Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:25]([F:24])([F:35])[F:36])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccccc1C(F)(F)F
Yield: 75.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 2-(trifluoromethyl)benzoic acid (110 mg, 0.581 mmol), oxalyl chloride (84 mL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (175 mg, 75%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[S:10][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Li].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:52][C@@H:53]1[CH2:57][CH2:56][CH2:55][N:54]1[CH2:58][C@@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1>CN(C=O)C.ClCCl>[CH2:1]([S:3]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:60]3[CH2:61][CH2:62][CH2:63][C@H:59]3[CH2:58][N:54]3[CH2:55][CH2:56][CH2:57][C@H:53]3[CH3:52])=[O:17])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)s1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)cc2)s1
Yield: 50 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 5 mL 50% DMF/dichloromethane using 4-(5-ethanesulfonyl-thiophen-2-yl)-benzoic acid, Lithium salt (118 mg, 0.39 mmol), EDC-HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), DIEA (0.17 mL, 1.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (61 mg, 0.36 mmol) to give the title compound (80 mg, 50% yield). MS (ES+) 447.3 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=1.[OH-].[Na+].Cl>CCO>[CH2:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:15])=[O:2])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(CCC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
96A (824 mg, 4 mmol) was suspended in EtOH (4 mL) and aqueous NaOH (1 M, 20 mL) and was heated under reflux conditions for sixty minutes. Upon cooling to room temperature, the solution was acidified with HCl (conc.), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (633 mg, 82%). NMR 1H (ppm, CDCl3): 7.94-7.91 (m, 2H), 7.42 (d, J3=7.6 Hz, 1H), 7.36 (t, J3=7.7 Hz, 1H), 2.69-2.64 (m, 2H), 1.62-1.49 (m, 3H), 0.94 (d, J3=6.3 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: COc1ccc(OB([O-])[O-])cc1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoylamino)-benzyl)piperidine (0.4 g), 4-methoxyphenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was ref luxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-methoxyphenyl)-cinnamoylamino)benzyl)piperidine (Compound 84) (0.38 g) as colorless crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:12]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Nc1ccc(C2=Cc3ccccc3C2)cc1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmol) of indene, 4.38 g (20 mmol) of para-amino-iodo-benzene and 0.134 g (0.6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. After that all triethylamine was removed under reduced pressure. The residue was treated with 80 ml of 15% HCl. Forming precipitate was separated and washed with dichloromethane. The resulting substance was treated with the mixture 50 ml of dichloromethane and 50 ml of 5% KOH in water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yield of product was 21%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH2:24]([O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:25]
Reactant: CCOc1ncccc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CCOc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 27 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-ethoxypyridin-3-ylboronic acid were reacted to give 283 (0.045 g, 27%). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.2, 1H), 8.15 (dd, J=4.9, 1.8, 1H), 7.92 (s, 1H), 7.65 (dd, J=7.3, 1.8, 1H), 7.55 (dt, J=11.2, 5.6, 1H), 7.13 (d, J=8.4, 1H), 7.02-6.93 (m, 1H), 5.84 (dt, J=13.2, 6.6, 1H), 4.55-4.39 (m, 4H), 3.45 (t, J=5.0, 2H), 1.59 (d, J=6.6, 6H), 1.38 (t, J=7.0, 3H). MS (ESI(+)): m/z 434.1 (M+H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][C:12](=O)[NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[C:1]1([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COC(CCc2ccccc2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: c1ccc(CCC2CNCCO2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 2-(β-phenylethyl)morpholine-5-one (430 mg.) in dry tetrahydrofuran (4 ml.) is added to a stirred suspension of lithium aluminium hydride (200 mg.) in dry ether (20 ml.) at such a rate that the mixture refluxes gently. After complete addition, the mixture is stirred and refluxed for 2 hours, then it is cooled and there are successively added water (0.2 ml.), sodium hydroxide solution (2N, 0.2 ml.) and water (0.6 ml.) and stirring is continued for 15 minutes. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 2-(β-phenylethyl)morpholine as an oil which may be converted to its hydrogen oxalate salt, m.p. 151°-152° C. or its hydrogen maleate salt, m.p. 120°-122° C. on recrystallisation from methanol/ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: COCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 6 h
Yield: 45.4 %

Procedure:
A mixture of methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoate (300 mg, 11.28 mmol) (D41), polystyrene bound triphenylphosphine (1.71 g of loading 1.12 mmol/g, 1.92 mmol), and 4-methoxybutan-1-ol (200 mg, 1.92 mmol) in THF (5 ml) was treated dropwise with diethyl azodicarboxylate (0.302 ml, 1.92 mmol). The mixture was stiffed at room temperature for 6 hrs and then filtered. The resin was washed with THF and the filtrate was concentrated and chromatographed on silica gel (elution with ethyl acetate/hexane) to give methyl 3-(4-methoxybutoxy)-5-(2-oxopyrrolidin-1-yl)benzoate (280 mg).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[C:20]([O:25]CC3C=CC(OC)=CC=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[C:20]([OH:25])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reaction time: 16 h
Yield: 39 %

Procedure:
To a stirred solution of 1-cyclohexylmethyl-5,6-difluoro-2-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]-1H-benzoimidazole (2.32 g, 5 mmol) in dichloromethane (40 ml) was added boron tri bromide (1M solution in dichloromethane; 21 ml, 21 mmol) at 25° C., and the resulting mixture was allowed to stir for 16 h at the same temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bi carbonate solution, further diluted with dichloromethane (30 ml). Organic layer was washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude material. Crude product was purified by column chromatography using silica gel (5-10% ethyl acetate/n-hexane) to give the title compound as a colorless solid (39%). MS (Turbo Spray): m/z=344.3 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[CH3:16][O:17][P:18]([O-:21])[O:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]([P:18]([O:19][CH3:20])([O:17][CH3:16])=[O:21])[OH:3])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: COP([O-])OC
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 4.32 g of p-nitrobenzyl glyoxalate and 2.0 ml of dimethylphosphite in 25 ml of benzene is added a catalytic amount of p-toluenesulfonic acid. The reaction is heated at reflux temperature for 1.5 hours. The formed water is removed using a Dean-Stark trap. After cooling, the solvent is removed in vacuo and the resulting crystals are slurried in ethyl acetate and collected to give 3.48 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[Cl:37])=[O:27])[CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:39])[O:14][CH2:15][C@@H:16]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[Cl:37])=[O:27])[CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propyl 3-phenylisoxazol-5-ylcarbamate (0.4 g, 0.7 mmol, 1.0 equiv.) in MeOH (5 mL) at 0° C., was added HCl/Dioxane (4 N, 3 mL). The mixture was warmed up to RT, stirred for 1 h, concentrated and purified on silica gel column using a mixture of DCM and MeOH to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 3-phenylisoxazol-5-ylcarbamate (0.35 g, 96%, white solid). LRMS (M+H+) m/z 521.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[CH3:28][O:29][CH2:30][C@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH2:36][CH2:37][C:38](N(OC)C)=[O:39].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CCCCCC.O>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]2[C:18]=1[CH:24]=[C:38]([CH2:37][CH2:36][N:32]1[CH2:33][CH2:34][CH2:35][C@@H:31]1[CH2:30][O:29][CH3:28])[O:39][C:16]2=[O:25]
Reactant: COC[C@H]1CCCN1CCC(=O)N(C)OC
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: COC[C@H]1CCCN1CCc1cc2c(C)cccc2c(=O)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
Diisopropylamine (3.03 g) was dissolved in tetrahydrofuran (30 mL) and a solution (1.58 mol/L, 17.7 mL) of n-butyllithium in n-hexane was added dropwise under a nitrogen stream at −78° C. Subsequently, a solution of N,N-diethyl-2,3-dimethylbenzamide (3.28 g) in tetrahydrofuran was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. A solution of (R)-3-(2-methoxymethylpyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.22 g) in tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 30 min. After the completion of the reaction, concentrated hydrochloric acid (15 ml) and water (30 mL) were added and the mixture was heated under reflux. Tetrahydrofuran and hexane were evaporated and the mixture was further heated under reflux for 6 hr. After the completion of the reaction, the reaction mixture was cooled to room temperature and basified by adding potassium carbonate. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with chloroform:methanol=50:1 was concentrated to give (R)-5-methyl-3-[2-(2-methoxymethylpyrrolidin-1-yl)ethyl]isocoumarin (3.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyridin-3-yl-benzaldehyde, of Preparation 23, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ8.82 (d, 1H), 8.56 (m, 1H), 7.85 (m, 1H), 7.53 (d, 2H), 7.45 (d, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.96 (m, 2H), 6.78 (dd, 1H), 4.51 (s, 2H), 3.84 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H); MS 405 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27](O)=[O:28]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([CH:23]4[CH2:24][CH2:25][CH2:26][O:22]4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)C1CCCO1
Product: Cc1ccc(NC(=O)C2CCCO2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′biphenyl-3-yl)tetrahydrofuran-2- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and tetrahydrofuran-2-carboxylic acid. using method D. NMR; δH [2H6]—DMSO 9.65,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.63-7.60,(2H, m), 7.41,(2H, d), 7.22,(1H, d), 4.36,(1H, m), 3.97,(1H, q), 3.81,(1H, q), 3.16,(2H, t), 2.17,(4H, m), 1.97,(1H, m), 1.84,(2H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.12 min, MH+379.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
In a 750 ml sulfonating flask, 30.0 g (0.252 mol) of 4-hydroxybenzonitrile, 84.0 g (0.252 mol) of 1-bromooctadecane and 48.7 g (0.353 mol) of finely ground potassium carbonate are introduced into 200 ml of N-methylpyrrolidone (NMP) under a nitrogen atmosphere and heated at 120° C., with stirring. After being stirred for 15 hours, the mixture is cooled to room temperature and poured into 2 liters of water, whereupon a light-beige solid precipitates out, which is filtered off and washed with water. After drying at 60° C. and 150 mbar, there are obtained 90.8 g (97% of theory) of a colourless crystalline solid of formula
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ncn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 10.0 g of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005, Ex. 28) in 150 ml of glacial acetic acid, under nitrogen, at ice bath temperature, was added portionwise 4.15 g of sodium cyanoborohydride. The reaction mixture was stirred in the cold for 30 minutes then at room temperature for 21/2 hours. Then about 50 ml of water was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried in vacuo to give 8.8 g of the desired product, mp 241°-243° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[N:10]=[C:9]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:8]=2[C:7]1=[O:31]>C(O)(C(F)(F)F)=O>[F:15][C:12]1[C:13]2[CH2:14][NH:6][C:7](=[O:31])[C:8]=2[C:9]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[N:10][C:11]=1[NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](Nc1nc(-c2cnn(C)c2)c2c(c1F)CNC2=O)C(N)=O
Yield: 45.5 %

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (39.8 mg, 0.078 mmol) in TFA (5 mL) was heated at 60° C. for 2 h. After removal of solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC. The fractions were collected and the solvent stripped to dryness via rotary evaporation to yield the title compound (12.8 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.82-1.00 (m, 6H), 1.45-1.60 (m, 1H), 1.67-1.83 (m, 2H), 3.87 (s, 3H), 4.36 (s, 2H), 4.50-4.64 (m, 1H), 6.88-7.02 (m, 2H), 7.44 (s, 1H), 8.28 (s, 2H), 8.83 (s, 1H). [M+H] calc'd for C17H21FN6O2, 361. found, 361.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:12][C:13]1[CH:18]=[C:17]([N:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]2=[O:1])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccn(-c2cccc(F)c2)c(=O)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate 89-1 (153 mg, 1.00 mmol), (3-fluorophenyl)boronic acid 6-6 (280 mg, 2.00 mmol), Cu(OAc)2 (36 mg, 0.2 mmol), molecular sieves (4 Å, activated, 200 mg), pyridine (162 μL, 2.0 mmol) and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 172 mg, 1.1 mmol) in DCM (2.0 mL) was stirred at room temperature under dry air. The mixture was then filtered through celite (washed with ethyl acetate); and the filtrate was washed with 5% ammonia solution, dried with Na2SO4 and concentrated with rotavap. The residue was subjected to silica gel column chromatography with 1:3 ethyl acetate/DCM as eluent to give methyl 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylate as a solid 89-2.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.[Pd]>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccc(N)cc2o1
Yield: 101.2 %

Procedure:
2-Methyl-6-nitrobenzoxazole (10.0 g, 56 mmol) and 10% Pd/C (3.4 g) in MeOH (10 mL) were hydrogenated at rt for 16 h. The reaction mixture was filtered through Celite and wash with MeOH (100 mL). The filtrate was concentrated under vacuum to obtained crude 2-methylbenzo[d]oxazol-6-amine (8.4 g), (MS: ESI +ve, 149.07 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 2.47 (s, 3H), 5.24 (s, 2H), 6.56-6.53 (dd, J=2, 1H), 6.70-6.70 (d, J=1.6, 1H), 7.25-7.23 (d, J=8.4, 1H).