium hydride (381 mg, 60% dispersion in mineral oil, 9.51 mmol) was added. The reaction was stirred for 30 minutes and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.90 g, 9.51 mmol) in THF (10 mL) was added. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the desired product (1.15 g, 35% yield) as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 64.6 %

Procedure:
3-fluoroaniline (40 g) was dissolved in MeOH and the solution was cooled to 0° C. Tert-butyl 4-oxo-1-piperidinecarboxylate (79 g, 1.1 eq), acetic acid (26.8 ml, 1.3 eq) and sodium cyanoborohydride (29 g, 1.3 eq, portionwise) were added successively to the solution. The reaction mixture was stirred at room temperature until completion. The reaction mixture was then cooled to 0° C. and an aqueous solution of NaOH (20%) was poured into the mixture (pH˜10). The precipitate was filtered off, washed with water, dried and recrystallised from iPrOH to give tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (68.5 g).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])#[N:2].CCN(CC)CC.[H][H]>C1COCC1>[O:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[S:8][C:9]=2[C:10](=[O:11])[NH:2][CH2:1][CH2:3]1
Reactant: N#CCOc1c(C(=O)O)sc2ccccc12
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCOc2c1sc1ccccc21
Yield: 55 %

Procedure:
A mixture of the methyl ester of 3-(cyanomethoxy)benzo[b]thiophene-2-carboxylic acid (405 mg, 1.64 mmols) [J. Hetero. Chem., 12:1037 (1975)], 0.5 mL of Et3N and 0.50 g of RaCo in 50 mL of THF is heated at 100° C. under 1200 psi of hydrogen. The reaction mixture is concentrated in vacuo. Column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate provides 2,3-dihydro-[1]benzothieno[2,3-f]l,4-oxazepin-5(4H)-one in 55% yield, mp 244°-245° C.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>COCCOC>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][C:7]34[C:15](=[O:16])[N:14]([C:17]5[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=5)[C:13](=[O:25])[N:12]3[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=2)[CH:29]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCCN12
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4cccnc4)cc3)CCCCN12
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,8-diazabicyclo(4.3.0]nonane-7,9-dione (0.360 g) and 3-pyridineboronic acid (0.225 g) in DME (20 mL) was added CsF (0.615 g) and the mixture was degassed with nitrogen. After 10 minutes, Pd(PPh3)4 was added and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated. The residue was redissolved in EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: hexane/acetone: 3/2, Chromatotron) afforded the titled compound (0.172 g). MS (m/z) 466 (MH+). mp 276.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:26]([OH:28])=[O:27])=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 10.7 %

Procedure:
6-(4-tert-Butyl-phenyl)-1-methyl-1H-indole-3-carboxylic acid was prepared from 6-(4-tert-butyl-phenyl)-1-methyl-1H-indole (0.541 g, 2.05 mmol), n-butyllithium (0.98 mL, 2.5 mmol), crushed dry ice (3 g, 70 mmol) in dry THF (10 mL) according to the procedure described in Example 60. Purification by flash chromatography using 10-50% ethyl acetate in hexane and 100% ethyl acetate as eluants afforded the title compound as a light yellow solid (0.0675 g, 10.7%), mp: 236-238° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 306. 1HNMR (400 MHz, DMSO-d6): δ 12.8-13.0 (br s, 1H), 7.8 (s, 1H), 7.65-7.7 (m, 3H), 7.45-7.5 (m, 2H), 7.4 (dd, 1H, J=8.3 Hz and 1.6 Hz), 7.2 (d, 1H, J=0.75 Hz), 4.05 (s, 3H) and 1.35 ppm (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (0.2 g, 0.383 mmol) was taken in DCM (3 mL), to it TFA (0.6 mL) was added at 0° C. and stirred at room temperature for 3 h. On completion of reaction, DCM was removed under reduced pressure, saturated NaHCO3 solution was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (60% yield). LCMS: 423.25 (M+1)+; HPLC: 99.121% (@ 254 nm) (Rt; 4.628); 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (t, J=4.8 Hz, 1H); 8.26 (s, 1H); 7.49 (s, 1H); 5.89 (s, 1H); 5.22-5.16 (m, 1H); 4.36 (d, J=4.8 Hz, 2H); 3.04 (d, J=12.0 Hz, 2H); 2.84-2.92 (m, 1H); 2.60 (t, J=, 8.4 Hz, 2H); 2.20 (s, 3H); 2.10 (s, 3H); 1.65-1.81 (m, 4H); 1.49 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncccc2C(F)(F)F)cn1
Yield: 94.8 %

Procedure:
Heat a mixture of 2-chloro-3-trifluoromethylpyridine (37 g, 0.2 mol), 2-methoxypyridine-5-boronic acid (32 g, 0.21 mol), tetrakis(triphenylphosphine)palladium(0) (9 g, 7 mmol) and 2M potassium carbonate (150 mL) in toluene (500 mL) under a nitrogen atmosphere at 90° C. for 8 hours. Cool the reaction mixture and separate the layers. Extract the aqueous layer with ethyl acetate (2×250 mL) and wash the combined organics with 4M sodium hydroxide (250 mL), water (250 mL), and brine (250 mL). Dry (MgSO4) and concentrate under reduced pressure. Purify the resulting oil by flash chromatography on silica gel (50% ether/50% hexane) to give the title compound (48.2 g, 95%) as a colorless oil.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]1[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]1=[O:25])=[O:10])C1C=CC=CC=1.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/C(O)=O)[N:31]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.[Pd]>[NH2:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH3:38])[C:9]([NH:11][CH:12]2[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:13]2=[O:25])=[O:10])[N:31]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CON1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1CN(OCC(=O)OC(C)(C)C)C1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[[3-[(Benzyloxycarbonyl)amino]-2-oxo1-azetidinyl]oxy]acetic acid. 1,1-dimethylethyl ester (1.4 g, 4.0 mmol) was dissolved in 25 ml of dry dimethylformamide and hydrogenated with 1 g of 10% palladium on charcoal as catalyst. After 20 minutes the catalyst was filtered and a mixture of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (4.4 mmol). 1-hydroxybenzotriazole hydrate (0.15 g, 1.0 mmol). dicyclohexylcarbodiimide (0.81g. 4.4 mmol) and 30 ml of dry dimethylformamide was added. The mixture was stirred overnight at room temperature. The precipitated dicyclohexyl urea was filtered off and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 5% NaHCO3 and dried over MgSO4. Filtration and evaporation in vacuo gave the title compound which solidified by stirring with ether/petroleum ether; melting point 120° C. dec.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=C(CC(C)N3CCCC3)C(=O)NCCC2)c1

Procedure:
The solution of 1.36 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 0.52 g of pyrrolidine and 0.1 g of p-toluenesulfonic acid hydrate in 10 ml of benzene is refluxed with water separation for 4 hours and evaporated. The residue is dissolved in 15 ml of ethanol and the solution hydrogenated over 0.1 g of platinum oxide at atmospheric pressure and room temperature. The mixture is filtered, the filtrate evaporated and the resulting oil dissolved in 2 N hydrochloric acid. The solution is washed with benzene, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from petroleum ether and hexane, to yield the 3-(2-pyrrolidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 94° to 96°.