Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2ncccc2I)cc1)c1nc2ccccc2[nH]1
Temperature: 115 °C
Reaction time: 64 h

Procedure:
A solution of 2-fluoro-3-iodopyridine (3.052 g, 13.69 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (4.89 g, 20.53 mmol) and cesium carbonate (7.58 g, 23.27 mmol) in N-Methyl-2-pyrrolidinone (20 mL) was degassed and heated to 115° C. After 64 h, the reaction was cooled to 23° C., diluted with EtOAc (250 mL) and washed with water (100 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-1.5% methanol/dichloromethane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 404.1 (M+1).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:1]1([C:11]2([OH:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH:14]=[CH:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2C=Cc2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry THF (prepared from cyclopropylbromide (8.0 g, 0.067 mol), magnesium turnings (1.3 g, 0.053 mol) and dry THF (35 ml)) was placed under an atmosphere of nitrogen. A solution of 5H-dibenzo[a,d]cyclohepten-5-one (6.0 g, 0.028 mol) in dry THF (15 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (35 ml) was carefully added. The mixture was diluted with water (50 ml) and extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 8.6 g of crude 5-cyclopropyl-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([NH:30][CH3:31])=[O:29])=[C:11]([Br:27])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:51][C:50]([CH3:52])=[CH:49][CH2:48][N:30]([CH3:31])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]2[C:14](=[O:26])[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:16][CH2:17][N:12]2[C:11]=1[Br:27])=[O:29]
Reactant: CNC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)=CCN(C)C(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 8-(benzyloxy)-6-bromo-2-(4-fluorobenzyl)-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxamide (0.24 g, 0.50 mmol) in anhydrous DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.55 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes and treated with 4-bromo-2-methyl-2-butene (0.15 mL, 1.5 mmol; passed through activated basic alumina). The reaction mixture was stirred at rt for 40 minutes and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate. Collection and concentration of appropriate fractions provided the titled product. ES MS M+1=486,488 (1:1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90348.4 %

Procedure:
Ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (1.6 g., 0.0064 mmol) is dissolved in tetrahydrofuran (40 mL). N-bromosuccinimide (1.14 g., 0.0064 mmol) is added in small portions at 25°-28° C. After the addition is complete, the solution is stirred overnight at room temperature. The solution is concentrated in vacuo and the solid residue partioned between water and ether. The ether layer is separated and dried over magnesium sulfate. Work-up of the ether extract leaves 1.9 g (90%) of a white solid which is purified by stirring with a mixture of 80/20 hexane/ethyl acetate. The insoluble solid (1.3 g, 62%) is collected and has m.p. 161°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Solvent: c1ccncc1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 99.7 %

Procedure:
A mixture of 0.5 g of 4-bromopyrazole and 1.43 g of tritylchloride in 30 ml of pyridine was stirred at reflux for 18 hours. The pyridine was removed in vacuo and the resulting residue was purified by silica column chromatography (ethylacetate/hexane=1:1) to yield 1.32 g of 4-bromo-1-N-tritylpyrazole.
Reaction SMILES: [Na].O.[CH3:3][C:4]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:5][C:6]([O:8]CC)=[O:7]>CO>[CH3:17][C:4]1([CH3:3])[CH:11]([CH:12]=[C:13]([Cl:14])[Cl:15])[CH:5]1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reaction time: 2 h
Yield: 88 %

Procedure:
1.4 Parts of metallic sodium was dissolved in 50 parts of anhydrous methanol, and 5.5 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate prepared in the same manner as in Example 1 was added to the solution. The mixture was agitated for 2 hours under reflux of methanol. The liquid reaction mixture was naturally cooled, and 20 parts of water was added thereto and the mixture was agitated at 40° to 50° C. for 2 hours. Then, methanol was distilled under reduced pressure, and the residue was neutralized with hydrochloric acid and extracted with diethyl ether. The ether extract was dried and the ether was distilled to obtain 3.7 parts of the crystal of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylic acid. The yield was 88 % based on ethyl 3,3-dimethyl-4,6,6-trichlorohexenoate.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][NH:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[Cr](Cl)([O-])(=O)=[O:17].[NH+]1C=CC=CC=1.C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[O:17]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]1[CH2:2][CH2:3][NH:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)NCC(O)c1ccccc1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NCCC1C=CC=CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of N-(2-hydroxy-2-phenyl-ethyl)-2-methyl-propanamide (15.0 g, 72 mmol), prepared in the previous step, and pyridinium chlorochromate (23.7 g, 110 mmol) in 300 ml of methylene chloride was stirred at room temperature for 5 hours. The reaction was filtered and the filtrate concentrated under reduced pressure to give a dark residue. Chromatography of the residue on silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent gave N-(2-oxo-phenyl-ethyl)-2-methyl-propanamide (6.07 g, 41%) as a light green solid, mp 88-93° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O.CN(C=O)C>[Zn].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.O>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: COC(=O)c1ccc(CN2CCOc3cc([N+](=O)[O-])ccc32)cc1
Agent: Cl[Fe](Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Yield: 87.7 %

Procedure:
The same operation as in Example (100b) was performed using methyl 4-[(7-nitro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101a) (0.35 g, 1.07 mmol), zinc (0.7 g, 10.7 mmol), iron trichloride hexahydrate (0.12 g, 0.4 mmol), DMF (5 mL) and water (5 mL), to obtain 0.28 g of the crude title compound as a brown oily substance (88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=1.O1CCOCC1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[NH2:8][C:6]1[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([Cl:27])[CH:29]=2)[CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=O)cnn12
Temperature: 95 °C
Yield: 38 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate (1.1 g, 3.8 mmol) was added to 1,4-dioxane (15 mL) along with 3-chloroaniline (2.4 mL, 22.6 mmol) and p-toluenes ulfonic acid monohydrate (73 mg, 0.4 mmol). The reaction was heated at 95° C. for 12 hours then cooled to room temperature, diluted with water and filtered. Analysis of the recovered solid by LCMS showed product mass (M+1=288), as well as, product with chloro aniline imine mass (M+1=397). To completely convert this mixture to the desired product, the solid was dissolved in 6 mL of MeOH/conc. HCl solution (1:1) and heated at 60° C. for 1.5 hours. The reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as orange-red solid in 38% yield. LCMS (M+1=288)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](F)[C:19]([CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[Cl:15][C:16]1[C:17]([N+:24]([O-:26])=[O:25])=[CH:18][C:19]([CH3:23])=[C:20]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]2=[O:1])[CH:21]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: Cc1cccnc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1-n1cccc(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.50 g (13.8 mmol) of 2-hydroxy-3-methylpyridine in 70 ml of DMF are admixed at 0° C. with 2.31 g (20.6 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 2.87 g (15.1 mmol) of 2-chloro-4-fluoro-5-methylnitrobenzene are added while continuing to stir at RT. After 17 h, the mixture is admixed with 1000 ml of water and then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and, after filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (2:1 cyclohexane/ethyl acetate). This affords 2.15 g (56% of theory) of the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C@H:23]1[CH2:28][C@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1.[I-].[K+]>CN(C)C=O>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][C@@H:27]([CH3:29])[CH2:28][C@H:23]([CH3:22])[CH2:24]2)=[CH:7][CH:8]=1)=[O:11]
Reactant: C[C@@H]1CNC[C@@H](C)C1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1

Procedure:
A mixture of methyl 4-(3-chloropropoxy)benzoate (4.57 g), potassium carbonate (8.29 g), cis and trans-3,5-dimethylpiperidine (5.31 mL) and a catalytic amount of potassium iodide in N,N-dimethylformamide (100 mL) is stirred overnight at 100° C. The suspension is filtrated and the precipitate washed with ethanol. The filtrate is concentrated under reduced pressure and purified by chromatography over silica gel with a gradient of dichloromethane/methanol from 98/2 to 90/10. Fraction containing the expected products are pooled and concentrated under reduced pressure yielding 5.33 g of cis and trans-1-{3-[4-(methoxycarbonyl)phenoxy]propyl}-3,5-dimethylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccncc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-(aminomethyl)pyridine (0.010 mL, 0.099 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(pyridin-4-ylmethyl)amino methyl]indol-2-yl}isoindolinone.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1.[CH3:23][C:24]1([CH3:40])[C:33](=[O:34])[NH:32][C:31]2[N:30]=[CH:29][C:28](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:27][C:26]=2[CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][C:24]1([CH3:40])[CH2:25][C:26]2[C:31](=[N:30][CH:29]=[C:28](/[CH:35]=[CH:36]/[C:37](=[O:38])[N:11]3[CH2:12][CH2:13][C:14]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[CH:15][CH2:16]3)[CH:27]=2)[NH:32][C:33]1=[O:34]
Reactant: C1=C(Cc2nccs2)CCNC1
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc2NC1=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
DIPEA (0.33 mL, 1.83 mmol) was added to a stirred solution of 2-((1,2,3,6-tetrahydro-pyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (158 mg, 0.73 mmol), (E)-3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (Intermediate-22) (150 mg, 0.61 mmol), HOBt (98 mg, 0.73 mmol) and EDC.HCl (232 mg, 1.22 mmol) in dry DMF (2 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (160 mg, 51%); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 2.79 (s, 2H), 2.18-2.04 (m, 2H), 1.08 (s, 6H); LC-MS: 409.2 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[NH:16][CH:17]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:42]=2)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][N:20]3[CH:21]=[CH:22][N:23]=[C:24]([NH2:42])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Reactant: O=CNC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Product: Nc1nccn2cnc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-formamide: Prepared according to the procedures for Cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]Amide, White solid, 1H NMR (CDCl3, 400 MHz) δ 5.03 (s, 2H), 6.62 (d, 1H, J=8.0 Hz), 6.88-6.97 (m, 3H), 7.22-7.24 (m, 1H), 7.32-7.41 (m, 5H), 8.29 (bs, 1H), 8.35 (d, 1H, J=2.4 Hz), 8.51 (d, 1H, J=2.0 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>O1CCOCC1.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>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccccn2)C1
Temperature: 110 °C
Yield: 91 %

Procedure:
To a 350 mL sealable flask was added t-butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.67 g, 11.77 mmol) and tri-n-butyl(2-pyridyl)tin (5.2 g, 14.12 mmol. The mixture was dissolved in dioxane (100 mL) and tetrakis(triphenylphosphine)palladium(0) (2.72 g, 2.354 mmol) was added. The mixture was flushed with N2 and the flask was sealed and heated to 110° C. After heating the mixture for 65 h, the mixture was cooled to rt and was filtered through a pad of CELITE® to remove the solids. The CELITE® was washed with MeOH and the organic solution was concentrated under reduced pressure. The residue was purified using BIOTAGE® flash chromatography and a 10-50% EtOAc in hexanes gradient. The expected product, tert-butyl 5-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.33 g, 10.72 mmol, 91% yield), was isolated as a thick yellow oil. LC/MS: m/z 311.02 (M+H)+, 2.257 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 8.70 (d, J=4.88 Hz, 1H) 7.77 (t, J=7.32 Hz, 1H) 7.40 (d, J=7.93 Hz, 1H) 7.23-7.32 (m, 3H) 7.19 (br. s., 1H) 4.64 (br. s., 2H) 3.55 (br. s., 2H) 2.86 (t, J=5.95 Hz, 2H) 1.48 (br. s., 9H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 86.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1 H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 9f (25.1 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the mixture was stirred until all dissolved, and piperidine (50 μL, 0.5 mmol) was then added to the reaction solution. Upon completion of the addition, the reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 9 (51 mg, yield 80%) as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:7]2[N:12]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cncc(N2CCCCC2)n1
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCCC2)n1

Procedure:
To a suspension fo 1.28 g of 6-(1-piperidinyl) pyrazine-2-carboxylic acid in 18 ml of tetrahydrofuran, 0.95 ml of triethylamine and 0.84 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 0.58 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 30 minutes at room temperature, and then refluxed for 12 hours. The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.55 g of the desired compound as yellow columns. The obtained crystal was consistent with that of (a).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].I[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1>C(O)C>[CH2:1]([NH:4][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 93.6 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.3 ml (15.8 mmol) of n-propylamine and 960 mg (1.6 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 790 mg of ethyl 4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=120° C., yield=56%).