Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(O[K])(C)(C)C.CC(O)(C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCOCCBr
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCOCC2

Procedure:
To a solution of 6-bromo-1-indanone (1.033 g, 4.89 mmol) in anhydrous THF (100 mL) under N2 atmosphere at room temperature was added a solution of tBuOK in tBuOH (1 M, 10.3 mL, 10.3 mmol) within 30 min (the color turned to deep black upon a drop of tBuOK solution was added), followed by 1-bromo-2-(2-bromoethoxy)ethane (1.134 g, 0.62 mL, 4.89 mmol). The reaction was quenched with saturated aqueous NH4Cl, and extracted with ether two times. The combined organic phases were washed with H2O, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black tar. It was purified by flash chromatography on silica gel yield 300 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([CH3:28])([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([NH:27][CH2:12][C:4]2[C:3](=[O:14])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(N)CCN(Cc2ccccc2)C1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)c(CNC2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (956 mg, 5.11 mmol), 1-benzyl-3-methylpyrrolidin-3-amine (972 mg, 5.11 mmol), and acetic acid (0.877 ml, 15.32 mmol) were combined in CH2Cl2 (25 ml) and stirred for 30 min. Sodium triacetoxyborohydride (3248 mg, 15.32 mmol) was added and the reaction stirred for 2.5 hours before being partitioned between CH2Cl2 and satd. bicarb. The aqueous portion was extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was carried on crude.
Reaction SMILES: [S:1]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O:4][CH:5]=[C:6]([F:8])[F:7])(=[O:3])=[O:2].[S:16]([O-:19])([OH:18])=[O:17].[Na+:20].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O.CO>[F:8][C:6]([F:7])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:5][O:4][S:1]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:3])=[O:2].[Na+:20]
Reactant: O=S([O-])O
Reactant: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 16 %

Procedure:
9.3 g of 2,2-difluoroethenyl tosylate, which had been synthesized by a conventional technique, was dispersed in 17 g of water and 37 g of methanol, after which 4.7 g of sodium hydrogen sulfite and 0.5 g of benzoyl peroxide were added. The reaction mixture was stirred at 80° C. for 40 hours. The reaction solution was allowed to cool, after which methanol was distilled off in vacuum. Toluene was added, followed by separatory operation to separate a water layer. A saturated sodium chloride aqueous solution was added to the water layer whereupon white crystals settled out. The crystals were collected by filtration, washed with a small volume of saturated sodium chloride aqueous solution and then dried in vacuum, obtaining the target compound, sodium 1,1-difluoro-2-tosyloxyethanesulfonate. White crystals, 2.5 g (yield 16%).
Reaction SMILES: [Pb:1]=O.[OH-].[Na+].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7]>>[C:5]([O-:9])(=[O:8])[CH:6]=[CH2:7].[Pb+2:1].[C:5]([O-:9])(=[O:8])[CH:6]=[CH2:7]
Reactant: O=[Pb]
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)[O-]
Product: [Pb+2]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
111.5 gms of lead monoxide is taken in 0.1 NaOH and the mixture stirred in a round bottom flask for 30 minutes at room temperature, 72 gms of acrylic acid is then adding by a dropping funnel and a period of 1 hour. The mixture is heated under reflux conditions to 35° C. for 1 hour. The yield was 93% of lead acrylate after filtration, washing and drying.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][CH2:16][OH:17].[C:18]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([OH:35])[C:29]([CH3:37])([CH3:36])[CH2:28]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCCC>ClC1C=CC=CC=1.CCCCCCC.C(OCC)(=O)C>[C:18]([O:26][CH:27]1[CH2:28][C:29]([CH3:37])([CH3:36])[N:30]([O:35][CH2:15][CH2:16][OH:17])[C:31]([CH3:33])([CH3:34])[CH2:32]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCI
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Clc1ccccc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCCO

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-iodoethanol and 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The crude reaction mixture is passed through silica gel with heptane and then heptane/ethyl acetate to afford the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH:32]OCC)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH:32][NH:14][C:13]1[N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23]
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccc(OC)cc1)C(=O)OCC
Temperature: 120 °C
Yield: 53 %

Procedure:
2-(4-Methoxybenzyl)-2H-pyrazol-3-ylamine hydrochloride (5.582 g) was neutralized with a saturated sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. To the obtained yellow oil, 2-ethoxymethylenemalonic acid diethyl ester (3.89 mL, 0.7 equivalents) was added. The mixture was stirred at 120° C., and 2-ethoxymethylenemalonic acid diethyl ester (about 1 equivalent in total) was further added thereto while stirring at 120° C. to consume the raw material. The reaction solution was purified by silica-gel column chromatography (ethyl acetate/hexane=2/1 to 3/0) to give 2-{[2-(4-methoxybenzyl)-2H-pyrazol-3-ylamino]methylene}malonic acid diethyl ester (5.420 g, yield: 53%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.[H][H]>C(O)C.O.[C].[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:20][CH2:19]2)=[O:22])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc([N+](=O)[O-])cc4)CC3)c2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Yield: 29 %

Procedure:
In 50 ml of ethanol was suspended 1.5 g (3.7 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-nitrophenyl)-1-piperazinecarboxamide obtained in Example 77, and a suspension of 500 mg of 10% palladium-carbon in 10 ml of water and 10 ml of ethanol was added thereto, followed by stirring in a stream of hydrogen at room temperature for 5 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. Then, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate to give the desired compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:10]([N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:17]=1)[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH3:35])=[CH:34][CH:33]=1)([CH3:11])[CH3:12]
Reactant: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed at 60° C. for 72 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3:methanol=70:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (38.4 mg, 37.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1ccc(CO)cc1

Procedure:
In a manner similar to Preparation Al 88.5 g of 3-nitro-4-chloropyridine, 68.7 g of 4-aminobenzyl alcohol and 46.9 g of sodium bicarbonate in 500 ml of ethanol to give 56.3 g of the titled intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:28](O)[CH3:29]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH2:28][CH3:29])=[O:10])[NH2:8])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CCO
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Yield: 51 %

Procedure:
A 47 g (0.21 mole) portion of 3,4-dimethoxyphenylalanine in 450 ml of absolute ethanol was treated with 31 ml of concentrated H2SO4. The reaction mixture was refluxed for 5 hours and poured into 1.6 l. of H2O. The solution was basified with a solution of 61 g of K2CO3 in 200 ml of water. The basified solution was extracted with three 600 ml portions of ethyl acetate. The combined extracts were washed with 1.4 l. of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 27 g (51%) of the desired product, a light yellow-brown viscous oil which crystallized upon refrigeration.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:9].C(O)(=O)C>C1COCC1.CO>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH3:1])=[O:23])[CH2:20][CH2:21]2)=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
(Trimethylsilyl)diazomethane (2.0 M solution in hexane, 2.7 mL, 5.40 mmol) was added to a mixed solution of 1-(4-cyanophenyl)piperidine-4-carboxylic acid (1.13 g, 4.91 mmol) in THF (13 mL) and methanol (6.5 mL) (2:1, v/v), and the mixture was stirred at room temperature for 1 hour. Acetic acid (appropriate amount) was added to the reaction solution to stop the reaction. Then, the solvent was distilled off under reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the obtained residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=80/20] to obtain the title compound (1.06 g, yield: 88%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CO[C@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (21 mg, 72%), MS (ISP) m/z=418.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol?) and (R)-2-methoxypropanoic acid
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[C:16]1([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:15])[CH:3]=[C:4]([N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)C=C(n2ccnc2-c2ccccc2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-phenyl-1H-imidazole as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: [C:1]1([C:13](=O)[C:14]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22](C(OC(C)(C)C)=O)[CH:21]=2)(C)[C:15](OC)=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[NH2:37][NH2:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(=O)C>[C:1]1([C:13]2[NH:38][NH:37][C:15](=[O:16])[C:14]=2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NN
Reactant: COC(=O)C(C)(C(=O)c1cn2c3c(cccc13)CCC2)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(-c2cn3c4c(cccc24)CCC3)c1-c1c[nH]c2ccccc12
Yield: 17 %

Procedure:
To a solution of tert-butyl 3-(1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-methoxy-2-methyl-1,3-dioxopropan-2-yl)-1H-indole-1-carboxylate (6) (0.26 g, 0.52 mmol) in glacial acetic acid (2 mL) was added hydrazine (35% in H2O, 0.25 mL) followed by a catalytic amount of camphor sulfonic acid (10 mg). The reaction mixture was then microwaved at 210° C. for 10 hours. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (10 mL) and aqueous Na2CO3 (20 mL). The organic layer was separated, dried using Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase (HPLC, C-18) chromatography using trifluoroacetic acid as a modifier to give the desired product (7) (0.033 g, 17% yield) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 11.44 (s, 1H), 11.18 (s, 1H), 7.91 (d, J=4.2 Hz, 1h), 7.6 (d, J=1.4 Hz, 1H), 7.37-7.28 (m, 2H), 7.15-7.1 (m, 1H), 7.08-6.96 (m, 2H), 6.95-6.88 (m, 1H), 6.82 (t, J=6.8 Hz, 1H), 4.08-3.88 (m, 2H), 2.9-2.78 (m, 2H), 2.08-1.96 (m, 2H), 1.82 (s, 3H); LCMS [M+H]: 369.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:12]1([C:18]([NH:2][CH:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)C1CCCCC1)C(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 23.6 g of ethyl alpha-aminoacetoacetate hydrochloride in 450 ml of chloroform cooled to 0° C. was added 19.52 ml of cyclohexylcarbonyl chloride. After 20 minutes at 0° C. 36 ml of triethylamine was added dropwise over a period of 30 minutes. The reaction mixture was allowed to warm to room temperature, was washed with water (2×300 ml) and brine (300 ml) and dried over magnesium sulfate. Removal of the solvent in vacuo gave 35.1 g of an oil which on chromatographing on 400 g of silica gel (hexane-ethyl acetate; 7.5:2.5; v:v) gave 13.9 g of product, m.p. 74°-75° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:18]1[C:17]2[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:16]=2[N:15]=[C:14]1[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2cccc(C(=O)OC)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCn1c(C2CCCNC2)nc2cccc(C(=O)OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Methyl 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-7-carboxylate (44B) (1.91 mmol, 400 mg) in DCM (10 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (15-40% CH3CN in H2O) to afford methyl 1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylate (44C) (0.36 mmol, 120 mg, yield: 18.8%). EST-MS: m/z 332.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol, as prepared in step f of Example 1, (430 mg, 2.0 mmol) and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a colorless syrup (895 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2H), 1.47 (s, 9H), 1.80 (d, 2H), 1.89 (m, 1H), 2.24 (s, 3H), 2.72 (t, 2H), 3.68 (d, 2H), 4.13 (m, 2H), 6.47 (t, 1H), 6.52 (d, 1H), 6.58 (d, 1H), 7.38 (t, 1H), 7.61 (m, 2H), 7.97 (dd, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:23]2[CH2:25][CH2:24]2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[C:10]([Cl:22])[CH:9]=2)=[O:4].[OH-].[K+]>C(O)C.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Cl:22])[N:7]=[C:6]([CH:23]1[CH2:24][CH2:25]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6,7-dichloro-2-cyclopropyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and KOH in a mixture of ethanol/water. White solid. MS (ESI): 358.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[O:3]1.CC(O)=O>C(O)C.[Fe]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[O:3][C:2]([CH3:1])([CH3:35])[C:6](=[O:7])[C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a stirred of 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.6 g, 1.28 mmol) in ethanol (10 mL) was added AcOH (1.28 mL) at RT under N2 atmosphere. After being stirred for 10 min at RT, the reaction mixture was heated to 70° C. and Fe (0.524 g, 9.04 mmol) and FeCl3 (0.062 g, 0.38 mmol) were added under N2 atmosphere. The reaction mixture was stirred at 70° C. for 2 h. After completion of starting material (by TLC), reaction mixture was cooled to RT, and the volatiles were evaporated in vacuo to obtain the crude product. The crude product was extracted in EtOAc (25 mL), washed with water (2×10 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (400 mg, 71%), as a yellow solid.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C(Cl)CCl>>[C:22]1([CH2:21][O:28][NH:29][C:7]([C:5]2[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=2)=[O:9])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc(C(=O)NOCc2ccccc2)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
To a solution of diethyl 1,3,5-benzenetricarboxylate (3.192 g, 20 mol) and O-benzylhydroxyamine hydrochloride (4.789 g, 19 mmol) in 40 mL were added N-methylmorpholine (2.2 mL, 20 mmol) and EDC (3.834 g, 20 mmol) at 0° C., and the mixture was stirred at room temperature for 20 hours. The solvent was removed by evaporator and the residue was dissolved in EtOAc (150 mL). The organic solution was washed with 1 N HCL (150 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4, and concentrated to give white solid. This material was recrystallized from EtOAc to give 4.154 g of white powder (59% yield).