Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>C(#N)C.C(Cl)Cl>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([NH:1][CH2:16][C:15]3[C:14]([CH3:13])=[CH:21][C:20]([F:22])=[CH:19][C:18]=3[CH3:23])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(F)cc(C)c1CNc1cccn2c(C)c(C)nc12
Yield: 43.4 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine (0.5 g, 3.1 mmol) was dissolved in acetonitrile (6 ml). To the solution were added 2,6-dimethyl-4-fluoro-benzylbromide (0.67 g, 3.1 mmol) and potassium carbonate (0.47 g, 3.4 mmol). The mixture was refluxed for 16 h. Methylene chloride (12 ml) and a sodium chloride solution (20 ml) was added. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography (ethyl acetate:petroleum-ether 1:1). 400 mg of the title compound was obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:40])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:6]=2[N:7]=1.[H-].[Na+].[CH3:43]I>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:40])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[O:14][CH3:43])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2nc(N)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold mixture of the product from Step A (475 mg, 0.7 mmol) in THF (7 mL) was added NaH (60% in mineral oil, 29 mg) and stirred at 0° C. for 0.5 h. Then MeI (48 μL) was added and reaction mixture stirred at rt for 24 h. The reaction was quenched with MeOH and the mixture evaporated. The crude product was purified on a silica gel column (5×3.5 cm) using hexane/ethyl acetate (9/1, 7/1, 5/1 and 3/1) as eluent. Fractions containing the product were combined and evaporated to give the desired compound (200 mg) as a colorless foam.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]([CH2:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([CH2:19][C:20](O)=[O:21])[C:14]1=[O:23])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].O[N:30]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.O.Cl.O1CCOCC1>[ClH:1].[CH2:2]([O:9][C:10](=[O:11])[CH2:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([CH2:19][C:20](=[O:21])[NH2:30])[C:14]1=[O:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CN1CCN[C@@H](CC(=O)OCc2ccccc2)C1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)CN1CCN[C@@H](CC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
(S)-3-Benzyloxycarbonylmethyl-2-oxopiperazine-1-acetic acid hydrochloride (7.5 g) and sodium hydrogencarbonate (4.2 g) were dissolved in a mixture of 50 ml of dioxane and 50 ml of water. To the solution was added at 0° C. 5.5 g of di-t-butyl bicarbonate, and the mixture was stirred vigorously for one hour. The reaction mixture was concentrated to half of its original volume, and washed with ether then there was added 30 ml of a 10% aqueous solution of potassium hydrogen sulfate, followed by extraction with methylene chloride. The extract solution was dried over anhydrous magnesium sulfate, which was then concentrated to give a crude product. The crude product was dissolved in 50 ml of dioxane. To the solution was added 2.6 g of N-hydroxysuccinimide, then 5.2 g of dicyclohexylcarbodiimide. The mixture was stirred for one hour at room temperature. Insolubles were filtered off. To the filtrate was added 10 ml of 25% aqueous ammonia, and the mixture was stirred vigorously for one hour. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in methylene chloride, and the solution was washed with water. The methylene chloride layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give an oily product. The oily product was dissolved in 2N HCl-dioxane, and the solution was stirred for one hour. The reaction mixture was subjected to evaporation to dryness to give a crude product, which was recrystallized from ethanol to afford 2.0 g of the title compound as colorless prisms, m.p. 201°-202° C.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH2:2]2.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.BrBr>[N:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:7]2[CH2:8][CH:1]3[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)[CH2:2]3)[CH2:6]2)=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)cc1
Reactant: ClCCCCc1ccncc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCN2CC3CN(CCCCc4ccncc4)CC(C2)O3)cc1
Yield: 57.3 %

Procedure:
4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile (0.80 g, 2.92 mmol, see preparation D above) was dissolved in MeCN (30 mL) and mixed with 4-(4-chlorobutyl)pyridine (0.74 g, 4.39 mmol, from step (i) above) and K2CO3 (1.62 g, 11.71 mmol). 1 drop of Br2 was added and the mixture was refluxed for 24 h. The mixture was filtered and evaporated. Purification by chromatography on silica, eluting with DCM:4% MeOH (satd. with ammonia), gave 0.68 g (57.2%) of the title compound.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]([CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24]CC1C=CC=CC=1)=[O:16])([O:3][CH3:4])=[O:2].[H][H]>CO.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]([CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1O

Procedure:
A solution of (28) (0.11 g., 0.25 mM) in methanol (11 mL) containing 10% palladium on carbon (30 mg.) is shaken in a 40 p.s.i. hydrogen atmosphere until no (V) remained (TLC analysis). The filtered solution was then concentrated in vacuo to give the title compound (29), used immediately in step P.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:35])=[N:30][N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CN(C=O)C.C(O)(=O)C>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:35])=[N:30][N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)nn(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(F)nn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-fluoro-1-methyl-1H-indazol-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (37 mg, 0.058 mmol) and 5M NaOH (0.23 mL, 1.15 mmol) in MeOH (0.5 mL) and THF (2 mL) was stirred at 45° C. for 2 hours. DMF (0.3 mL) and acetic acid (73 μL) were added and reaction mixture was concentrated to ˜0.3 mL, filtered using a syringe filter, diluted with methanol. Purified using Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) and lyophilized to give product. LCMS-ESI+: calc'd for C33H29ClFN4O3S: 615.2 (M+H+); Found: 615.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.80 (d, J=5.4 Hz, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 8.02 (dd, J=5.3, 1.6 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J=28.4, 8.6 Hz, 2H), 7.76-7.67 (m, 1H), 7.60 (br s, 3H), 5.28 (s, 1H), 4.01 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[Br-].[K+]>C(C(C)=O)C(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH:11]([CH3:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(Br)C(=O)OCc1ccccc1
Reactant: Oc1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(Oc1cc(Br)ccc1Br)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2,5-Dibromophenol (53 g) and benzyl 2-bromopropionate (48.6 g) in methyl iso-butyl ketone (250 ml) containing suspended potassium carbonate (13.8 g) was heated under reflux with stirring overnight. The mixture was cooled to 40°, 5% sodium hydroxide solution (100 ml) was added, and the mixture was stirred to dissolve the solid potassium bromide. The aqueous phase was separated with fresh methyl iso-butyl ketone (50 ml). The combined extracts were washed with water (50 ml), dried, and evaporated under reduced pressure. The residue was distilled and the benzyl (2,5-dibromophenoxy)propionate collected at 180°-185°/0.5 Torr. On cooling, the distillate solidified and had a melting point of 52° C. Compounds 1, 5, 6, 14 to 16, 18 to 20, 22 and 23 were made by a similar procedure.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH3:23])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:23])[C:35]([NH:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)=[O:36])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)n2)cc1)C(=O)OC
Reactant: O=C=Nc1ccc2ccccc2c1
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc4ccccc4c3)n2)cc1)C(=O)OC
Yield: 62 %

Procedure:
In a manner similar to that of Example 7(i), starting with 0.4 g (0.8 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]propanoate and 2-naphthyl isocyanate, 0.2 g (62%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalen-2-ylureido)pyrid-2-yl]phenyl}propionate is obtained.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[C:5]([C:9]1[C:10](=[O:26])[CH2:11][CH:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([NH2:24])[C:17]=2[CH3:25])[CH2:13][C:14]=1[OH:15])(=[O:8])[CH2:6][CH3:7].C(OCC)(=O)C>O.C(O)(=O)C>[C:5]([C:9]1[C:10](=[O:26])[CH2:11][CH:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([NH:24][C:2]([NH2:3])=[O:1])[C:17]=2[CH3:25])[CH2:13][C:14]=1[OH:15])(=[O:8])[CH2:6][CH3:7]
Reactant: N#C[O-]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NC(N)=O)c2C)CC1=O
Reaction time: 1 h

Procedure:
A solution of potassium cyanate (0.54 g, 6.66 mmol) in water (3 ml) was added cautiously to a solu tion of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.32 mmol) in acetic acid (9 ml) and water (3.2 ml). Stirring was continued for 1 hr then allowed to stand for 15 hr. Water and ethyl acetate were added. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield 2-propionyl-3-hydroxy-5-(3-ureido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a brown semi solid (0.96 g, 84%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.11 (3H,t); 2.20 (3H,s); 2.32 (6H,s); 2.4-4.1 (7H,m); 5.12 (2H,brs); 6.82 (1H,s); 7.25 (1H,brs).
Reaction SMILES: C(O)C.[OH:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]([O:23]CC)=[O:22])=[CH:18][C:17]=3[CH:26]=2)=[CH:9][CH:8]=1)[CH3:6]>O1CCCC1>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]=3[CH:26]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)O)cc3)ccc2o1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 ml of ethanol was added to a solution of 23.9 g of 6B in 300 ml of tetrahydrofuran, then 195.7 g of 2.5% sodium/mercury amalgam was added in portions, at room temperature. The mixture was stirred at room temperature overnight. The mercury was separated, the solid was collected and dissolved in 300 ml of water. The solution was acidified to pH=1 with concentrated hydrochloric acid. The solid was collected, washed with water and dried (P2O5 ; reduced pressure, 45° C.). The product was dissolved in tetrahydrofuran, the solution was filtered and its volume reduced to 30 ml by evaporating the solvent under reduced pressure. The resulting solution was triturated with ether. The solid was collected and dried in a vacuum oven over P2O5 to give 2,3-dihydro-5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylic acid (6C), mp: 155°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylate (Eldon E. Baird and Peter B. Dervan, J. Am. Chem. Soc. 1996, 118, 6141-6146) (5.0 g, 19.67 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.81 g (81%) of the title product. 1H NMR (CD3OD) 12.79 (s, 1H), 10.48 (br, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 3.78 (s, 3H), 1.49 (s, 9H); 13C NMR 158.47, 153.82, 123.64, 121.56, 109.58, 79.52, 37.06, 28.42; MS m/z−239.2 (M−H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][CH2:29]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].C(OCC)C.C1(C)C=CC=CC=1>[CH:12]1([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:35])[NH:30][CH2:29]4)=[CH:3][N:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: Brc1cnc(NC2CCCCC2)c2nccn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1NCc2cc(-c3cnc(NC4CCCCC4)c4nccn34)ccc21
Temperature: 90 °C
Yield: 36 %

Procedure:
The product of Step 1 (70 mg, 0.24 mmol), Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one, 77 mg, 0.3 mmol), tetrakis palladium triphenylphosphine (69 mg, 0.06 mmol), sodium carbonate solution (1.5 M, 1.28 mL, 1.92 mmol) and dioxane (3.8 mL) are combined in a flask. The mixture is degassed with nitrogen for 10 min then sealed and heated at 90° C. for 16 h. Brine is added and the mixture is washed with dichloromethane followed by ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated in vacuo to afford a brown oil. The crude material is purified by column chromatography, eluting with 5% methanolic ammonia (7 N) in dichloromethane to give a brown solid. Trituration with 1:1 toluene:diethyl ether yielded the title compound as an off-white solid (30 mg, 37%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 2.24 min (99.6%), m/z (APCI) 348 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[O:24][C:23](=[O:32])[CH:22]=1)[CH3:19].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:27]2[CH:26]=[C:25]3[C:30]([C:21]([O:20][CH2:18][CH3:19])=[CH:22][C:23](=[O:32])[O:24]3)=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(=O)oc2cc(O)ccc12
Reactant: OCCCN1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: CCOc1cc(=O)oc2cc(OCCCN3CCN(Cc4ccccc4)CC3)ccc12
Yield: 61.2 %

Procedure:
Condensation of 1-benzyl-4-(3-hydroxypropyl)piperazine (12.5 g) with 4-ethoxy-7-hydroxycoumarin (11 g) as described in Example 4(b) gave 13.8 g (52%) of the title compound as its dihydrochloride of m.p. (ethanol) 240°-241° C.; (Found; C, 59.89; H, 6.47; N, 5.68; Cl, 14.44; C25H30N2O4.2HCl requires; C, 60.60; H, 6.51; N, 5.66; Cl, 14.31%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C.Cl>C(O)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.04 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester in a mixture of 25 ml. of acetic acid and 25 ml of 25% hydrochloric acid are heated under reflux for 90 minutes. The customary work up gives 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:9]>>[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CC(C)(C)C(N)=O
Product: CCN(CC)c1ccc(C(NC(=O)C(C)(C)C)NC(=O)C(C)(C)C)cc1
Yield: 77 %

Procedure:
Compound 51 was prepared from pivalamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 77%. 1H NMR (400 MHz, DMSO) δ 7.70 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.52 (t, J=8.4 Hz, 1H), 3.30-3.33 (m, 4H), 1.12 (s, 18H), 1.05-1.08 (m, 6H). LC-MS (ESI): m/z 262.2 (M+H)+. HRMS (ESI) for C21H36N3O2 (MH+): calcd, 362.2802. found 362.2795.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[BrH:19]>>[Cl:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=[C:9]([Br:19])[CH:8]=1
Reactant: Br
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc2c(Cl)cc(Br)nc2c1

Procedure:
7-Methoxy-4-chloroquinoline(13 g, 67 mmol) was refluxed for 24 hours with 47% hydrobromic acid (30 ml). After allowing to cool, aqueous solution of saturated sodium bicarbonate was added for neutralization and the resulting crystals were filtered. The obtained crystals were washed with water, sufficiently dried and recrystallized from ethanol to obtain 9 g of 4-chloro(bromo)-7-hydroxyquinoline [a mixture of 4-chloro-7-hydroxyquinoline and 4-bromo-7-hydroxy-quinoline (7 : 3)]. This mixture was used without further purification as the starting material in a next reaction.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1>CN(C)C=O>[O:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.9 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (7.5 mg, 0.19 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 40 minutes at room temperature. 1-Chloromethyl-3-phenoxybenzene (32.8 mg, 0.15 mmol) described in Manufacturing Example 35-1-1 was then added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (20 mg, 47%).