Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].Cl>C1COCC1.CO>[CH3:29][C:18]1[N:19]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[S:21][C:17]=1[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:30])=[O:2])=[CH:14][CH:13]=1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2sc(-c3ccc(C)cc3)nc2C)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2sc(-c3ccc(C)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ester 3.2 was dissolved in THF/MeOH/10% NaOH(aq) (1:1:1) solution (15 mL). After stirring at room temperature over 30 minutes, the mixture was acidified with 1N HCl (aq.) until pH=4. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4 and concentrated. The crude residue was triturated with 20% ethyl acetate in hexanes (20 mL). The precipitate was filtered and compound 3 was acquired as a pale yellow powder (315 mg, 0.8 mmol). MS ESI m/e: 406 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.86 (2H, d, J=7.5 Hz); 7.36 (2H, d, J=9 Hz); 7.26 (2H, d, J=8 Hz); 6.96 (2H, d, J=8.5 Hz); 5.18 (2H, s); 4.1 (1H, m); 2.77 (2H, m); 2.52 (3H, s); 2.43 (3H, s); 1.86 (3H, s).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li]CCCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>C1COCC1>[CH3:24][C:19]1([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21][B:17]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])[O:18]1
Reactant: Cc1ccsc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-bromo-3-methylthiophene (337 mg, 1.9 mmol) in 8 mL of THF at −40° C. was added n-BuLi (0.8 mL, 2.5 M/hexanes), and the reaction was allowed to stir for 30 min. At this time 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol) was added, and the reaction was allowed to warm to ambient temperature, and stirring was continued for 1 h. The reaction was then cooled to 0° C. and quenched with satd aq NaHCO3 (10 mL). The mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by silica gel preparative thin layer chromatography (20% EtOAc-hexanes) afforded 224 mg (53%) of the title compound as an oil. 1H-NMR (CDCl3; 400 MHz): δ 1.36 (s, 12H), 2.5 (s, 3H), 6.99 (d, 1H, J=4.8 Hz), 7.50 (d, 1H, J=4.8 Hz).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A solution of [5-(3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine (III-80) (250 mg, 0.56 mmol), in dichloromethane (3 mL) at 0° C. was treated with TFA (2 mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane (3×5 mL) and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3 mL) and water (3 mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80° C. under vacuum to afford III-79 as an off-white powder (122 mg, 63%): mp 205-207° C.; 1H NMR (DMSO) δ 1.68-1.83 (2H, m), 2.65-2.80 (4H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H, m), 8.45-8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23](OC(F)(F)F)=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1.[F:31][C:32](OB(C1C=CC=CC=1)O)([F:34])[F:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:32]([F:34])([F:33])[F:31])=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: OB(OC(F)(F)F)c1ccccc1
Reactant: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCCN1Cc1ncccn1
Product: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCCN1Cc1ncccn1

Procedure:
Compound 2 is prepared in a manner similar to that of Compound 1 except that 4 trifluoromethyl phenyl boronic acid is used in place of 4-trifluoromethoxy phenyl boronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14].O>C1COCC1>[CH3:12][N:13]([CH3:14])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added 50% dimethylamine solution (29 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give dimethyl-4-nitrobenzylamine (20.7 g) as orange oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20](=[O:24])[NH:21]2)=[C:16]([CH3:25])[CH:15]=1)C1C=CC=CC=1.CCOCC>CCO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20](=[O:24])[NH:21]2)=[C:16]([CH3:25])[CH:15]=1
Reactant: Cc1cc(OCCCCOCc2ccccc2)nc2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(OCCCCO)nc2[nH]c(=O)ccc12
Yield: 81.5 %

Procedure:
A sixth intermediate compound, 7-(4-Hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: 7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (7.31 g, 21.6 mmol) was hydrogenated using 20% Pd/C (1.0 g) in EtOH (100 mL). The product precipitated out of solution before the double bond was reduced. DMF (75 mL) was added and the mixture was heated to dissolve the solids. More 20% Pd/C (1.0 g) was added and the hydrogenation was continued, however the double bond was resistant to further hydrogenation under these conditions. The reaction mixture was filtered and the solvent was concentrated to give a slurry. Et2O was added and the solid was collected by filtration and dried to give 7-(4-hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (4.37 g, 17.6 mmol, 81%). 7-(4-Hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (3.0 g, 12.08 mmol) was hydrogenated using 20% Pd/C in acetic acid (mL) for x h. The reaction mixture was filtered and concentrated to give a mixture of the sixth intermediate compound and the corresponding acetylated compound. The mixture was suspended in MeOH (30 mL) and H2O (10 mL) and the pH was adjusted to 14 by addition of 50% aqueous NaOH. The mixture was warmed to 45° C. Glacial acetic acid was added to bring the pH to 7.5 and the MeOH was removed under reduced pressure. The resulting solid was filtered, washed with H2O and dried to give the sixth intermediate compound as a solid (2.78 g, 11.1 mmol, 92%). MS: APCI: M+1: 251.1 (Exact Mass: 250.13).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[C:3]=1[C:16]([O:18]CC)=O.[CH:21]([NH2:23])=O>>[OH:18][C:16]1[C:3]2[C:4]3[CH:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[CH:21][N:23]=1
Reactant: NC=O
Reactant: CCOC(=O)CC1CCc2sc(N)c(C(=O)OCC)c21
Product: CCOC(=O)CC1CCc2sc3ncnc(O)c3c21
Temperature: 180 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
To a 10-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of 15.2 (500 g, 1.68 mol, 1.00 equiv) in formamide (5 L) at room temperature. The resulting solution was stirred for 5 h at 180° C. in an oil bath. The reaction mixture was cooled to room temperature and then quenched by the addition of 10 L of water/ice. The resulting solution was extracted with 3×5 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The solids were collected by filtration to afford 200 g (43%) of ethyl 2-[12-hydroxy-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetate (15.3) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:17](Br)[CH:18]=[CH2:19]>CO.CN(C)C=O>[CH2:19]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium hydroxide (8.0 gm, 0.2 ml) in methanol (170 mL) was added dropwise to a solution of 6-hydroxybenzothiazole-2-sulfonamide (23.0 gm, 0.1 mol) and allyl bromide (10.0 mL, 0.12 mol) in dry dimethylformamide (100 mL). This mixture was stirred at room temperature for 16-20 hours and then poured into hydrochloric acid-ice water. The precipitate was collected by filtration, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. This residue was triturated with methylene chloride and the crystalline product was collected. (wt. 9.9 gm), m.p. 184°-187° C. A sample was recrystallized from 1,2-dichloroethane, m.p. 193°-195° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([F:37])=[C:21]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[CH3:35][N:33]([CH3:34])[C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:21]2[C:20]([F:37])=[C:19]([C:3]3[C:4]4[C:12]5[C:7](=[CH:8][C:9]([N:13]6[CH2:18][CH2:17][O:16][CH2:15][CH2:14]6)=[CH:10][CH:11]=5)[NH:6][C:5]=4[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:1][CH:2]=3)[CH:24]=[CH:23][CH:22]=2)=[O:36])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C=O
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C(CN)c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)c3ccc(N(C)C)cc3)c2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of N-(3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-fluorophenyl)-4-(dimethylamino)benzamide (0.321 g, 0.640 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.279 mL, 1.408 mmol) in 1,4-dioxane (30 mL) at room temperature was added hydrogen chloride (4 N in 1,4-dioxane) (0.480 mL, 1.92 mmol). The mixture turned to heterogeneous and it was stirred room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (30 mL), basified with NaHCO3 solution to pH 10, and extracted with ethyl acetate (4×40 mL). The combined extract was washed with brine (30 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added 1,4-dioxane (1 mL) and p-xylem (15 mL) and 10% Pd/C (0.4 g), and the mixture was heated at 140° C. under an ambient atmosphere for 4.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (120 ml), washed with brine (25 ml), and dried over anhydrous MgSO4. Removal of solvent under vacuum, followed by triturating with Et2O (8 mL), provided the desired product (0.144 g, 0.238 mmol, 37.1% yield) as a tan solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([O:35][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a mixture of 233 mg of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 168 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 170 mg of DBU and 5 xl of DMF was added 36 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. After chloroform and 10% citric acid were added to the residue and the resultant mixture was shaken thoroughly, the resulting chloroform layer was collected and then successively washed with a 5% aqueous solution of sodium hydrogencarbonate and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol: 100:1), whereby 210 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:28][C:23]=2[N:22]=[N:21]1>>[CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:28][C:23]=3[N:22]=[N:21]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(OCC2CO2)cc1
Reactant: NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21
Product: CS(=O)(=O)Oc1ccc(OCC(O)CNCCn2nnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-methylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, white solid (13 mg, 15%), MS (ISP) m/z=449.4 [(M+H)+], mp 280° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methylsulfonyl-phenyl)-1H-benzo[d]imidazole (intermediate O) (70 mg, 199 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (53.2 mg, 239 μmol).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[CH2:22]1
Reactant: COc1ccc(C2CCCNC2)cc1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(4-methoxyphenyl)piperidine.HCl (38 mg, 0.17 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 3 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 18 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][CH2:3]1
Reactant: Ic1ccccc1
Reactant: CC1(C)CCNc2cc(Br)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)CCN(c2ccccc2)c2cc(Br)ccc21
Temperature: 185 °C

Procedure:
To a solution of 0.19 g (0.78 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-7-bromoquinoline and 5.5 g (3.0 mL, 27 mmol) of 4-iodobenzene stirring under argon, were added 0.30 g (2.2 mmol) of potassium carbonate and 0.12 g (0.63 mmol) of copper(I) iodide. The resulting mixture was heated at 185° C. for 96 hours. The reaction was cooled to room temperature, water was added, and the mixture was extracted with methylene chloride (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give an oil. The residue was purified by flash chromatography (hexanes) to give the product as a clear oil. PNMR (300 MHz, CDCl3) d 1.33 (6 H, s), 1.84 (2 H, t, J=6.1 Hz), 3.62 (2 H, t, J=6.1 Hz), 6.77 (1 H, d, J=2.0 Hz), 6.81 (1 H, dd, J=8.2, 2.0 Hz), 7.10 (1 H, d, J=8.2 Hz), 7.16-7.23 (3 H, m), 7.39 (2 H, 2 doublets overlapping).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCc1ccccn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 59.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 2-(2-chloroethyl)pyridine (0.42 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.41 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 2.5 g (9.6 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b), 1.1 ml (8 mmol) of triethylamine, 1.2 g (8 mmol) of 5-amino-1,3-dihydro-benzimidazol-2-one [J. Amer. Chem. Soc., 80, 1657. (1958)] 3.03 g (8 mmol) of HBTU and 80 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated, then 100 ml of 8% sodium hydrogencarbonate solution is added. The precipitated product is filtered off and recrystallized from methanol to yield 1.51 g (48%) of the title compound. Melting Point: >260° C. (methanol)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a solution of 3-{2-[2-((S)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl ester (127 mg, 0.23 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (130 mg) and the resulting mixture stirred under an atmosphere of H2 for 18 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo affording the title compound (109 mg, 86%). LCMS (method A): RT 3.06 min [M+H]+ 549.4
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)[O:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[C:14]([C:16]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:18]([CH2:19][N:27]([CH2:25][CH3:26])[CH3:28])[CH:17]=3)[O:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2]
Reactant: CCNC
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(C=O)c3)n2)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Yield: 88.6 %

Procedure:
The title compound (2.14 g) was prepared starting from 3-[3-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methyl-benzaldehyde (2.13 g, 6.61 mmol) and N-ethyl-methylamine (1.56 g, 26.4 mmol) according to Method B. LC-MS: tR=0.61 min; [M+1]+=366.22; 1H NMR δ 1.06 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H), 2.14 (s, 3H), 2.28 (s, 3H), 2.41-2.48 (m, 5H), 2.65-2.72 (m, 2H), 3.54 (s, 2H), 7.46 (s, 1H), 7.67-7.71 (m, 2H), 7.89 (s, 1H), 7.93 (s, 1H), 8.93 (s, 1H).