Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClCCl.CN(C)C=O>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([Cl:1])[C:3]=1[F:13])[CH3:15]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(F)c(Cl)c1F
Reaction time: 0.75 h
Yield: 100.6 %

Procedure:
To a solution of 3-chloro-2,4,5-trifluorobenzoic acid (Example 20, 4.90 g, 23.3 mmol) in dichloromethane (50 mL) is added oxalyl chloride (5.1 mL, 58.2 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (50 mL) and treated with ethanol (10 mL, 172 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound (5.59 g). 1H NMR (CDCl3): δ 7.76-7.68 (m, 1H), 4.40 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].CN(C)[CH:21]=[C:22]([N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]1=[O:34])[C:23](OCC)=[O:24]>>[OH:24][C:23]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:21][C:22]=1[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]1=[O:34]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccccc1=O
Product: O=C(NCC1CCOCC1)c1ccc(-n2ncc(-n3ccccc3=O)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 188 using 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and ethyl 3-(dimethylamino)-2-(2-oxopyridin-1(2H)-yl)acrylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.32 (m, 2H) 1.62 (d, J=12.9 Hz, 2 H) 1.81 (ddd, J=11.1, 7.3, 4.0 Hz, 1 H) 3.20 (t, J=6.3 Hz, 2 H) 3.24-3.31 (m, 2 H) 3.86 (dd, J=11.2, 2.7 Hz, 2 H) 6.31 (t, J=6.6 Hz, 1 H) 6.44-6.59 (m, 1 H) 7.48 (t, J=7.8 Hz, 1 H) 7.80 (br. s., 1 H) 8.27-8.61 (m, 2 H) 8.73 (br. s., 1 H) 8.92 (s, 1 H) 13.12 (br. s., 1 H). MS m/z 396 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])[CH:18]=[CH:19][C:20]=1[CH3:21])=[O:13].[CH3:40][N:41]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O>[CH3:40][N:41]1[CH2:47][CH2:46][CH2:45][N:44]([CH2:8][C:9]2[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:43][CH2:42]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCCN(C)CC2)c1
Temperature: 80 °C

Procedure:
Potassium carbonate (0.138 g) was added to a mixture of N-[3-(3-chloromethylbenzamido)-4-methylphenyl]-2-morpholinopyridine-4-carboxamide (0.232 g) and 1-methylhomopiperazine (1 ml) and the mixture was stirred and heated to 80° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and water (25 ml) was added. The resultant solid was isolated, washed with water and dried under vacuum at 55° C. There was thus obtained the title compound (0.176 g); NMR Spectrum: (DMSOd6) 1.72 (m, 2H), 2.21 (s, 3H), 2.24 (s, 3H), 2.6 (m, 8H), 3.53 (m, 4H), 3.67 (s, 2H), 3.74 (m, 4H), 7.1 (d, 1H), 7.23 (m, 2H), 7.51 (m, 3H), 7.8 (s, 1H), 7.84 (d, 1H), 7.9 (s, 1H), 8.25 (d, 1H), 9.86 (s, 1H), 10.28 (s, 1H): Mass Spectrum: M+H 543.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-])=O)=[CH:8][CH:7]=1.[OH-].[NH4+]>[Fe].O>[Cl:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][CH:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Cl)nc1N
Yield: 86 %

Procedure:
4.484 g of iron powder is added to a solution containing 78 ml of acetic acid and 3.415 g of 6-chloro-3-nitro-2-pyridinamine. The reaction medium is heated at 60° C.-70° C. for 2 hours 45 minutes, then left to return to ambient temperature. After pouring into 200 ml of water, 200 ml of ammonium hydroxide is added until pH9 is achieved, followed by extraction with ethyl acetate, drying, filtering and concentrating. 3.14 g of crude product is obtained which is chromatographed on silica eluting with an ethyl acetate triethylamine mixture 95/5. 2.43 g of sought product is obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][CH3:17])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[CH:28]([O:31][C:32]1[CH:37]=[N:36][CH:35]=[C:34]([Sn](C)(C)C)[N:33]=1)([CH3:30])[CH3:29]>CN(C=O)C.[Cu]I.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>[CH:28]([O:31][C:32]1[N:33]=[C:34]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH:16][CH3:17])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:3]=2)[CH:35]=[N:36][CH:37]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Oc1cncc([Sn](C)(C)C)n1
Reactant: CNc1nc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)no1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNc1nc(-c2ccc3c(c2)c(-c2cncc(OC(C)C)n2)cn3S(=O)(=O)c2ccc(C)cc2)no1
Temperature: 90 °C
Yield: 31.7 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,2,4-oxadiazol-5-amine (250 mg, 0.50 mmol) and 2-isopropoxy-6-(trimethylstannyl)-pyrazine (168 mg, 0.55 mmol) in dry DMF (2.5 mL) for 15 min. To the mixture was added CuI (95 mg, 0.50 mmol) and Pd(PPh3)4 (59 mg, 0.050 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with H2O. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,2,4-oxadiazol-5-amine (80 mg, 31.5%). MS (ESI, pos. ion) m/z: 505.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)(O)[O-].[Na+].COCCOC>CCOC(C)=O.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[CH3:44])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C)n4)cc3)cc2)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1-(4′-{3-Methyl-4-[6-bromo-pyridin-2-ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (0.050 g, 0.09 mmol), o-tolylboronic acid (0.016 g, 0.12 mmol), sodium bicarbonate (0.040 g, 0.48 mmol), and bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.007 g, 0.009 mmol) were combined in 3:1 DME:H2O (2 mL) and warmed with stirring to 70° C. After 3 hrs, the mixture was cooled to room temperature diluted with EtOAc (30 mL) and extracted with H2O (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated, and the crude residue was purified on reverse-phase preparative HPLC to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.CS(O[Na])=O.[C-:25]#[N:26].[K+]>CN(C=O)C>[CH3:18][C:15]1([CH3:19])[CH2:16][CH2:17][CH:12]([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:25]#[N:26])[C:3]=3[CH:11]=2)[CH2:13][CH2:14]1
Reactant: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: [C-]#N
Agent: CS(=O)O[Na]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C#N)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To a mixture of 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.1 g) and DMF (220 mL) were added CH3SO2Na (11 g) and KCN (10 g), followed by heating and stirring at 70° C. for 15 hours. The reaction mixture was concentrated to about a half of the amount under reduced pressure, diluted with water (300 mL), and then stirred. The precipitate was collected by filtration. To the precipitate was added chloroform, followed by dissolving therein, and MgSO4, activated carbon (10 g), and silica gel (100 mL) were added thereto, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:19]O>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:19]
Reactant: NO
Reactant: COc1ccc(Oc2ccc(C=O)c(F)c2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CN)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mg (0.73 mmol) of 2-fluoro-4-(4-methoxy-phenoxy)-benzaldehyde were stirred with 180 μl (3 mmol) of hydroxylamine solution (50% in water) in 5 ml DMF at 100° C. for 1 h and then stirred overnight at ambient temperature. The mixture was evaporated down, dissolved in 10 ml of 7M methanolic ammonia and combined with 50 mg Raney nickel. It was then shaken for 4 h at ambient temperature and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the residue was evaporated down and purified by reversed-phase chromatography.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[OH:14].[Cl:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[C:31](=[O:42])[C:32]3[CH:39]=[C:38]([CH2:40]Cl)[O:37][C:33]=3[N:34]([CH3:36])[CH:35]=2)=[O:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[Cl:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[C:31](=[O:42])[C:32]3[CH:39]=[C:38]([CH2:40][N:11]([CH2:12][CH:13]([OH:14])[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH3:10])[O:37][C:33]=3[N:34]([CH3:36])[CH:35]=2)=[O:29])=[CH:24][CH:23]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccnc1
Temperature: 90 °C
Yield: 37.5 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL) and 2-(methylamino)-1-pyridin-3-ylethanol (Preparation 39, 0.094 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3, 96/4, 95/5) followed by recrystallization from ethyl acetate to yield 0.074 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 145-149° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.54, 8.50, 8.40-8.39, 7.69-7.67, 7.41-7.33, 7.29-7.25, 6.83, 5.33, 4.77-4.73, 4.55, 3.88, 3.71, 2.67-2.55, 2.32; MS (ESI+) m/z 481 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)[CH:13]=[CH:12][C:11]=2[C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH2:33][C:34]([OH:36])=[O:35])[CH:26]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+:38]>C(O)C>[Na+:38].[CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)[CH:13]=[CH:12][C:11]=2[C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH2:33][C:34]([O-:36])=[O:35])[CH:26]=2)[CH2:7][CH3:8])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOc1ccc(-c2ccc(-c3cc(CC(=O)O)ccc3OC)c(CN(CC)C(=O)C3CC3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2ccc(-c3cc(CC(=O)[O-])ccc3OC)c(CN(CC)C(=O)C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetic acid (26.0 g, 53.2 mmol) was dissolved in ethanol (180 mL), sodium hydroxide (53.2 mL, 1N aq.) was added and the reaction was stirred at room temperature for 1 hour. The solution was filtered to remove solid impurities then concentrated. The residue was dissolved in water (˜150 mL) then frozen and lyophilized to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@H:10]3[O:20][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[C:13]2[O:12][C@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@@H:10]([OH:20])[C@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 51.3 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (751 mg, 2.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, 2.67 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (691 mg, yield: 51%).
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([O:34][C:29]4[CH:30]=[CH:31][C:32]([F:33])=[C:27]([F:26])[CH:28]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1c(Oc2ccc(F)c(F)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 130 °C
Yield: 19 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-2-pyrrolidone (0.2 ml) was added K2CO3 (0.044 g, 0.32 mmol) followed by 3,4-difluoro phenol and the reaction mixture was heated at 130° C. overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and ethyl acetate layer was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 3% methanol in DCM to give the product (0.015 g, 19%) as a white solid.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:6]=2[CH:5]=1)(O)=O.CN1CCN(C)C1=O.N12CCCN=C1CCCCC2>Cl>[Cl:13][C:12]1[C:6]2[CH:5]=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCN(C)C1=O
Product: Clc1cccc2sccc12
Temperature: 177.5 °C
Reaction time: 6 h

Procedure:
A mixture of 2-carboxy-4-chlorobenzo[b]thiophene (50.00 g), 1,3-dimethyl-2-imidazolidinone (DMI; 200 ml), and 1,8-diazabicyclo[5.4.0]-undec-7-ene (140.7 ml) was heated at 160 to 195° C. with stirring for 6 hours. After the mixture was cooled to 10° C., the mixture was added to 3N-hydrochloric acid (350 ml) cooled to 10° C. After the mixture was extracted with toluene (500 ml), the toluene layer was washed with 3N-hydrochloric acid, water, aqueous sodium bicarbonate solution, water, saline, and water in this order, and then concentrated to obtain 4-chlorobenzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:35])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]O)[CH2:7][CH2:6]2.C(N(S(F)(F)[F:42])CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:35])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][F:42])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1OCCOCCO)CC2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1OCCOCCF)CC2
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To solution of compound 5a (0.20 g, 0.41 mmol) in dichloromethane (60 ml) was added slowly (Diethylamino)sulfur trifluoride (DAST) (0.13 g, 0.81 mmol) at 0° C. The reaction mixture was stirred overnight under an atmosphere of nitrogen and then quenched with water (30 ml). The organic layer was separated and washed with saturated sodium carbonate solution (2×15 ml) and dried over sodium sulfate. Volatile components were removed under reduced pressure. The crude product was purified by silica gel column chromatography using ether:methanol (100:20) as the mobile phase to give 6a (0.07 g; 36% yield) as a viscous colorless oil. 1H NMR spectrum (300 MHz, CDCl3): 1.65-1.69 (m, 4H), 2.32 (s, 3H), 2.50-2.59 (m, 2H), 2.70-2.73 (m, 2H), 2.78-2.82 (m, 2H), 3.45-3.48 (m, 2H), 3.54 (s, 2H), 3.69-3.73 (m, 1H), 3.72-3.82 (m, 7H), 3.87-3.90 (m, 2H), 4.19-4.22 (m, 2H), 4.43-4.47 (m, 1H), 4.59-4.63 (m, 1H), 6.50 (s, 1H), 6.58 (s, 1H), 6.80-6.84 (d, 1H), 7.05-7.20 (m, 1H), 7.97-7.99 (m, 1H), 8.21 (s, 1H). The free base was converted into oxalic acid salt and re-crystallized in methanol and ethyl acetate solvent. Mp 89.2-89.55° C. Elemental Analysis: C27H37FN2O5.H2C2O4.0.5H2O (C, H, N). Calcd: C, 59.27; H, 6.86; N, 4.77; Found: C, 58.95; H, 6.84; N, 4.85.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=COCCC1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Yield: 86.2 %

Procedure:
A solution of 4,5-dichloropyridazin-3(2H)-one (10 g, 60.6 mmol) in tetrahydrofuran (60 mL, 1.0M) was treated with pyridinium para-toluene sulfonate (3.03 g, 12.1 mmol) and 3,4-dihydro-2H-pyran (8.5 mL, 93.2 mmol). The reaction was heated at reflux for 5 h and was then treated with a second aliquot of 3,4-dihydro-2H-pyran (5.5 mL, 60.3 mmol). The reaction was stirred at reflux overnight. After this time, the reaction was concentrated in vacuo, taken up in ethyl acetate (250 mL), and washed with a 2N aqueous sodium hydroxide solution (2×250 mL). The organics were then washed with a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (Biotage, 330 g, 10% ethyl acetate/hexanes) afforded 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (13.01 g, 86%) as an off-white solid; ES+-HRMS m/e calcd for C9H10N2O2Cl2 [M+Na+] 271.0011, found 271.0012.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:45][CH:46](Cl)[CH3:47])(=[O:44])[CH2:42][CH3:43]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O>[C:41]([O:45][CH:46]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:47])(=[O:44])[CH2:42][CH3:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCC(=O)OC(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)CC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) in DMF (1 mL) was added Et3N (165 mg, 1.64 mmol). The reaction was stirred at 10° C. for 10 min, followed by the dropwise addition of a solution of TBAB (264 mg, 1.64 mmol) in DMF (0.5 mL) and a solution of 1-chloroethyl propionate (67 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The mixture was stirred at 10° C. for another 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to afford the title compound as a white solid (141 mg, 58%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:6][CH:7]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[Cl-].[NH4+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Yield: 99.6 %

Procedure:
A suspension of N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(pyridin-3-yl)phenyl]amine (3.7 g, 10 mmol), sodium sulphide nonahydrate (7.2 g, 30 mmol) and ammonium chloride (1.6 g, 30 mmol) in methanol (15 ml) was heated under reflux for 90 minutes. The reaction was cooled, evaporated to dryness and the residue suspended in ethyl acetate (200 ml). This was washed with water, brine, dried over anhydrous sodium sulphate, filtered and evaporated to dryness to afford 5-bromo-N2-[3-(pyridin-3-yl)phenyl]-pyridine-2,3-diamine as a yellow oil (3.4 g, 100%) which was used without purification; m/z (ES+) 341 and 343 (M++H).