Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Si:13]([O:20][CH2:21][CH:22]=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[C:16]([Si:13]([CH3:15])([CH3:14])[O:20][CH2:21][CH2:22][NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Tryptamine (3.34 g, 20.85 mmol) and t-butyldimethylsilyloxylacetaldehyde (2.44 g, 13.99 mmol) is dissolved in dichloromethane (200 ml) for 10 minutes. The mixture is cooled to 0° C. and it is added sodium triacetoxyborohydride (5.38 g, 25.38 mmol). The mixture is warmed slowly to room temperature and stirred for 18 hours. Then water is added and the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The crude product is purified by a silica gel flash chromatograph using dichloromethane-methanol eluent.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([C:7]([O:9]C(C)(C)C)=O)[CH2:3][CH:2]1[C:14]([O:16]C)=[O:15].C(O)(C(F)(F)F)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH:63]([C:65]1[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=1)C(O)=O)=[O:64].[OH-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[CH:63]([C:65]1[CH:73]=[C:72]([CH:71]=[CH:67][CH:66]=1)[C:7]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:9])=[O:64]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: O=Cc1cccc(C(=O)N2CCNC(C(=O)O)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of 1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate 29 (1.0 g, 2.9 mmol) in DCM (20 mL) was added TFA (2.31 g, 20.3 mmol) at 0° C. The reaction mixture was stirred at RT for 4 h. TLC analysis indicated complete conversion of SM. Reaction was concentrated to remove excess of TFA and sticky solid so obtained was taken in DCM (20 mL). To this suspension, HATU (1.65 g, 4.34 mmol), NMM (293 mg, 2.9 mmol), 3-formylbenzoic acid (435 mg, 2.9 mmol), and DMAP (10 mg) were added. Reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. The reaction mixture was diluted with DCM and washed with water; organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The sticky solid so obtained was added to a solution of NaOH (65 mg, 1.6 mmol) in MeOH (5 mL). Reaction mixture was stirred at rt for 7 h. The reaction was monitored by TLC. When SM was completely consumed, reaction mixture was concentrated under vacuum. The solid was suspended in water and acidified to pH 6 using 1 N HCl. The suspension was filtered and the precipitate was triturated with ethanol to give 766 mg (20%) of 4-(3-formylbenzoyl)piperazine-2-carboxylic acid 32 as sticky solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCN)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(CCCNC(C)=O)OCC
Reaction time: 4 h
Yield: 96 %

Procedure:
97 g. of 3-aminopropanephosphonic acid diethyl ester is dissolved in 400 ml. of dry pyridine and 55 g. of acetic anhydride is added with stirring. The mixture is then boiled for 4 hours with refluxing and freed of the low-boiling components by evaporation in a light vacuum. Gaschromatographically pure N-acetyl-3-aminopropanephosphonic acid diethyl ester is obtained in a 96% yield by shortcut distillation in vacuo. It is a pale yellow, highly viscous oil with a boiling point of 166° to 160° C. (0.4 Torr).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14](I)=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+].O.ClCCl>CN1CCCC1.[Cu]I>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:21]([F:26])([F:25])[F:20])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Agent: [Cu]I
Agent: CN1CCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of methyl 2-(4-fluorophenoxy)-5-iodonicotinate (step 1, 373 mg, 1.0 mmol), sodium trifluoroacetate (1.36 g, 10 mmol), and copper(I) iodide (960 mg, 5.0 mmol) in 1-methyl-pyrolidine (8.0 mL) was stirred at 160° C. for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extacted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by TLC plate developing with hexane/ethyl acetate (1/1) to afford 32 mg (10%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, s), 7.13 (1H, d, J=6.3 Hz), 3.99 (3H, s); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl>[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:16]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN(C)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(CN2CC[C@@H](N(C)C)C2)cc1
Yield: 98.8 %

Procedure:
Methyl 4-(bromomethyl)benzoate 5 (0.5 g, 2.2 mmol), (R)—N,N-dimethylpyrrolidin-3-amine (0.523 g, 4.6 mmol) and potassium carbonate (0.392 g, 2.8 mmol) were stirred at room temperature for 18 h in ethyleneglycol dimethylether (3 mL) then diluted with DCM (20 mL), washed with brine, dried over MgSO4 and concentrated to give title compound 6 (0.57 g, 96% yield).
Reaction SMILES: Cl([O-])=O.[Na+].[CH:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:24]#[N:25])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1)=[O:6].O.P([O-])([O-])([O-])=[O:28].[Na+].[Na+].[Na+].OO.S([O-])([O-])=O.[Na+].[Na+].Cl>O.CC#N>[C:24]([C:12]1[CH:11]=[C:10]2[C:15]([C:7]([C:5]([OH:28])=[O:6])=[CH:8][NH:9]2)=[CH:14][C:13]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)#[N:25]
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2C#N)cc1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 119.7 %

Procedure:
A solution of sodium chlorite (8.1 mg, 0.072 mmol) in water (2 mL) was added dropwise to a solution of 3-formyl-5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile (50.0 mg, 0.18 mmol), sodium phosphate monohydrate (5.60 mg, 0.04 mmol) and 25% hydrogen peroxide (25.9 mg, 0.19 mmol) in MeCN (2 mL) and water (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and warmed to room temperature. Additional sodium chlorite (16.2 mg, 0.144 mmol) and MeCN (5 mL) were added, and the reaction mixture was stirred at room temperature for another 16 hours. The reaction was quenched with sodium sulfite (46.6 mg, 0.362 mmol) and acidified with concentrated HCl (1 mL) to form precipitates. The solid was filtered, washed with water (5 mL) and air dried to give the title compound (14 mg, 26% yield). MS (ES−) 291.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (br. s., 1H), 12.14 (br. s, 1H), 8.29 (d, J=2.73 Hz, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.50 (d, J=8.20 Hz, 2H), 7.08 (d, J=8.39 Hz, 2H), 3.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:41]3[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: COc1ncccc1B(O)O
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1-c1ncc(N2CCOCC2)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 90 °C
Reaction time: 21 h

Procedure:
A stirred mixture of N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (50.1 mg, 0.11 mmol), 2-methoxypyridin-3-ylboronic acid (32.9 g, 0.22 mmol), ground 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (9.1 mg, 0.022 mmol), palladium (II) acetate (2.7 mg, 0.012 mmol), and potassium phosphate tribasic (70.5 g, 0.33 mmol) in DMF (1.0 mL) and Water (0.04 mL) was purged 3 times with argon and placed under vacuum 3 times. The reaction mixture was carefully heated to 90° C. After 21 h, the reaction was cooled to rt, then diluted with water and extracted 3 times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified over basic alumina (0-50% EtOAc in hexanes) to afford an impure yellow film. This film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a solid as 5,7-difluoro-N-(2′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (pos.) m/e: 541.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[C:17]([O:16][C:14](=[O:15])[NH:13][C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][OH:11])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (Chem-Impex) (15 g, 44 mmol) in tetrahydrofuran (31 mL, 380 mmol) with stirring, 1.0 M borane-THF complex in THF (130 mL) was added dropwise to keep temperature at 0° C. (about 15 min). After addition the reaction mixture was stirred at room temperature for 1 h, cooled with an ice-bath, quenched with AcOH:MeOH (1:5, 70 mL), and partitioned between saturated aqueous NaHCO3 solution and DCM, dried over sodium sulfate and evaporated under reduced pressure to give 13.2 g (92% yield) of the crude desired product, which was used in the next reaction with no further purification. LC-MS found: 330.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[C:12]#[N:13].[CH:14]1(Br)[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:14]1([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=3)[C:5]([C:12]#[N:13])=[CH:6]2)[CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCC1
Reactant: Cc1cc2[nH]cc(C#N)c2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1F)c(C#N)cn2C1CCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 5-fluoro-6-methyl-1H-indole-3-carbonitrile (1.0 g, 5.8 mmol), cyclobutylbromide (0.81 mL, 8.6 mmol) and cesium carbonate (3.9 g, 12.1 mmol) in DMF (10 mL) was stirred at 90° C. overnight. The mixture was then poured into ice water and extracted with ethyl acetate. The organics were combined and washed with water, brine and dried over Na2SO4 and evaporated. The residue was purified by flash chromatography with 5-35% ethyl acetate in hexane to give 1-cyclobutyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (1.2 g, 92%). 1H NMR (500 MHz, CDCl3): 7.68 (1H, s), 7.35 (1H, d, J=9.6 Hz), 7.17 (1H, d, J=6.1 Hz), 4.83-4.79 (1H, m), 2.68-2.60 (2H, m), 2.48-2.37 (5H, m), 2.05-1.96 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:17]2[C:13](=[N:14][N:15]([CH2:18][C:19]([C:35]#[N:36])([CH3:34])[NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[N:16]=2)[CH:12]=[C:11]([Cl:37])[CH:10]=1)(C)(C)C.C[Si](I)(C)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[C:17]2[C:13](=[N:14][N:15]([CH2:18][C:19]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)([C:35]#[N:36])[CH3:34])[N:16]=2)[CH:12]=[C:11]([Cl:37])[CH:10]=1
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(CNC(=O)OC(C)(C)C)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(C#N)(Cn1nc2cc(Cl)cc(CN)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a solution of {6-chloro-2-[2-cyano-2-methyl-2-(4-trifluoromethoxy-benzoylamino)-ethyl]-2H-benzotriazol-4-ylmethyl}-carbamic acid tert-butyl ester (100 mg) in DCM (2 mL) was added trimethylsilyl iodide (0.05 mL). After 20 minutes, the mixture was quenched with methanol and concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (70 mg, 87%). Rf=0.2 (1:1 EA/heptane). MS (ES): M/Z [M+H]=453. 1H NMR: (500 MHz, CHLOROFORM-d): 1.86 (s, 3H), 4.21 (d, J=3.4 Hz, 2H), 5.16 (d, J=13.7 Hz, 1H), 5.43 (d, J=13.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.33 (d, J=0.7 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J=1.5 Hz, 1H) and 7.88 (d, J=8.7 Hz, 2H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH:9]([S:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH:9]([S:12][C:13]1[C:18]([O:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)Sc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Sc1ncccc1OC1CCCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
7.29 g of 2-chlorocyclohexanone are added at room temperature to a mixture of 8.4 g of 2-isopropylthio-3-hydroxypyridine and 7.6 g of potassium carbonate in 120 ml of dimethylformamide, and the mixture is stirred for one hour at 45°-50° C. After the addition of 1.46 g of 2-chlorocyclohexanone and 1.52 g of potassium carbonate and after 2 hours of a further analogous addition of 0.73 g of 2-chlorocyclohexanone and 0.76 g of potassium carbonate, the suspension is stirred for a further 3.5 hours at 45°-50° C. The resulting reaction solution is poured onto a mixture consisting of 200 ml of ice-water, 50 ml of 2N acetic acid and 100 ml of ethyl acetate, washed three times with 300 ml of ethyl acetate and 100 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated by evaporation. The residue is triturated with petroleum ether and filtered. 9.57 g of the desired ketone having a melting point of 106°-110° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=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.C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure E by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.25 g, 5.04 mmol), 4-methyl-2-(tributylstannyl)pyridine (2.12 g, 5.54 mmol), Pd(PPh3)4 (0.58 g, 0.50 mmol), and toluene (25 mL) at 100° C. for 18 h. Purification by column chromatography (silica gel, 0-20% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Reactant: COC(=O)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)nc3)c(C)o2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (0.9 g), methyl 5-aminopyridine-2-carboxylate (0.5 g), sodium carbonate (0.5 g) and sodium iodide (0.9 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg) were added ethyl β-alaninate hydrochloride (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg), triethylamine (168 μL) and N,N-dimethylformamide (10 mL) was added. The obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (171 mg, 35%) as an amorphous compound.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:56]([NH2:60])(=[O:59])[CH:57]=[CH2:58].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:58]=[CH:57]/[C:56]([NH2:60])=[O:59])[CH:14]=2)[CH2:9]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OCC(C)C)CCc3cc(Br)ccc3C2)cc1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OCC(C)C)CCc3cc(/C=C/C(N)=O)ccc3C2)cc1
Temperature: 110 °C
Yield: 94.6 %

Procedure:
To a 10 ml pressure tube, the bromide from Example 42B (125 mg, 0.24 mmol), palladium(II)acetate (2.7 mg, 0.012 mmol), tri-o-tolylphosphine (110 mg, 0.36 mmol), acrylamide (34 mg, 048 mmol), triethylamine (0.12 ml, 0.8 mmol) and DMF (2 ml) were added. After purging with nitrogen, the reaction mixture was heated at 110° C. for overnight. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified on column of silica gel to provide the titled compound (115 mg, 95%) as a white solid. 1HNNMR (DMSO-d6, 300 MHz), δ 9.13 (b, 1H, NH), 7.45 and 7.30 (b, 2H, NH2), 7.01 (b, 1H, NH), 7.36, 7.32, 6.56 and 6.52 (AB, J=12 Hz, 2H, CH═CH), 7.32, 7.30, 6.61 and 6.58 (AB, 4H, J=9 Hz, Ar—H), 3.76–3.66 (m, 2H, OCH2), 3.27 (q, J=3.0 Hz, 4H, 2NCH2), 3.33, 3.29, 3.07 and 3.03 (AB, J=12 Hz, 2H, CH2), 2.80–2.71 (m, 2H, CH2), 2.35 and 2.09 (m, 2H, CH2), 1.79 (m, H, CH), 1.04 (t, J=3.0 Hz, 6H, 2CH3), 0.84 (d, J=6.0 Hz, 6H, 2 CH3). MS (ESI) (M+1)+ 507, (M−1)+ 505.