Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])(C)C.N1C=CN=C1>CN(C=O)C>[CH2:30]1[CH2:1][O:2][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:31][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:29]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of methyl 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-hydroxycyclopentyl]acetate (61) in DMF (80 ml) were added t-butyldimethylsilyl chloride (2.11 g) and imidazol (0.95 g), and the resultant mixture was stirred. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (62). Yield: 5.41 g((71.2 g)
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1>CC(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=1[CH3:3]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1sc(C(=O)O)cc1Br
Reaction time: 5 h

Procedure:
A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 mL) was added dropwise to 5-methyl-2-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCl3 (456 mg, 2.81 mmol) in AcOH (28 mL) at 25° C. After 5 h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH3:9].C([Li])CCC.C([O:17][B:18](OCC)[O:19]CC)C>O1CCCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:19])[OH:17])[CH3:9]
Reactant: CCc1ccccc1Br
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 25 g (135 mmol) of 1-bromo-2-ethylbenzene in 280 mL of dry tetrahydrofuran, kept at −78° C. in an oven-dried 3 neck flask, was added slowly (keeping the temperature below −68° C.) 67.5 mL of 2.5N n-Butyl lithium in hexanes solution (169 mmol, 1.25 eq.). The reaction was stirred for an additional 1 h, and then 69 mL (405 mmol, 3 eq.) of triethylborate was added slowly, keeping the temperature below −68° C. The reaction was stirred for an additional 40 minutes and then the dry ice bath was removed, the reaction was allowed to warm up to room temperature, and then was poured into 300 mL of ice cold saturated ammonium chloride solution. 200 mL of ice cold ethyl acetate was added, and the mixture stirred for another 30 min. The layers were separated. The organic layer was washed with water, and brine. It was then dried over magnesium sulfate, and concentrated to give 19 g (92% yield) of product. The boronic acid was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:15]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])(=[O:17])[CH3:16]
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)C(C)C2(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture, stirred at ambient temperature in the absence of the humidity of the air, of 25 g of 1,1,2,3,3-pentamethyl indane and 13 cm3 of acetyl chloride, there are added, in small portions, 23 g of aluminum chloride in a manner such that the temperature does not exceed 40° C. Stirring is maintained for 2 hours after the end of the addition and the reaction mixture is left overnight. The next day, it is poured into 200 cm3 of ice water and then extracted three times with 150 cm3 of dichloromethane. The organic phases are combined, washed with sodium bicarbonate and then with water and dried on magnesium sulfate. The solvent is removed by evaporation under a vacuum and 31 g of 5-acetyl-1,1,2,3,3-pentamethyl indane in liquid form which is directly used for the following reactions are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC=Cc1ccccc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: C(=C/c1ccccc1)\CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and cinnamyl bromide to produce the above.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[N:11]=[CH:12][N:13]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:14]=2)C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][N:25]=[CH:26]2>O1CCOCC1.CN(C=O)C>[CH:15]1([N:13]2[CH:14]=[C:10]([NH:9][C:8]([NH:20][C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[CH:24][N:25]=[CH:26]4)=[O:19])[N:11]=[CH:12]2)[CH2:16][CH2:17][CH2:18]1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Nc1cn(C2CCC2)cn1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1cn(C2CCC2)cn1)Nc1cccc2cnccc12
Temperature: 70 °C
Yield: 51.4 %

Procedure:
To a 1 dram vial with septa screw cap was added (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol), and 1:1 dioxane-DMF (1 mL). The reaction mixture was heated at 70° C. for 2 h. The reaction mixture was adsorbed onto silica gel and was purified by silica gel chromatography (40:1 chloroform-methanol) to afford 30 mg (52% yield) of 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; 1H NMR (400 MHz, CD3OD) δ9.21 (d, J=1.7 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 7.98 (d, J=5.4 Hz, 1H), 7.84 (dd, J=2.3, 8.3 Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m, 2H); MS (AP/Cl): 308.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: Cc1ccc2c(c1)NC(=O)C2(C)C
Reactant: ClCCOC1CCCCO1
Product: Cc1ccc2c(c1)N(CCO)C(=O)C2(C)C

Procedure:
Prepared from 3,3,6-trimethyloxindole (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 3.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.8 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19](B(O)O)=[C:18]([O:26][CH3:27])[CH:17]=1>C(Cl)Cl.CO>[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: CS(=O)(=O)CCNc1cnccc1I
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Light brown foam (76%). MS (ESI): m/z=343.09 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[Mg].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)c1ccc(Cl)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc([Si](C)(C)C)cc2)cc1

Procedure:
C-1) A Gringnard reagent consisting of 0.2 mol of 4-trimethylsilylchlorobenzene and 0.2 mol of magnesium was prepared in tetrahydrofuran, mixed with 0.2 mol of 4-methylbenzaldehyde and subjected to Oppenauer oxidation reaction to obtain 4-methyl-4'-trimethylsilylbenzophenone represented by the following chemical structural formula: ##STR19## The reaction product was actually used in the form of a 15% solution in isopropyl alcohol.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]([O:13][C:14](Cl)=[O:15])[CH:11]=[CH2:12]>[OH-].[Na+].O>[CH2:10]([O:13][C:14]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)N1CCC(C(=O)O)CC1
Reaction time: 1 h

Procedure:
A solution of isonipecotic acid (5.0 g) in 4N sodium hydroxide (9.7 ml) and water (6 ml) was stirred while adding dropwise and simultaneously allylchloroformate (6.0 ml) and 4N sodium hydroxide (16 ml). The reaction mixture was then stirred for 1 hour and washed with ether (50 ml). The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were then washed with water, dried and evaporated to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([N:40]=[C:41]=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>ClCCl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([NH:40][C:41]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:16][CH2:17]2)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: c1ccc(N2CCNCC2)c(COc2ccncc2)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2COc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
The impure 1-[2-(Pyridin-4-yloxymethyl)phenyl]piperazine (˜50 mg) was dissolved in 5 mL of dichloromethane along with triethylamine (50 μL, 0.36 mmol). 3,5-Bis(trifluoromethyl)phenyl isocyanate (50 μL, 0.29 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in 2 mL methanol. The reaction mixture was purified by reverse phase HPLC to give 10 mg of product as a white solid. 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.28 (d, 2H), 8.17 (s, 2H), 7.73 (s, 1H), 7.49 (d, 1H), 7.38 (t, 1H), 7.18-7.25 (m, 4H), 5.39 (s, 2H), 3.80-3.85 (m, 4H) 3.00-3.04 (m, 4H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][CH:20]([F:41])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([O:39]C)=O)=[N:29]1>C(Cl)Cl>[F:41][CH:20]([F:19])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([N:3]([O:4][CH3:5])[CH3:2])=[O:39])=[N:29]1
Reactant: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added AlMe3 (1.8 M solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0° C. After stirring at 0° C. for 1 h, a solution of methyl 1-[2-(difluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5:87 g, 17.99 mmol) in CH2Cl2 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals: NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62 (1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, s).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:29][C:30](=[O:33])[NH:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.C([O-])(=O)C.[Na+]>O>[CH2:22]([NH:29][C:30](=[O:33])[NH:31]/[N:32]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(=O)NCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NCc2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
To a suspension of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 1.20 g of 4-benzylsemicarbazide hydrochloride in 20 ml of a mixture of ethanol and water (2:1) was added 0.50 g of sodium acetate. The mixture was stirred for 18 hours at room temperature, and then concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue. The precipitates were collected by filtration, washed with water, and recrystallized from aqueous ethanol to obtain 1.21 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-benzylsemicarbazone) having a melting point of 164°-165° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].[BH4-].[K+].O>O1CCCC1>[OH:12][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[C:4]=2[CH2:5][CH2:6]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc2c1CCC2O
Yield: 94.7 %

Procedure:
1.46 g of 4-cyano-1-indanone in 131 ml of tetrahydrofuran is cooled to +5° C., 1 g of potassium borohydride is added in small fractions, with agitation for one hour 15 minutes, followed by pouring over 200 ml of water containing sodium chloride, and extraction with isopropyl ether. The organic phase is dried, brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture (6-4). 1.40 g of expected product is obtained, M.p.=98° C.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([O-:19])=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: [NH4+]
Reactant: CN(C)N=Nc1c(C(=O)[O-])[se]c2c1CCCC2
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1c(C(N)=O)[se]c2c1CCCC2
Temperature: 25 °C
Reaction time: 66 h
Yield: 18 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (60 mL) was added a mixture of ethyl and methyl esters of 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate (600 mg) in THF (6 mL) for 5 min. A catalytic amount of PEG-400 was added and stirred at rt for 66 h. The solution was poured into ice cooled water and extracted with chloroform (3×150 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as a pale brown color solid (100 mg, 18%), which was recrystallized from chloroform-hexane (70 mg), mp 198-202° C. IR (Neat) νmax 3347, 3163, 2932, 2860, 1631, 1342, 1313, 1220, 1103, 1020, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, s, —CONH2), 6.07 (1H, s, —CONH2), 3.51 (3H, br s, —NCH3), 3.14 (3H, br s, —NCH3), 2.80-2.82 (2H, m, H-4), 2.64-2.65 (2H, m, H-7), 1.72-1.80 (4H, m, H-5,6); 13C NMR (100 MHz, CDCl3): δ 165.9, 149.5, 145.9, 132.6, 129.5, 29.0, 28.6, 23.1, 22.7; LC-MS (positive ion mode): m/z 321, 323 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[CH3:36][N:34]([CH3:35])[C:32]([C:17]1[CH:18]=[C:19]2[C:24](=[C:15]([CH:13]([NH:4][C:3]3[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:2]=3[F:1])[CH3:14])[CH:16]=1)[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])=[O:33]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1c(F)ccc(F)c1F
Agent: Br
Product: CC(Nc1c(F)ccc(F)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.2 %

Procedure:
2,3,6-trifluoroaniline (0.086 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,6-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (42 mg, 43%) as a white solid. Mass Spectrum: M+H+ 476. NMR Spectrum (DMSOd6): 1.56 (d, 3H), 2.75 (bs, 3H), 2.97 (bs, 3H), 3.50-3.59 (m, 4H), 3.69-3.80 (m, 4H), 5.38-5.47 (m, 1H), 5.57 (s, 1H), 6.05 (d, 1H), 6.60-6.70 (m, 1H), 6.86-6.96 (m, 1H), 7.73 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C>[C:44]1([CH:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=4)=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[C:40]([O:42][CH3:43])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCC(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of intermediate (10) (0.007 mol) and Na2CO3 (0.007 mol) in DMF (50 ml) was stirred at room temperature. Methyl 2-bromo-2-phenylacetate (0.007 mol) was added dropwise. The mixture was stirred for 3 hours. The solvent was evaporated. The residue was triturated under hexane, filtered off and dried, yielding 3.37 g of methyl α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-phenyl]-1-piperidineacetate (intermediate 11, mp. 138° C.).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH2:17])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2].[Br:39][CH:40]([CH2:44][CH2:45]Br)[C:41](Br)=[O:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:45][CH2:44][CH:40]([Br:39])[C:41]2=[O:42])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Br)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of N,N'-bis-[2,3-diacetyloxypropyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (8.73 g, 10 mmol) in N,N-dimethylacetamide (100 ml) was treated with 2,4-dibromobutyroyl bromide (4.02 g, 13.0 mmol) under an atmosphere of nitrogen and the reaction mixture was stirred for 50 hours at ambient temperature. The mixture was then treated with ground potassium carbonate (1.65 g, 12.0 mmol) and stirred for 30 minutes at ambient temperature. An additional portion (1.65 g, 12.0 mmol) of finely ground potassium carbonate was added and the mixture was stirred for 1.9 hours. The suspended salts were filtered and the solvent was evaporated to obtain a brown oil. This crude product was purified by silica gel flash chromatography to isolate N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide, as a white powder (7.28 g, 71% yield), m.p. 110°-112°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O-:12])=O.ClCl.S(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:17])=[O:12]
Reactant: O=C([O-])c1cc2ccccc2[nH]1
Reactant: O=S(Cl)Cl
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1cc2ccccc2[nH]1

Procedure:
In step 1 of Scheme A, bromobenzaldehyde compound a is reacted with azido ester b under basic conditions to yield indole 2-carboxylate ester c. Compound c is then treated in step 2 with benzyl compound d in the presence of alkali metal hydride to afford 1-benzyl indole compound e. In step 3 a Buchwald reaction is carried out by reaction of compound e with protected piperazine f (other cyclic amine may be used) in the presence of suitable catalyst to provide piperazinyl indole g. The ester portion of compound g is hydrolized under basic conditions in step 4 to afford indole-2-carboxylate compound h. In step 5, indole-2-carboxylate compound h is reacted with a chlorine agent such as thionyl chloride, phosphorus oxychloride of oxalyl chloride, to afford indole-2-carboxylic acid chloride compound i. In step 6 acid chloride compound i is reacted with amine i to afford indole-2-carboxamide compound k. Compound k is then deprotected in step 7 to afford compound m, which is a compound of formula I in accordance with the invention.