Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:34]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:35])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)N1CCCCC1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)N4CCCCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available piperidine-1-carbonyl chloride as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][O:33][C@H:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:36]3[CH2:37][CH2:38][CH2:39][C@H:34]([O:33][CH3:32])[CH2:35]3)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@H]1CCCNC1
Reactant: CCC1(CC)CCC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
A mixture of 4-[4-bromo-2-(4,4-diethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (153 mg, 0.32 mmol) produced in Example (38c), (S)-3-methoxypiperidine hydrochloride (72.8 mg, 0.48 mmol) produced in Example (50a), sodium t-butoxide (200 mg, 2.08 mmol), palladium(II) acetate (14.4 mg, 0.064 mmol), tri-t-butylphosphonium tetrafluoroborate (57.7 mg, 0.192 mmol) and xylene (4 mL) was stirred for 6 hours and 10 minutes at an external temperature of 100° C. under a nitrogen atmosphere. To the reaction mixture were further added sodium t-butoxide (100 mg, 1.04 mmol), palladium(II) acetate (7.2 mg, 0.032 mmol) and tri-t-butylphosphonium tetrafluoroborate (27.9 mg, 0.096 mmol), followed by stirring for 1 hour at an external temperature of 100° C. under a nitrogen atmosphere. The reaction mixture was air-cooled to room temperature and then purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 59 mg of the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: COc1ccc2nc(Cl)cnc2c1
Solvent: CCO
Product: COc1ccc2nc(Nc3cccc(C(C)(C)C)c3)cnc2c1
Temperature: 80 °C

Procedure:
A solution containing 2-chloro-6-methoxyquinoxaline (synthesized as described in J. Chem. Soc. Perkin Trans 2001, 978-984) (1 eq), 3-t-butylaniline (2 eq) in ethanol was heated at 80° C. overnight. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:5]=1[CH2:6][NH2:7].[N-:14]([C:17]#[N:18])[C:15]#[N:16].[Na+]>>[C:15]([NH:14][C:17]([NH:7][CH2:6][C:5]1[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH3:2])=[NH:18])#[N:16]
Reactant: COc1cccc(OC)c1CN
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Product: COc1cccc(OC)c1CNC(=N)NC#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
15 ml 2N hydrochloric acid were added to 5.0 g (29.9 mmol) 2,6-dimethoxybenzylamine and the aqueous phase was subsequently removed under vacuum. The residue was then dissolved in 50 ml 1-butanol and 2.66 g (29.9 mmol) of sodium dicyanamide were added. The reaction mixture was heated for 5.5 hours at reflux and stirred for 12 hours at room temperature. The precipitate formed was filtered off, was washed with diethylether; 6.81 g.
Reaction SMILES: CON(C)[C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:8]=[C:7]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])[CH:6]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Mg]Br>C1COCC1>[C:4]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH:8]=[C:7]([S:18]([F:20])([F:19])([F:22])([F:23])[F:21])[CH:6]=1)(=[O:24])[CH3:26]
Reactant: CON(C)C(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
N-Methoxy-N-methyl-3-(pentafluorosulfanyl)-5-(2,2,2-trifluoroacetylamino)benzamide (1.65 g) was dissolved in THF (25 ml). At 0° C., lithium bis(trimethylsilyl)amide (0.9 ml) was added while stirring. After 30 min, methylmagnesium bromide (3.5 ml, 3M in diethyl ether) was added dropwise. After the addition had ended, the ice bath was removed and the mixture was stirred at RT for 2 h. While cooling, 1N hydrochloric acid, water and EA were then added. After removing the organic phase, the aqueous phase was extracted twice more with EA. The combined EA phases were dried with magnesium sulfate, filtered and concentrated. The crude product is a mixture of N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide and 1-[3-amino-5-(pentafluorosulfanyl)phenyl]ethanone, and so the crude product (1.3 g) was taken up in methylene chloride (60 ml) and admixed with triethylamine (155 μl). Thereafter, trifluoroacetic anhydride (160 μl) was added while stirring. After stirring at RT for 3 h, water and saturated sodium hydrogencarbonate solution were added, the phases were separated and the DCM phase was washed three times more with water. The DCM phase was dried with magnesium sulfate, filtered and concentrated. 1.3 g of the title compound were obtained. LC-MS Rt: 1.61 min [M+H]+:358.0
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](F)[CH:8]=1>CS(C)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Add pyrrolidine (0.97 g, 13.67 mmol) to a solution of 4-chloro-2-fluoro-1-nitrobenzene (2 g, 11.40 mmol) in 8 mL anhydrous DMSO under N2. Stir the reaction mixture at 80° C. for 1 h. Cool the mixture, pour into ice-H2O and extract with Et2O (3×30 mL). Wash the organic phase with water and brine, dry over MgSO4, filter, and concentrate. Chromatograph the residue on silica gel using hex/EtOAc 9:1 as eluent to afford 2.29 g (89%) of 1-(5-chloro-2-nitro-phenyl)-pyrrolidine as a yellow solid. Add tin chloride (10 g, 44.15 mmol) to a solution of 1-(5-chloro-2-nitrophenyl)pyrrolidine (2 g, 8.83 mmol) in 25 mL of EtOH under nitrogen. Heat the reaction mixture at 70° C. for 3 h. After cooling, pour the mixture into ice-water, basify (pH=9) with NH4OH, and extract with EtOAc (3×100 mL). Dry the organic phase over MgSO4, concentrate, and purify the residue by silica gel chromatography using hex/EtOAc 8:2 as eluent to obtain 1.56 g (88%) of 1-(2-amino-5-chlorophenyl)pyrrolidine as an oil.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Br:24][C:25]1[CH:26]=[C:27]([O:34][CH3:35])[C:28]([N+]([O-])=O)=[N:29][CH:30]=1>O>[Br:24][C:25]1[CH:30]=[N:29][C:28]([F:1])=[C:27]([O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cnc1F
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Tetrabutyl ammonium fluoride (1.0 M THF solution: 3.9 ml) was added to a DMF (5 ml) solution of 5-bromo-3-methoxy-2-nitropyridine (CAS No. 152684-26-9) (450 mg), and the obtained mixture was stirred at 70° C. for 72 hours. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=10:1 to 2:1), so as to obtain the title compound (258 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH2:25][CH3:26])=[C:18]3[N:23]([CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:25]([C:17]1[C:18]2[N:23]3[C:22]([CH:21]=[CH:20][CH:19]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:24]3[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:11][CH:12]=1)[CH3:26]
Reactant: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)cn2ccccc12
Reactant: COC(=O)C#CC(=O)OC
Product: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2c(C(=O)OC)c(C(=O)OC)c3cccc1n32

Procedure:
2-(4-(tert-Butyldimethylsilanyloxymethyl)phenyl)-1-ethylindolizine prepared in example 97, step 2, was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 4-ethyl-3-(4-(tert-butyldimethylsilanyloxymethyl)phenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate, which was hydrolysed and desilylated by the general synthetic principle outlined in example 23, step 7, to afford 4-ethyl-3-(4-hydroxymethylphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals in 63% yield. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.35 (t, 3H); 3.11 (q, 2H); 4.61 (d, 2H); 7.50 (d, 2H); 7.61 (d, 2H); 8.03 (dd, 1H); 8.32 (d, 1H); 8.42 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9](I)=[CH:8][CH:7]=[CH:6][C:5]=1[F:11].C([Mg]Cl)(C)C.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1c(F)cccc1I
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a 500 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) and anhydrous THF (150 mL). This mixture was cooled to 0° C. and i-PrMgCl (13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After 10 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58 mL, 27.3 mmol) was added. The mixture was allowed to warm to room temperature, and after 30 min NH4Cl(aq) (150 mL, 13 wt % solution) was added. The layers were mixed and then separated, and the aqueous layer was extracted with 100 mL of MTBE. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a final mass of 6.07 g (90% wt %, 75% yield). 1H NMR (400 MHz, CDCl3): 7.47-7.38 (m, 2H), 7.17-7.11 (m, 1H), 3.92 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:25]([NH2:26])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[C:25]([NH:26][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC/MS. Evaporation of product-containing fractions yielded the product as a white solid (15 mg, 19%). (LC/MS: Rt 3.91, [M+H]+ 342.66).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:26]2[CH:20]1[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:25]=12.[CH3:34][N:35]([Si](C)(C)C)[S:36]([CH2:39][CH3:40])(=[O:38])=[O:37]>>[N+:31]([C:28]1[CH:29]=[CH:30][C:24]2[O:23][CH2:22][CH2:21][C@@H:20]([OH:19])[C@H:26]([N:35]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH3:34])[C:25]=2[CH:27]=1)([O-:33])=[O:32]
Reactant: CCS(=O)(=O)N(C)[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1CCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCS(=O)(=O)N(C)[C@@H]1c2cc([N+](=O)[O-])ccc2OCC[C@H]1O
Temperature: 65 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
2 g of tetrabutylammonium fluoride were added with stirring to a mixture of 6 g of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine and 9.5 g of N-methyl-N-trimethylsilylethanesulfonamide. The reaction mixture was then heated for 3 h at 65° C., stirred overnight at RT and poured onto ammonium chloride solution. It was extracted several times with EA, and the organic phase was washed with water and dried over sodium sulfate. After concentration and recrystallization of the solid residue from isopropanol, 7.1 g of trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol were obtained, m.p. 133-135° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.O.[NH4+]=[S:20]>C(C(C)=O)C(C)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]([NH2:11])=[S:20])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
The N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (2.61 g) was dissolved in methyl isobutyl ketone (13.01 g), to which ammonium sulfide solution, yellow (8.12 g) having an S content of 6% was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 9 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 2.67 g of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea as a solid (90% yield in appearance). The percentage area of gas chromatography was 85%.
Reaction SMILES: Br[C:2]1[CH2:8][NH:7][C:6](=[O:9])[C@H:5]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH2:8][NH:7][C:6](=[O:9])[C@H:5]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(N[C@@H]1CC=C(Br)CNC1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC=C(c2ccc(O)cc2)CNC1=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
Palladium acetate (1 mg, 0.003 mmol) was added to a solution of benzyl (3R)-6-bromo-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (18 mg, 0.053 mmol), 4-hydroxyphenylboronic acid (9 mg, 0.064 mmol), sodium carbonate (2M in water; 0.066 mL, 0.133 mmol) and trisodium 3-[bis(3-sulfonatophenyl)phosphino] benzenesulfonate (5 mg, 0.088 mmol) in N,N-dimethylformamide (0.45 mL) and water (0.15 mL) and heated to 80° C. After 1.5 h, the mixture was allowed to cool to ambient temperature and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (15 mg). MS 353 (M+1).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([N:73]3[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]3)[CH:68]=2)[C:56]=1[CH3:79].CC(C)([O-])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]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[C:69]([N:73]5[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]5)[CH:68]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccnc(N3CCNCC3)c2)nc2cc(F)cc(F)c2c1Cl
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(-c2ccnc(N3CCNCC3)c2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 2,5-dimorpholinopyridin-3-amine (0.085 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)quinoline (0.1 g, 0.27 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (2.7 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=6.3 Hz), 7.62-7.66 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.46-7.53 (1H, m), 6.91 (1H, s), 6.81 (1H, dd, J=5.0, 1.1 Hz), 6.45 (1H, d, J=2.5 Hz), 3.65 (8H, m), 3.44-3.53 (4H, m), 3.32 (4H, m), 3.00 (4H, br. s.), 2.78-2.88 (4H, m), 1.99 (3H, s). Mass Spectrum (ESI) m/e=603.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[ClH:14].[CH2:15]([OH:17])C>CO>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12](=[NH:13])[O:17][CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C#N)CC2)c1
Reactant: CCO
Agent: Cl
Solvent: CO
Product: COC(=N)C1(c2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
1-(3-Methoxyphenyl)cyclopropanecarbonitrile (56 mg, 0.32 mmol) was dissolved into a saturated solution of hydrogen chloride in ethanol (1 mL). The reaction mixture was stored in the refrigerator (4° C.) for three days. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in ethanol (0.5 mL) and silica sulfuric acid (125 mg), prepared by following the literature (Tetrahedron, 2001, 57, 9509-9511), was added. The reaction mixture was stirred at room temperature for 2 h. The silica was filtered off and the filtrate was cooled to 0° C. and gaseous hydrogen chloride was bubbled through the solution for 30 seconds. The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give an oil. The oil was dissolved into a solution of hydrogen chloride in methanol (1.25 M, 1 mL). Gaseous hydrochloric acid was bubbled into the solution and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as an oil (40 mg, 51%). The material was used without further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O.C1COCC1.CCCCCC>[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]([OH:23])[CH2:30][C:29]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.6M n-hexane solution (23.5 ml) of n-butyl lithium was added to a THF solution (5 ml) of diisopropyl amine (5.3 ml) under an argon atmosphere at -40° C., and the mixture was stirred for 5 minutes and 30 minutes under ice-cooling. After cooling to -78° C., ethyl acetate (3.7 ml) was dropwise added, and the mixture was stirred for 15 minutes. A THF solution (18 ml) of N-(tert-butoxycarbonyl)-L-prolinal (4.98 g) was dropwise added at -78° C. and the mixture was stirred for 1.5 hours. Saturated ammonium chloride (20 ml) was added, and the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into water, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give the title compound (5.73 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16](CC#C)=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:4].C=O.CNC>O1CCOCC1.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12
Agent: C=O
Agent: CNC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Nc1cccc(C)c1COc1cccn2cc(C)nc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (230 mg) in 1.4-dioxane (4.6 ml) were added 36% formaldehyde (105 mg), 50% dimethylamine in water (142 mg) and cuprous chloride (12.5 mg). After the mixture was stirred at 50° C. for 5 hours, 1.4-dioxane was evaporated under reduced pressure. The resultant residue was dissolved in chloroform (20 ml) and insoluble material was filtered off. The filtrate was washed with an aqueous solution of sodium bicarbonate and water in turn, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(4-N,N-dimethylamino-2-butynyl(-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo-[1,2-a]pyridine (175 mg).