Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([Cl:12])=[N:9]3)=[CH:16][N:15]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(Cl)nc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
To a 5 mL microwave vial, 7-bromo-2-chloroquinoxaline (0.100 g, 0.410 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.189 g, 0.457 mmol), dichlorobis(di-tert-butylphenylphosphine)palladium(II) (0.0138 g, 0.0222 mmol) and potassium carbonate (0.513 ml, 1.03 mmol) were mixed into 1,4-dioxane (4 mL). The mixture was degassed by bubbling nitrogen through for 5 min. The reaction mixture was stirred at 90° C. for 1.5 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Upon addition of DCM, precipitate came out and it was collected via filtration to afford a white solid (0.0746 g) as the desired product. The filtrate was purified by silica gel column chromatography (eluent: EtOAc in hexanes 0%-50%) to afford another 0.0512 g of the product. The combine yield was 0.1258 g. MS (ESI pos. ion) m/z calcd for C19H11C12FN4O2S: 448.0; found 448.8 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.38-7.50 (m, 2 H) 7.79-7.89 (m, 2 H) 8.18-8.35 (m, 3 H) 8.40 (d, J=1.75 Hz, 1 H) 8.80 (d, J=2.34 Hz, 1 H) 9.05 (s, 1 H) 10.56 (br. s., 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:10])([F:11])[F:9]
Reactant: O=C(NCCCCO)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCCNC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-(4-hydroxybutyl)trifluoroacetamide (1.65 g; 8.9 mmol) was dissolved in anhydrous DCM (9 mL) and cooled to 0° C. A solution of Dess-Martin periodinane (15% in DCM; 30 mL; 14.0 mmol) was added to the cooled solution and stirred first at 0° C. for 10 min and then at room temperature for 2.5 h. The reaction was quenched with 1:1 10% sodium thiosulfate and saturated NaHCO3 and the biphasic mixture vigorously stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography (Hex:EtOAc 2:1+1% MeOH) providing N-(4-oxobutyl)trifluoroacetamide in a yield of 1.15 mg (71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1[NH:8][N:9]=[C:10]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[C:6]=1[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[N:74]1CCCN(C)[C:75]1=[O:81]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[C:10]1[NH:9][N:8]=[C:7]2[C:23]3[C:4]([CH2:5][C:6]=12)=[CH:3][C:2]([C:75]([NH2:74])=[O:81])=[CH:25][CH:24]=3
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1onc(-c2ccccc2)c1-c1n[nH]c2c1Cc1cc(Br)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1cc(C(N)=O)ccc1-2
Temperature: 100 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of 6-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-1,4-dihydroindeno[1,2-c]pyrazole (250 mg, 0.6 mmol), hexamethyldisilazane (0.9 ml, 4.2 mmol), diisopropylethylamine (0.2 ml, 1.2 mmol) and 1,3-bis(diphenylphosphino)propane (25 mg, 0.06 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5 ml) was degassed with nitrogen for 0.5 h, Pd(OAc)2 (13 mg, 0.06 mmol) was added and carbon monoxide was bubbled through the reaction whilst heating to 100° C. After 2 h the stream of carbon monoxide was replaced with a balloon of carbon monoxide and the reaction was heated at 100° C. for 16 h. The reaction was cooled, partitioned between H2O and EtOAc and the organic layer washed with H2O (×10), dried (MgSO4) and evaporated. The residue was chromatographed on silica, eluting with 3% methanol/dichloromethane to give a yellow oil which was crystallised from CDCl3 to give the title compound as a white solid (40 mg, 19%). 1H NMR (360 MHz, CDCl3) δ 7.92 (s, 1H), 7.81 (s, 1H), 7.51 (d, J=6.8 Hz, 2H), 7.47–7.37 (m, 3H), 3.33 (s, 2H), 2.60 (s, 3H), m/z (ES+) 357 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[C:7]([F:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1
Product: CC(=O)Nc1ccc(C=NNC(N)=S)c(F)c1
Yield: 45 %

Procedure:
4-Acetamido-2-fluorobenzaldehyde 20 then is reacted with thiosemicarbazide to form 4-acetamido-2-fluorobenzaldehyde thiosemicarbazone 17 in 45% yield. An exemplary scheme for this reaction is shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
A mixture of 32 mg (0.065 mmol) [(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 57 uL (0.325 mmol) DIPEA and 11.2 mg (0.097 mmol) mesyl chloride in 1.5 mL DMF was shaken for 90 min at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 16 mg (43%) of the title compound as off-white solid. MS m/e: 570.4 [M+11]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:13]1[CH:12]=[C:11]([C:10]2[N:9]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: COC(=O)CCCBr
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 4) (300 mg, 1.07 mmol), methyl 4-bromobutanoate (291 mg, 1.61 mmol) and cesium carbonate (697 mg, 2.14 mmol) in DMF (4 mL) was stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and was washed with 1M HCl (3×10 mL). After the third wash, the mixture was concentrated in vacuo. The residue was triturated with diethyl ether and dried under vacuum at 50° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2([CH3:25])[CH2:24][O:23]2)=[O:21])=[CH:15][C:14]=1[CH3:26]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:25][C:22]([OH:23])([CH3:24])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[C:14]([CH3:26])[CH:15]=2)=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1F
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc(F)c(C)c2)cc1

Procedure:
3-(4-Acetylaminophenoxy)-N-(4-fluoro-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 61 c starting from 4-acetamidophenol and 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide. 1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.00 (3H, s), 2.20 (3H, s), 3.90 (1H, d, J=9.5 Hz), 4.15 (1H, d, J=9.5 Hz), 6.03 (1H, s), 6.84 (2H, d, J=8.7 Hz), 7.03-7.08 (1H, m), 7.44 (2H, d, J=8.7 Hz), 7.54-7.57 (1H, m), 7.67-7.69 (1H, m), 9.62 (1H, s), 9.75 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:30])=[O:29].Br[C:33]1[S:37][C:36]([CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:31][C:2]1([CH3:1])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14]([C:33]4[S:37][C:36]([CH2:38][N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:29])=[O:30]
Reactant: Brc1ccc(CN2CCCC2)s1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCCC5)s4)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (75 mg, 0.17 mmol), 1-[(5-bromo-2-thienyl)methyl]pyrrolidine (50 mg, 0.17 mmol), PdCl2(dppf)-CH2Cl2 adduct (20 mg, 0.024 mmol), and potassium carbonate (100 mg, 0.72 mmol) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) in a 2-5 mL microwave tube. The mixture was degassed by bubbling argon through for 5 minutes, then heated in a biotage microwave at 100° C. for 5 minutes. The crude reaction mixture was filtered through a thiol SPE cartridge (polymer labs) to remove palladium, and concentrated. The residue was dissolved in ˜3 mL of dmso, and filtered through a syringe filter. The crude product was purified by ammonium hydroxide Gilson HPLC, and the desired fractions were concentrated. The product was further purified by trituration from diethyl ether to afford 18.6 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH3:26])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1CC
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A mixture of 4-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (1.0 g, 3.40 mmol) in DMF (2 mL) was added drop wise to a suspension of NaH (100 mg, 4.0 mmol) in DMF (5 mL). The reaction mixture was stirred for 30 min. Ethyl iodide (624 mg, 4.0 mmol) diluted in 1 mL of DMF was added drop wise at room temperature and the mixture was stirred for an additional 1 hr. The reaction mixture was diluted with 100 mL of EtOAc and washed with 100 mL of saturated ammonium chloride, brine (50 mL), dried over anhydrous sodium sulfate and the solvent was removed to afford crude 4-benzyloxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (1.15 g). This material was diluted in 30 mL of ethanol and 100 mg of 10% Pd/C was added. The mixture was placed on a Parr shaker for hydrogenation at 50 psi for 3 hr. The mixture was filtered and the solvent was removed to afford 1-ethyl-4-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.730 g, 92% yield) as a white solid. LCMS for C13H15NO3 calcd. (m/e) 233, observed 234 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[C:34]([C:40](O)=[O:41])[C:33]2=[O:43])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:34]5[C:33](=[O:43])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][C:35]=5[CH3:39])=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1cc(C)n(-c2ccc(F)cc2)c(=O)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (116 mg, 0.357 mmol) and 1-(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (112 mg, 0.429 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (123 μL, 0.714 mmol) and HATU (163 mg, 0.428 mmol), and the mixture was stirred at room temperature for 4 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a white solid. The obtained solid was washed with ethyl acetate and collected by filtration to give the title compound (110 mg, 54%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([C:35]([F:38])([F:37])[F:36])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:30]1([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]3[CH:10]=[CH:9][C:8]4[N:7]5[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]5=[CH:5][C:4]=4[CH:3]=3)=[CH:25][C:26]=2[C:35]([F:36])([F:37])[F:38])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Yield: 62.3 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.563 g, 1.960 mmol), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.515 g, 1.960 mmol) and cesium carbonate (0.703 g, 2.156 mmol) in DMF (4 mL) were heated to 50° C. for 16 h in a 20 mL sealed scintillation vial. The reaction mixture was filtered by vacuum filtration through Celite® and washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was taken up in EtOAc (25 mL), washed with water (2×25 mL), saturated NaCl (20 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give a yellow sticky oil. A precipitate, formed by addition of hexanes to the oil, was collected by filtration, was washed with hexanes (3×20 mL) and dried (vacuum oven) to provide the title compound as a white solid (0.6273 g). LCMS m/z=514.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.57-1.72 (m, 4H), 1.81-1.87 (m, 2H), 1.95-2.04 (m, 2H), 2.15-2.24 (m, 1H), 2.53-2.67 (m, 2H), 2.71-2.81 (m, 1H), 3.20-3.27 (m, 1H), 3.57 (quintet, J=7.75 Hz, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 5.13 (s, 2H), 5.99 (s, 1H), 6.77 (dd, J=8.65, 2.08 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.62 (d, J=8.72 Hz, 1H) 7.68-7.70 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH2:34]>CO>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CS(C)(=O)=O
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: CO
Product: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (400 mg, 0.78 mmol) in methanol (10 mL) was added methyl vinyl sulfone (207 mg, 1.95 mmol). The resultant reaction stirred at ambient temperature for 24 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (446 mg, 92%). 1H NMR (300 MHz, DMSO-d6): 9.46 (d, J=0.4 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.24-8.24 (m, 2H), 7.78 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 4.86-4.86 (m, 1H), 3.27 (t, J=7.1 Hz, 2H obscured solvent peak), 3.03 (s, 3H), 2.92-2.80 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.21 (t, J=10.9 Hz, 2H), 2.22-1.98 (m, 2H), 1.92-1.92 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1cnc([C@H](N)Cc2c[nH]c3ccccc23)o1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cnc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(5-methyloxazol-2-yl)ethylamine (240 mg, 1.0 mmol) and 4-dimethylamino-4-phenylcyclohexanone (218 mg, 1.0 mmol) in 1,2-dichloroethane (15 mL) was mixed with powdered sodium triacetoxyboron hydride (317 mg, 1.5 mmol) and acetic acid (120 mg, 2.0 mmol) and stirred for 18 h at room temperature. The mixture was then diluted with ethyl acetate (80 mL), washed with sodium hydrogencarbonate solution (20 mL) and dried with sodium sulphate. The solvent was removed in a vacuum and the residue purified by flash chromatography (15 g, 12×2.5 cm) with methanol/dichloromethane (1:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:25]([C:24]4[CH:28]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=4[C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)=[O:26])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and Intermediate 13. MS (ESI) mass calcd. for C23H23FN6O3, 450.18; m/z found, 451.1 [M+H]+. 1H NMR (CDCl3): 8.68 (d, J=4.9 Hz, 2H), 8.25 (dd, J=8.7, 5.5 Hz, 1H), 7.28-7.15 (m, 2H), 7.12 (dd, J=8.6, 2.5 Hz, 1H), 5.31 (s, 1H), 3.84-3.65 (m, 7H), 3.63-3.33 (m, 5H), 3.13-2.86 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O>ClCCl>[Cl:24][C:4]1[C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]([C:14]([F:15])([F:16])[F:17])[O:9]2
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCc1c(O)cc2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a mixture of 100 mg (0.35 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 5 mL of anhydrous dichloromethane was added dropwise a solution of 0.42 mL (1.0 M in dichloromethane, 0.42 mmol) sulfuryl chloride. The resulting solution was stirred at room temperature for one hour. The sample was concd and the residue purified on a silica gel column with ethyl acetate:hexane: acetic acid to give 60 mg (52%) of a light yellow solid: 1H NMR(CDCl3/400 MHz) 7.71(s, 1H), 6.71(s, 1H), 5.99(s, 1H), 5.65(q, J=6.0 Hz, 1H), 2.38(m, 1H), 2.06(m, 1H), 0.84(t, J=7.6 Hz, 3H); MS (ESI+) 323.0 (M+1, 100); LCMS (ES−) 321 (M−H, 100); HRMS (ES−) m/z calcd for (M−1; C13H9ClF3O4) 321.0136, found 321.0118.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: Cc1cccc(OB(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3cc(C)ccc3n2)c1

Procedure:
3-methyl-phenyl-boric acid (1.3 mmol), 2-chloro-6-methyl-quinoline (1 mmol), tetrakis(triphenyl phosphine) palladium(0) (0.05 mmol), and potassium carbonate (3 mmol) are dissolved in a two-neck round bottom flask containing THF (30 ml) and H2O (10 ml). The mixture is then stirred for 24 hours in a bath of 100 degrees Celsius (C). Subsequently, when reaction no longer occurs, the THF and toluene are discarded. The mixture is extracted by using dichloromethane and water, which is then treated with vacuum distillation. Then, after filtering the mixture with a silica gel column, a solvent is treated with vacuum distillation. Thereafter, by using dichloromethane and petroleum ether, the mixture is re-crystallized and filtered, thereby yielding solid 2-(3-methylphenyl)-6-methyl-quinoline.