Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1)[NH2:27].C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[S:22])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[C:9]([NH:10]C(=O)OC(C)(C)C)=[CH:8][C:7](=[O:18])[CH:6]2[CH:4]1[O:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:10][C:9]1[C:3]([O:2][CH3:1])([O:19][CH3:20])[CH:4]2[CH:6]([O:5]2)[C:7](=[O:18])[CH:8]=1
Reactant: COC1(OC)C(NC(=O)OC(C)(C)C)=CC(=O)C2OC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(OC)C(N)=CC(=O)C2OC21
Reaction time: 3 h

Procedure:
A solution of compound 4 (300 mg, 1.1 mmol) in anhydrous dichloromethane (6 mL) was stirred in an ice bath under an inert nitrogen atmosphere. To this solution was added trifluoroacetic acid (1.5 mL) drop-wise and the solution was brought to room temperature, stirring 3 hours. After judging complete by thin layer chromatography, the solvents were evaporated and the residue was dissolved in ethyl acetate. Solid sodium bicarbonate (2 g) was carefully added and the solution was stirred 10 minutes. The salt was filtered and rinsed with ethyl acetate before evaporation of the solvent. The crude compound was purified over silica gel using a gradient of ethyl acetate (0 to 100%) in heptane. The product eluted in 100% ethyl acetate giving 178 mg (91%) of compound (5). The 1H NMR of the product was consistent with that reported in the literature (Synthesis 1998, 775).
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])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH:34]1[CH2:36][CH2:35]1)=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1>[CH:34]1([CH2:33][O:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])[C:22]([CH2:21][C:6]2[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31]3)[CH2:35][CH2:36]1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC4CC4)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (151 mg, 0.6 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)-acetamide hydrochloride SLA 47096B (235 mg, 0.6 mmol) followed by a 2 N aq. LiOH solution (0.612 mL, 1.2 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided N-(2-(6-(cyclopropylmethoxy)-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. The free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford N-(2-(6-(cyclopropylmethoxy)-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 83 as a brown solid (41 mg, 11% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=O)[CH:27]=[CH:28][CH:29]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:31]([CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
Part C: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 204-205° C., Mass Spec: 477(M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH2:15][CH3:16])[C:3]=1[C:17](=[O:20])[CH2:18][CH3:19].C(O)C.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH2:15][CH3:16])[C:3]([C:17](=[O:20])[CH2:18][CH3:19])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([NH2:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
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: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51c, 0.5 g, 1.41 mmol) in a mixture of toluene: ethanol (3:12 ml) was added 4-aminosulfonylbenzene boronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (2×20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silicagel (100-200 mesh) using 30-35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 32.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[CH:13]([OH:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[CH:13]([O:22][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)C(O)C(C)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)C(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate (5.7 g) and 2,6-lutidine (2.27 mL) in THF (80 mL) was added under ice-cooling tert-butyldimethylsilyl trifluoromethanesulfonate (3.44 mL) and, after warming to room temperature, the mixture was stirred for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→32/1) to give the title compound as a colorless oil (yield: 5.42 g, 70%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([CH3:27])[N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:21]=[C:22]([CH3:27])[CH:23]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Temperature: 90 °C

Procedure:
812 mg (3.48 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 167 mg (6.96 mmol) NaH is added over 5 min. 500 mg (3.48 mmol) 2-amino-4-chloro-6-methylpyrimidine is then added and the solution stirred at 90° C.— over night. 1 mL water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (29%). ESI-MS m/z 341.7 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6](C)[CH:5]=2.[CH:12]([Li])(CC)C.C1CCCCC1.C(OC(NC1C=CC(OCC)=CC=1C)=O)(C)(C)C.CON(C)C(=O)C>C1COCC1>[CH3:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [Li]C(C)CC
Reactant: Cc1ccc2cc(C)[nH]c2c1
Agent: CCOc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: CON(C)C(C)=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc2ccccc2n1C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
2,6-Dimethyl-1H-indole. A solution of 1.3M sec-butyl lithium/cyclohexane (81.0 ml, 0.105 mol) was added slowly to 11.05 g (0.05 mol) of N-tert-butoxycarbonyl-4-ethoxy-2-methylaniline in 150 ml of THF while keeping the temperature below −40° C. with a dry ice-ethanol bath. After 0.25 hours, 7.21 g (0.07 mol) of N-methoxy-N-methylacetamide in an equal volume of THF was added dropwise. The reaction mixture was stirred for 1 hour, the cooling bath removed and stirred an additional one hour. It was then poured into a mixture of 500 ml of ether and 500 ml of 1N HCl. The organic layer was separated, washed with water and dried over Na2SO4. After removing the solvent there remained 12.5 g of crude 1-(2-tert-butoxycarbonylamino-4-methylphenyl)-2-propanone. This material and 15 g of trifluoroacetic acid in 250 ml of CH2Cl2 was stirred at room temperature for 16 hours. The mixture was washed twice with water, a saturated Na2CO3 solution and dried over Na2SO4. After removing the solvent, the product was chromatographed on silica eluting with toluene to give 3.2 g (44% yield) of 2,6-(dimethyl-1H-indole melting at 74-76° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]>C(#N)C>[CH2:9]([NH:11][C:12]([C:14]1[C:18]([Br:1])=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCNC(=O)c1cc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (207 mg, 1.16 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-isoxazole-3-carboxylic acid ethylamide (564 mg, 1.06 mmol) in acetonitrile (20 mL). Ceric ammonium nitrate (290 mg, 0.53 mmol) was added and the reaction mixture was heated to reflux (affording homogeneous orange solution) and stirred for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and acetonitrile was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL) and dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a yellow oil which was purified by flash chromatography on silica gel (20 g, IST) eluting with 10-30% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide as yellow oil (326 mg, 53%). LCMS: [M+H]+ 613, 611.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:5]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2C(=O)Nc3ccc(Cl)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.15 g, 0.55 mmol) (from Example 1b supra), benzyl bromide (113 mg, 0.65 mmol), potassium iodide (108 mg, 0.65 mmol) and potassium carbonate (163 mg, 1.18 mmol) in acetone (5 mL) was heated at 60° C. for 20 hours. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloro-methane as solvent) to give two products. Lower Rf sample was recrystallized from ethyl acetate-hexanes to give rac-3-benzyl-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white crystals. (Yield 58 mg, 29.1%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=O)=[C:21]([CH3:29])[C:20](Br)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)#[N:2].C(O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)[C:17]3=[N:18][CH:19]=[CH:20][C:21]([CH3:29])=[C:22]3[N:23]=2)[CH2:28][CH2:27]1
Reactant: Cc1c(Br)cnc(NCc2ccc(-c3ccccc3C#N)cc2)c1NC(=O)C1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methyl-pyridine, 1.0 g (21.7 mmol) of formic acid, 3.5 g (34.6 mmol) of triethylamine and 10% Pd--C (300 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (100 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.3 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[CH:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.84 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (328 mg, 1.27 mmol) and K3PO4 (445 mg, 0.706 mmol), in DMF (6 mL)-water (0.6 mL) was added dichlorobis(triphenylphosphine) palladium (II) (30 mg, 0.042 mmol). The reaction mixture was heated at 90° C. for 95 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-4-carboxamide. 1H NMR (TFA salt, CD3OD) d (ppm): 7.57-7.78 (m, 5H), 7.4 (dd, 1H), 7.25 (s, 1H), 6.92-7.2 (m, 4H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.83 (m, 6H), 2.5 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:21])[CH:11]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:32])(=O)=O)=CC=1>C1COCC1>[Br:9][C:10]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH2:21][F:32])[CH:11]=1
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1cccc2c(Br)cc(CF)nc12
Temperature: -80 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (1.8 M in THF, 0.70 mL, 1.3 mmol) in anhydrous THF (1.0 mL) was added dropwise to a stirred solution of 4-bromo-2-methyl-quinolin-8-ol (100 mg, 0.420 mmol) in anhydrous THF (1.0 mL) at −80° C. After stirring for 1 h at −80° C., a solution of N-fluorobenzenesulfonimide (331 mg, 1.05 mmol) in anhydrous THF (1 mL) was added dropwise at −100° C. The reaction mixture was allowed to warm to −20° C. and was then quenched by the addition of concentrated aqueous NH4Cl (0.4 mL). The mixture was partitioned between DCM (30 mL) and water (5 mL). The aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM) to give the title compound. MS (m/z): 258.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:17])[F:18])[C:12]([F:13])([F:14])[F:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(CS(=O)c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene (4.13 g, 13.0 mmol) in carbon tetrachloride (50 mL) add NBS (2.31 g, 13.0 mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stir overnight at reflux. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound as colorless oil (2.3 g, 55%).
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[C:9](/[CH:21]=[CH:22]/[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])[CH:8]=[CH:7][C:6]=2[N:5]=1>[Pd].C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[C:9]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(/C=C/CN4CCCC4=O)cc3c21
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCCN4CCCC4=O)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon catalyst (0.1 g), methanol (50 mL), ethanol (50 mL) and 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one. The vessel was evacuated and charged with hydrogen gas (51 psi, 3.4×105 Pa). The reaction was shaken at ambient temperature overnight (approximately 18 hours). The reaction mixture was filtered to remove the catalyst and concentrated to dryness. The crude product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol in dichloromethane) followed by recrystallization from acetonitrile to yield 300 mg of 1-{3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]propyl}pyrrolidin-2-one as a white solid, mp 174-175° C.