Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:15])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].FC(F)(F)CO.[H][H]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C@H:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: [H][H]
Reactant: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: OCC(F)(F)F
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Into a flask were charged bis(norbornadiene)rhodium(I) tetrafluoroborate {[Rh(nbd)2]BF4}(41.55 mg, 0.1 mmol), Ligand D (69.73 mg, 0.1 mmol) and the enamine amide 2-4 (45 g, 111.1 mmol) under a nitrogen atmosphere. To this mixture a solvent mixture of 37.5 mL methanol (extra dry and degassed) and 112.5 mL 2,2,2-trifluoroethanol (distilled and degassed) were added. The slurry was then transferred under nitrogen into an stainless steel autoclave and sealed. The autoclave was then heated to 50° C. and pressurized to 500 psig with hydrogen. A sample taken after 17 hours was analyzed using HPLC, which confirmed the end of the reaction giving 94% assay yield and 94% ee.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[O:9][CH3:10].[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[CH3:10][O:9][C:3]1[C:4]([C:7]#[N:8])=[CH:5][S:6][C:2]=1[C:13]1[CH:12]=[CH:11][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=1
Reactant: COc1c(C#N)csc1Br
Reactant: OB(O)c1ccc2c(c1)CCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C#N)csc1-c1ccc2c(c1)CCCC2
Yield: 81.6 %

Procedure:
3.53 g of 5-bromo-4-metoxythiophene-3-carbonitrile synthesized in accordance with WO2006062247, 3.13 g of 5,6,7,8-tetrahydronaphthalen-2-yl boronic acid synthesized above in (3), 0.21 g of palladium acetate, 6.70 g of anhydrous potassium carbonate and 5.10 g of tetrabutylammonium bromide were mixed with 30 ml of 1,2-dimethoxyethane and 30 ml of water and allowed to react at room temperature for 19 hours with stirring. After addition of 200 ml of ethyl acetate and 150 ml of saturated aqueous sodium chloride, the reaction mixture was stirred at room temperature for 1 hour. The precipitated black solid was removed by suction filtration (through Celite). The filtrate was allowed to separate, and the ethyl acetate layer was withdrawn, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/15) to obtain 3.56 g of the desired product (yield 82%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1cccc(OCC(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OCC(=O)Nc2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Anthranilic acid 7.95 g (58 mmol) was dissolved in 10% aqueous sodium hydroxide solution 48 ml and to this solution, 3-methylphenoxyacetyl chloride 11.8 g (64 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 5 minutes and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration and washed with hot water to obtain N-(3-methylphenoxyacetyl)anthranilic acid 14.0 g (yield: 68%).
Reaction SMILES: S(=O)(=O)(O)O.C[C:7]1[C:15]([OH:16])=[C:14]([I:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[OH:16][C:15]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[I:17])[C:9]([O:11][CH3:18])=[O:10]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(I)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(O)c1
Yield: 70 %

Procedure:
59 ml (1.10 mol, 2.4 eq) of sulfuric acid are added to a solution of 121 g (0.458 mol, 1 eq) of methyl 3-hydroxy-4-iodobenzoic acid in 700 ml of methanol. The reaction mixture is refluxed for 6 days. The methanol is evaporated off and the reaction medium is then poured into water and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is concentrated and the solid obtained is filtered off and dried. 88.56 g of methyl 3-hydroxy-4-iodobenzoate are obtained in the form of white crystals. Yield=70%
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]>C(Cl)(Cl)Cl>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6]1
Reactant: NCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
8.6 Grams of N-(2-aminoethyl)morpholine, 7.2 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 18.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 21.1 g of the desired product. m.p. 65° C.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH3:15].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>O>[OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:27]([O-:29])=[O:28])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCN1C(=O)c2cccnc2C1(O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
7-Hydroxy-7-phenyl-6-(n-butyl)-6,7-dihydropyrrolo-[3,4-b]pyridin-5-one (47.15 g, 167 moles) was mixed with 250 mL of concentrated sulfuric acid (96%). The resulting mixture was placed in a cooling bath. Nitric acid (70%, 12 mL, 189 moles) was added at such a rate that the temperature remained below 45° C. The mixture was stirred for 30 minutes poured onto ice (500 g) and diluted with 1 L of water. The mixture was extracted twice with 700 mL of ethyl acetate. The organic solvent was removed yielding 7-hydroxy-7-(3-nitrophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]-pyridin-5-one, which was used without further purification.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[C:11](=[O:18])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[OH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][NH:9][CH2:10][C:11]1=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCN1CCO
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Hydrochloric acid (1.8 mL, 7.4 mmol, 4 M in 1,4-dioxane) was added to a solution of 4-tert-butyloxycarbonyl-1-(2-hydroxyethyl)-piperazin-2-one (0.45 g, 1.8 mmol) in 1,4-dioxane (5.0 mL). The mixture was stirred overnight and concentrated to give 1-(2-hydroxyethyl)-piperazin-2-one hydrochloride as an off-white solid (0.30 g, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:31])[CH:18]2[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:13](=[O:32])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:31])[CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)[C:13](=[O:32])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCN(c2ccncc2)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Yield: 55.4 %

Procedure:
A solution of 4-benzyloxycarbonyl-1-{methyl[1-(tert-butoxycarbonyl)-4-piperidinyl]amino}-2-piperazinone (8.49 g) in trifluoroacetic acid (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a mixture of the resultant residue, 4-chloropyridine hydrochloride (4.35 g) and triethylamine (11.54 g) in ethanol (180 ml) was reacted in a sealed tube at 150° C. for 18 hours. The reaction mixture was concentrated, and the residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried, and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (2.23 g) as a pale yellow amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][C:15](=[N:18][OH:19])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][CH:15]([NH:18][OH:19])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:20][CH:21]=1
Reactant: ON=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: ONC1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a stirred solution of 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopentenone oxime (1.85 g; 6.54 mM) in acetic acid (10 ml) was added sodium cyanoborohydride (0.62 g; 9.81 mM) portionwise at room temperature. After stirring for 2 hrs, additional sodium cyanoborohydride (0.25 g; 4 mM) and acetic acid (5 ml) was added. The mixture was stirred overnight. Acetic acid was removed in vacuo, and to the residue was added saturated aqueous NaHCO3 (50 ml). The whole was extracted with ethyl acetate (50 ml×1, 30 ml×1), and the combined organic layers were washed with water (50 ml), brine (50 ml), dried over MgSO4, and concentrated in vacuo. The residual oil was purified by flash column (SiO2) eluting with CH2Cl2 -ethanol (30:1) to give 1.07 g of the subtitle compound [F] as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH2:19]Br)=[O:4].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH2:19][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1nccs1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-6-oxo-1-thiazol-2-ylmethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (100 mg, 0.24 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (58 mg, 0.24 mmol), sodium iodide (71 mg, 0.47 mmol) and potassium carbonate (66 mg, 0.47 mmol) in DMF (5 mL) was stirred at r.t. for 16 h. Brine was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes) to give 41 mg of the title compound as a viscous oil. MS: (+) m/z 584.14, 586.09 (M+1, 79/81Br).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][S:37](Cl)(=[O:39])=[O:38])=[O:35]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:37]([NH:36][C:34]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)=[O:35])(=[O:38])=[O:39])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: O=C(NS(=O)(=O)Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)NC(=O)c2ccco2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) in chloroform (dried over alumina) and triethylamine (2 ml) was added 2-furoylsulphamoyl chloride in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium bicarbonate and methylene chloride. The combined organic liquors were dried (MgSO4), filtered and evaporated to give 0.35 g of solid which was crystallised from diisopropyl ether to give pure title compound (0.2 g), m.p. 138° C. Found: C, 51.30; H, 5.23; N, 7.41. C25H28ClN3O9S requires C, 51.59; H, 4.85; N, 7.22%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C(OCC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][P:21]([CH2:25][C:26](=[O:40])CC(O[Si](C(C)(C)C)(C)C)CCC)(=[O:24])[O:22][CH3:23]>>[CH3:19][O:20][P:21]([CH2:25][C:26](=[O:40])[CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:24])[O:22][CH3:23]
Reactant: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CCCCCO[Si](C)(C)C(C)(C)C
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Yield: 60 %

Procedure:
Dimethyl(3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 9 (1.55 g) was prepared in 60% yield using compound 8 according to the procedures described for compound 3 (see Schemes 1-3).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26].C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[NH:26])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CSC(=N)c1cccs1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 18 h
Yield: 79.6 %

Procedure:
A solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine (0.32 g, 1.326 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.756 g, 2.65 mmol) at room temperature and stirred overnight (18 h). The reaction was basified with sat. NaHCO3 solution (30 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.37 g, 80%) as a solid. 1H NMR (DMSO-d6) δ 10.94 (s, 1H), 7.71 (d, 1H, J=3.3 Hz), 7.59 (s, 1H, J=5.1 Hz), 7.31 (dd, 1H, J=2.7, 5.4 Hz), 7.22 (s, 1H), 7.10 (t, 1H, J=4.8 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.26 (brs, 2H), 6.05 (s, 1H), 3.10 (brs, 2H), 2.63 (t, 2H, J=5.1 Hz), 2.54-2.40 (m, 4H, merged with DMSO-peak), 1.06 (t, 3H, J=7.2 Hz); ESI-MS (m/z, %): 351 (MH+, 37), 294 (100); ESI-HRMS calculated for C20H23N4S (MH+), calculated: 351.1637; observed: 351.1636.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42](Br)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42]([C:5]3[CH:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: C=Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=Cc1cc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)cc(C(F)(F)F)c1
Yield: 62.7 %

Procedure:
2-(3-Trifluoromethyl-5-vinyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (135 mg, 0.45 mmol) and 5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (130 mg, 0.31 mmol) was reacted using Pd(PPh3)2Cl2 (20 mg, 0.03 mmol), Cs2CO3 (300 mg, 0.92 mmol) as described above to give the title compound (100 mg, 63%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]([CH3:19])=[C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=3)[C:22]([CH3:31])([CH3:30])[CH2:21]2)[C:16]2[C:11](=[CH:12][C:13]([F:32])=[CH:14][CH:15]=2)[N:10]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]([CH3:19])=[C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:27]=3)[C:22]([CH3:31])([CH3:30])[CH2:21]2)[C:16]2[C:11](=[CH:12][C:13]([F:32])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Prepared according to procedure N using 2-(2,5-difluorophenyl)-7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline (166 mg, 0.31 mmol) (described herein), morpholine (53.1 μL, 0.61 mmol), Pd2dba3 (41.9 mg, 0.046 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (43.6 mg, 0.091 mmol), and sodium 2-methylpropan-2-olate (88 mg, 0.915 mmol) in toluene (3.0 mL). The reaction mixture was stirred at 105° C. for 1 h. Purification afforded 2-(2,5-difluorophenyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methylquinoline as a yellow oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.88-7.99 (1H, m), 7.76-7.84 (1H, m), 7.27-7.35 (2H, m), 7.16 (2H, m), 7.09 (1H, d, J=8.1 Hz), 6.30-6.38 (1H, d), 5.57-5.69 (1H, s), 3.75 (6H, m), 2.98 (4H, d, J=2.4 Hz), 2.18 (3H, s), 1.52 (3H, s), 1.46 (3H, s). Mass Spectrum (ESI) m/e=504 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(-n2nc(C)cc2C(=O)NC2CCCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(O)cc2)n1
Temperature: -40 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid cyclohexylamide (630 mg, 2.01 mmol) in methylene chloride (30 mL) at −40° C. was added boron tribromide (6 mL, 1 M in DCM, 6 mmol). After the reaction was stirred at −40° C. for 10 minutes and at room temperature for 2 hours, it was quenched with saturated sodium bicarbonate. Ethyl acetate was added, and the mixture was stirred for 1 hour. The layers were separated, and the aqueous layer was extracted an additional time with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated to give 600 mg of the title compound which was used in the next reaction without further purification. LC-MS (C17H21N3O2 calculated 299) m/z 300 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[N:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[N:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1

Procedure:
tert-Butyl{1-[2-(7-chloro-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 139, 308 mg, 0.76 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH2:9][CH:10]([OH:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)CSc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: OC1CSc2ccc(Br)cc21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To dichloromethane (750 mL) suspension of 250 g of (4-bromophenylthio)acetic acid were added 2.5 mL of N,N-dimethylformamide and 132 g of thionyl chloride, which was then refluxed for 1 hour. After cooling the reaction mixture to 20° C., thereto was dropwise added dichloromethane (1500 mL) suspension of 148 g of aluminum chloride at 5 to 15° C., which was then stirred at 15 to 25° C. for 1.5 hours. Next, this reaction mixture was added dropwise to a mixed solution of 1310 mL of water and 188 mL of hydrochloric acid under cooling. The organic layer was separated, thereto was added 1250 mL of water, and the pH was adjusted to 3.0 with 5% potassium carbonate aqueous solution. The organic layer was separated and cooled to 5° C. Thereto were added 15.3 g of sodium borohydride and 500 mL of methanol, which was then stirred at 10 to 20° C. for 2 hours. To the reaction solution was added 750 mL of water, followed by adjustment to pH 7.0 using acetic acid and left unattended in room temperature overnight. To the reaction solution was added 200 mL of 5% potassium hydroxide aqueous solution, and the organic layer was separated. To the organic layer was 25.0 g of activated carbon, which was then stirred at room temperature. Insoluble matter was filtered off, and the solvent of filtrate was distilled off. To the resultant residue was added cyclohexane, the crystals precipitated were collected by filtration to provide 194 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol as pale red solid form.