Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.N#N.[H-].[Na+].CS(O[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34]S(C)(=O)=O)[CH:29]=1)(=O)=O.[OH-].[K+]>CN(C=O)C.CC(O)=O.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Reactant: CS(=O)(=O)OCc1cccc(OS(C)(=O)=O)c1
Agent: N#N
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(O)c1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred slurry of 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (0.192 g, 0.73 mmol) in DMF (5 mL), under an atm of N2, was added NaH (60%, 0.040 g, 1.0 mmol) and the resulting mixture stirred for 5 min. 3-[(Methylsulfonyl)oxy]benzyl methanesulfonate (0.246 g, 0.88 mmol) was added, and the resulting mixture stirred for 2 hours at room temperature. H2O was added and the mixture concentrated. Residual DMF was removed by evaporation from toluene. MeOH (20 mL) and KOH (1.0 g, 18 mmol) were added and the resulting mixture was stirred over night. The mixture was neutralised with HOAc, concentrated and purified on C8-HPLC (0.1% HOAc, gradient 5→100% CH3CN) to give 0.175 g (65%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.47 (s, 1H), 7.98 (s, 1H), 7.88 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.5 Hz), 7.12 (dd, 1H, J=8.0, 7.7 Hz), 6.74 (d, 1H, J=7.7 Hz), 6.70 (s, 1H), 6.66 (d, 1H, J=8.0 Hz). MS (ESI+) 369 (M+1H+), MS (ESI−) 367(M-1H+).
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[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[N:63][C:64]([N:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)=[CH:65][CH:66]=2)[C:50]=1[CH3:73].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]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:73])[C:51]([C:61]1[CH:62]=[N:63][C:64]([N:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)=[CH:65][CH:66]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccc(N3CCNCC3)nc2)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(-c2ccc(N3CCNCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

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), 5-morpholinopyridin-3-amine (0.057 g, 0.320 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.049 g, 0.51 mmol) in toluene (2.7 mL) at 100° C. for 2.5 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (2H, dd, J=4.9, 2.2 Hz), 7.89 (1H, dd, J=8.9, 2.4 Hz), 7.79 (1H, d, J=2.5 Hz), 7.56-7.60 (2H, m), 7.35-7.41 (1H, m), 6.93 (1H, d, J=8.8 Hz), 6.55 (1H, t, J=2.3 Hz), 3.70 (4H, m), 3.55 (4H, m), 3.08 (4H, m), 2.85 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>CN(C)C=O.O>[C:25]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2.0 g of 4-amino-N-(2,6-dimethylphenyl)benzamide in dimethylformamide were added 1 ml of pyridine followed by 710 μl of acetyl chloride. The reaction was stirrred at room temperature for 2 hours, diluted with water, and chilled to approximately 4° C. The title product was recovered by filtration in 85% yield, m.p. 293°-295° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C([N:14]1[CH2:22][CH:21]2[CH:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:19][C:20]2=[O:23])[CH2:15]1)C1C=CC=CC=1.C(OC(C)C)(C)C>ClCCCl>[C:30]1([C:17]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]3[CH:21]([CH2:22][N:14]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:15]3)[C:20](=[O:23])[CH2:19][CH2:18]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Solvent: CC(C)OC(C)C
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h

Procedure:
Vinyl chloroformate (56 cc) is added dropwise in the course of 10 minutes to a solution of (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone (193 g) in 1,2-dichloroethane (1,225 cc) cooled to +5° C. After stirring for 30 minutes at between 10° and 20° C., the reaction mixture is refluxed for 90 minutes, cooled and concentrated to dryness under reduced pressure (2.7 kPa then 1 kPa). The crystalline mass obtained is pounded with cold isopropyl ether (200 cc). The crystals obtained are drained, washed with isopropyl ether (2 * 100 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-vinyloxycarbonyl-4-perhydroisoindolone (177 g) melting at 178° C. is obtained.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:27][C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[C:30](O)=O>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:18](=[CH:24][CH:23]=[C:22]4[NH:25][C:30]([C:29]([F:34])([F:33])[C:28]([F:36])([F:35])[F:27])=[N:26][C:21]4=3)[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C(F)(F)C(F)(F)F)nc4c3O2)cc1

Procedure:
A solution of 1.0 g (2.4 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 30 mL of pentafluoropropionic acid was refluxed under nitrogen for 6 hours. The mixture was diluted to 400 mL with methylene chloride, washed with 400 mL of water and with 400 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 1% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 0.90 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 7.75 δ (2 H); doublet 7.3 δ (2H); doublet 7.15 δ (1H); doublet 6.9 δ (1H); multiplet 4.5 δ (1H); doublet of doublets 4.25 δ (1H); multiplet 4.2 δ (2H); doublet of doublets 4.1 δ (1 H); singlet 2.4 δ (3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Yield: 69.6 %

Procedure:
A mixture of 2-(4-bromophenyl)acetic acid (50 g, 0.23 mol), benzyl alcohol (26 mL. 0.25 mol) and p-toluenesulfonic acid (0.3 g) in 200 ml toluene were heated at reflux with the azeotropic removal of water (15 h). The yellow solution was washed with water (250 mL), saturated aqueous sodium bicarbonate (250 mL) and then dried (MgSO4). Concentration provided a light yellow solid that was recrystallized from cold hexanes to give benzyl 2-(4-bromophenyl)acetate (48.5 g, 0.16 mol) in 69% yield, mp. 47.5°-48° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: COCc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methoxymethyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[C:4]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][N:24]([CH3:25])[C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1C(=O)O
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of 0.10 g (0.40 mmol) 6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-carboxylic acid in 4 ml dicloromethane were added dropwise at 0° C. under argon 0.05 ml (0.6 mmol) oxalyl chloride and one drop of DMF. The reaction mixture was allowed to slowly warm to room temperature. After 1 h the mixture was concentrated in vacuo and redissolved in 2 ml dichloromethane. This solution was added dropwise at 0° C. to a mixture of 0.16 g (0.60 mmol) (3,5-bis-trifluoromethyl-benzyl)-methyl-amine and 0.14 ml (0.80 mmol) N,N-diisopropylethylamine in 2 ml dichloromethane. After 30 min. the reaction mixture was diluted with ethyl acetate and washed with a 1 M aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 0.29 g of crude product. Flash chromatography gave 0.21 g (quant.) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH3:13])[NH:7][C:8](=[O:10])[CH:9]=1.[Li+].[Br-].Br[CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:3][C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[C:8](=[O:10])[CH:9]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCCc1nc(C)cc(=O)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a stirred suspension of NaH (570 mg, 22.57 mmol, 95%) in dry DMF (35 ml) at 25° C. was added a solution of 4-methyl-2-propyl-1,6-dihydro-6-pyrimidone (2.64 g, 17.36 mmol) in dry DMF. After the effervescence has ceased, anhydrous LiBr (3.51 g, 40.0 mmol) was added followed by 4-[2-bromoethoxy]benzaldehyde (4.37 g, 19.08 mmol) in dry DMF at the same temperature. The reaction mixture was immersed in a preheated oil bath at 70° C. and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was chromatographed over silica gel using 3:7 EtOAc-pet. ether as eluent to obtain the title compound (1.61 g, 31%).
Reaction SMILES: C(=O)([O-])N.[C:5](Cl)(=O)[C:6](Cl)=[O:7].Cl.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=[NH:28])[O:24]C(C)C)=[CH:14]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:28])[NH:24][C:6](=[O:7])[CH:5]=2)=[CH:14]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cl
Agent: NC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C2=CC(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 3.0 g (9.57 mmol) of tert.butyl[1(R or S)-(6,7,8,9-tetrahydropyrido[1,2-a]indol-8(R or S)-yl)ethyl]carbamate in 150 ml of dichloromethane was treated dropwise at 0° C. with 1.28 g (10.3 mmol) of oxalyl chloride. After 5 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of dichloromethane and treated with 2.94 g (11 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 4.38 g (43 mmol) of triethylamine at 0° C. under nitrogen. After warming to room temperature, the solution was stirred for 24 hours, washed with water and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was dissolved in 30 ml of pyridine. The resulting solution was cooled to ice bath temperature and treated dropwise with 1.5 ml (10.8 mmol) of trifluoroacetic anhydride. After 15 minutes, the solvent was removed under reduced pressure and the residue was partitioned between 200 ml of ethyl acetate and 200 ml of 0.2M hydrochloric acid. The organic layer was washed with 50 ml of sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 1.35 g of 3-[8(R or S)-[1(R or S)-tert.butoxyformamidoethyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereomer A) in the form of a red solid of melting point 255°-7° C. Further elution gave 1.38 g of diastereomer B as a red solid of melting point 230°-233° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[O:33][CH3:34].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>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].ClCCl>[CH3:34][O:33][C:25]1[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:24]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.16 g), 4-bromo-3-methoxy-1-nitrobenzene (2.63 g) and DMF (31.6 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.50 g) and potassium carbonate (4.24 g) were added and stirred at 80° C. for 4 hours. After this mixture was concentrated under reduced pressure, water and ethyl acetate were added, and insoluble materials were filtered through celite. The organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:0 to 2:1) to give tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.21 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][CH3:37])=[O:4].[OH-].[K+].Cl.CCOC(C)=O>C1COCC1.CO.[Cl-].[Na+].O>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C@@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C@H:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH3:37])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)=[CH:24][CH:23]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 96 h
Yield: 55 %

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (934 mg) was dissolved in 120 mL of THF-MeOH (1-4) and 9 mL KOH was added over 1 hour. The resulting mixture stirred at room temperature for 4 days. The pH was adjusted to about 7 with 1 N HCl and brine and EtOAc added. The organic solution was dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (DCM-MeOH 99.5:0.5 to DCM-MeOH 95:5) to give 0.502 g of product after drying. LCMS: m/z 605.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g, 32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added. 2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was stripped onto silica and column chromatographed on silica with 5% to 100% EtOAc:Hexane to give 9.75 g (87%) of the title compound of Step C. 1H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t, J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[S:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1>C(O)C>[Br:9][C:10]1[S:14][C:13]([CH:15]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.1 %

Procedure:
A solution of pyruvic acid (10.0 mL, 143.9 mmol) in ethanol (13.0 mL) was added to a 0.5 M sodium hydroxide solution (393.0 mL). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 5-bromo-thiophen-2-carbaldehyde (25.0 g, 130.9 mmol) in ethanol (112.0 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid was washed with ethyl acetate, diluted with a 3N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 25.0 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2N=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.Cl[C:24]1C2C=CNC=2N=C(C2C=CC=CN=2)N=1.ClC1C=C(C2C=CC=C(C)N=2)N=C2NC=CC=12>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[CH:16][C:11]3=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)n1
Reactant: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Agent: Cc1cccc(-c2cc(Cl)c3cc[nH]c3n2)n1
Product: Cc1cccc(-c2cc(-c3cccnc3)c3cc[nH]c3n2)n1

Procedure:
6-(6-Methyl-pyridin-2-yl)-4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine is prepared by an analogous method to that for 2-(6-methyl-pyridin-2-yl)-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine (Example 2) by replacing 4-chloro-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 1) with 4-chloro-6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 6).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:14][CH2:15][CH2:16][CH2:17][CH:18]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:13])[C:11]=1[CH3:12].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.O>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[C:11]([CH3:12])[C:10](=[O:13])[NH:9]3)=[CH:4][CH:5]=2)[CH2:31][CH2:30]1
Reactant: Cc1c(C)c2ccc(OCCCC=O)nc2[nH]c1=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C)c2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
The crude 4-(5,6-dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (100 mg, 0.38 mmol) is dissolved in dichloroethane (7 mL) and 1-(2,3-dichlorophenyl)piperazine monohydrochloride (112 mg, 0.42 mmol) is added, followed by triethylamine (39 mg, 0.05 mL, 1.14 mmol). The mixture is stirred for 5 minutes and NaBH(OAc)3 (81 mg, 0.38 mmol) is added. The mixture is stirred at room temperature for 1 hour and water (5 mL) is added. The organic layer is separated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude solid is purified by column chromatography (1:9 methanol/ethyl acetate) to yield the title compound (123 mg, 68%) as a white solid. mp 161–163° C., 1H NMR (400 MHz, CDCl3) δ 8.98 (br s, 1H), 7.80 (d, 1H), 7.20–7.10 (m, 2H), 7.00–6.90 (m, 1H), 6.60 (d, 1H), 4.20 (t, 2H), 3.15–3.00 (m, 4H), 2.75–2.60 (m, 4H), 2.50 (t, 2H), 2.40 (s, 3H), 2.20 (s, 3H), 1.85–1.60 (m, 4H), MS ES+ 474.76 (M)+ (Exact Mass: 474.16).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:13]C(CC)CCBr.P(Br)(Br)Br.CC(CC)CCO>CCOCC.N1C=CC=CC=1>[CH3:13][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][CH2:1][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCC(C)CCBr
Reactant: CCCCCCc1cccnc1
Agent: BrP(Br)Br
Agent: CCC(C)CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C)CCCc1cccnc1

Procedure:
3-(4-Methylhexyl)pyridine was prepared in a similar manner to that described above with regard to 3-hexylpyridine but using 3-methyl-1-pentylbromide [prepared by adding over 1 h, at -30° C. and under N2, 22.5 g of PBr3 (0.083 mol; 7.8 ml) to a mixture of 21.6 g (0.212 mol) of 3-methyl-1-pentanol, 3.95 g of anhydrous pyridine and 88.4 ml of anhydrous sulfuric ether; the mixture was allowed to react for 1 h at -30° C. and then for 1 night at room temperature; the reaction product was extracted and washed in the usual manner and purified on a Vigreux column to provide 20.8 g of pure product].