Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=[O:5])[C:2]([CH3:4])=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=1[NH2:17]>C(O)C>[CH3:8][O:9][C:10]1[C:11]2[N:17]=[C:2]([CH3:4])[C:1](=[O:5])[NH:16][C:12]=2[N:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(C)=O
Reactant: COc1ccnc(N)c1N
Solvent: CCO
Product: COc1ccnc2[nH]c(=O)c(C)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0° C. was added a mixture solution of 70% aq HNO3 (2.5 mL) and 96% aq H2SO4 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2 h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3 mL) and NaOMe (125 mg) was added before the mixture was stirred at 60° C. for 16 h. 37% aq HCl was added drop-wise to adjust pH to 6. The mixture was cooled to 0° C., and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10% palladium on charcoal at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3 h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5:1 to 0:1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-1-yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (10 mL) and DCM (60 mL). Hydrazine monohydrate (3.6 g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)-hydrazine IIe (0.9 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:22][C@@H:21]1[NH2:23]>N1C=CC=CC=1>[NH2:19][C@H:20]1[CH2:22][C@H:21]1[NH:23][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: N[C@@H]1C[C@@H]1N
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3C[C@@H]3N)cc21

Procedure:
A mixture of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and cis 1,2-diamino cyclopropane [Synthetic Communications, 11(6), 493-495 (1981)] in pyridine is reacted as described in Example 1 giving the desired product.
Reaction SMILES: [CH:1]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:30]>C1(C)C=CC=CC=1>[Br:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: BrCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-(Benzhydryloxy)phenyl)methanol (500 mg, 1.72 mmol) was dissolved in toluene (20 ml) and pyridine (139 uL, 1.72 mmol) was added. The solution was cooled to 0° C. PBr3 (163 uL, 1.72 mmol) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 1 h. It was then washed with saturated K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain ((4-(bromomethyl)phenoxy)methylene)dibenzene as an oil, (450 mg, 74%). This intermediate was used in the following reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[C:14](O)(=[O:36])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:14]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])(=[O:36])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH3:35]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: COC(=O)/C=C/C(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (8.1 mmol) was takes up in 40 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 2.60 g, 8.1 mmol), HATU (3.4 g, 12.1 mmol) and DIEA (4.2 mL). The reselling reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 1.4 g of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. MS (EI) calcd for C29H42N2O4: 482.31; found 483 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:21][CH2:20][N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[S:11][N:10]=[N:9][C:8]=2[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2-c2nnsc2-c2cccnc21
Yield: 73.1 %

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (0.700 g) in tetrahydrofuran (5 mL) was added potassium bistrimethylsilylamide (0.5M in toluene, 3.5 mL). After 10 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 8-ethyl-(1, 2, 3)thiadiazolo[4',5':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.453 g). mp 194-196° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1.C=O.[BH3-][C:30]#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH3:30])[CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1
Reactant: [BH3-]C#N
Reactant: C[C@H]1CNCCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1CN(C)CCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-((2S)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole (1 equivalent) is dissolved in a mixture of MeOH and acetic acid (10: 1), on molecular sieves. Paraformaldehyde (10 equivalents) is added in one portion. The reaction mixture is stirred at room temperature overnight then solid NaCNBH3 is added in small portions. The reaction mixture is refluxed for 5 hours, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic solution is dried over Na2SO4, and the solvent removed under reduced pressure to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10](CN)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[C:25]([O:36]C)(=O)[C:26]1[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[CH:28][CH:27]=1.[CH:38]([N:41](CC)C(C)C)(C)C.[Cl-].[C:48](OC)(=O)C1C=CC(C([O-])=O)=CC=1>O1CCCC1>[CH3:48][C:28]1[CH:27]=[C:26]([C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[N:11]=[C:10]([NH:41][CH3:38])[N:9]=3)[CH:3]=2)=[O:36])[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)c(C)c3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 0 °C

Procedure:
A suspension of 2.000 kg (6.39 mol) of [4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine in 71.14 kg of tetrahydrofuran was stirred in a nitrogen atmosphere while being cooled at 0° C. To the suspension was added dropwise 16.70 kg of “monomethyl terephthalate chloride/N,N-diisopropylethylamine” solution (monomethyl terephthalate chloride content: 1.40 kg, 7.03 mol) over 1 hour and 26 minutes, and the container was washed with 1.40 L of 1,2-dimethoxyethane. The mixture was stirred at 0° C. for 13 hours and 4 minutes. Under cooling at 0° C., 36.5 kg of ethyl acetate was added to the reaction mixture and then 80.1 kg of a 5% aqueous solution of sodium hydrogencarbonate was added dropwise, and the mixture was stirred at 20° C. for 1 hour and 10 minutes. Then, 37.3 kg of ethyl acetate was added into the mixture, the mixture was stirred, and the water layer was separated. The organic layer was washed with 40.0 kg of a 5% aqueous solution of sodium chloride, 40.2 kg of water, and 40.1 kg of water in this order. The organic layer was concentrated under reduced pressure at a jacket temperature of 40° C., 23.70 kg of methanol was added to the residue, and stirred for 1 hour and 1 minute while being heated to 60 to 66° C. 23.60 kg of 2-propanol was added dropwise to the suspension over 1 hour while stirring the suspension at a jacket temperature of 50° C. Then, the suspension was cooled at a cooling rate of 10° C./hour and stirred at 20° C. for 12 hours and 23 minutes. The precipitated crystals were filtered, rinsed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol and 6.00 L of 2-propanol in this order to yield 5.52 kg of a crude product (content of the target compound: 2.57 kg, 5.44 mol) as pale yellow crystals (yield: 85.3%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH:25]([CH2:28][F:29])[CH2:26][F:27])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH:25]([CH2:26][F:27])[CH2:28][F:29])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81.1 %

Procedure:
A mixture of methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoate (3.6 g, 8.2 mmol) in THF (50 mL) and water (50 mL) was treated with 1M sodium hydroxide solution (8.2 mL, 8.2 mmol) and allowed to stir at RT for 210 minutes. The THF was removed in vacuo, the residue filtered and extracted with ethyl acetate (30 mL). The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired material as a pale yellow foam (2.84 g). 1H NMR δ (CDCl3): 2.36-2.44 (m, 2H), 4.26 (t, 2H), 4.37 (t, 2H), 4.62-4.79 (m, 5H), 7.08 (t, 1H), 7.56-7.57 (m, 1H), 7.58-7.59 (m, 1H), 8.17 (d, 1H), 8.27 (d, 1H); m/z 426 (M+H)+, 424 (M−H)−
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[O:20][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c([N+](=O)[O-])cc(C(C)=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (65 ml, 373 mmol) was added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (58.6 g, 247 mmol) in tetrahydrofuran (350 ml) under a nitrogen atmosphere while cooling on ice, and then chloromethyl methyl ether (24.5 ml, 322 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, ice water (250 ml) was added and extraction was performed twice with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid water, water, saturated aqueous sodium hydrogencarbonate and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to yield the title compound (69.4 g, 99.9% yield) as a light brown oil. This was used without purification for the following reaction.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:27])[C@H:8]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:26])[O:22][CH:23]([CH3:25])[CH3:24])[NH:9]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:26]=[C:21]([O:22][CH:23]([CH3:25])[CH3:24])[NH:20][CH2:19][CH2:18][CH2:17][C@@H:8]([C:7]([OH:27])=[O:6])[NH2:9]
Reactant: CC(C)OC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=N)NCCC[C@H](N)C(=O)O
Reaction time: 14 h
Yield: 271.5 %

Procedure:
To a 0° C. stirred solution of 0.54 g (1.32 mmol) N2-(tert-butoxycarbonyl)-N5-(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 ml dioxane was added 10 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred 14 h leaving a pale yellow precipitate. The dioxane was removed under reduced pressure and the residue suspended in ether. After stirring for 3 h, the ether was decanted and the solids dried under vacuum to give 0.52 g N5-(iminoisopropoxymethyl)-L-ornithine dihydrochloride. TLC (silica gel, ammonium hydroxide:methanol/1:25)Rf=0.27.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[CH:6]=1.[OH-].[Na+].C(#N)C>C(O)C.C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(C)=O)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a solution of [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (112 mg, 0.29 mmol) in ethanol (3 mL) and THF (3 mL) was added a sodium hydroxide solution (586 uL, 1.0 N) at room temperature. The resulting clear solution was stirred for 4 h. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of drying agent and concentration of the solvent under vacuum gave a solid which was treated with hot acetonitrile. After cooling in the refrigerator, the solids were collected by filtration and washed with acetonitrile to give [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid (65 mg, 60.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.50 (s, 1 H), 10.13 (s, 1 H), 7.93 (d, J=8.8 Hz, 1 H), 7.84 (s, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.45 (dd, J=8.8, 1.8 Hz, 1 H), 7.15 (m, 3 H), 3.84 (s, 2 H), 2.10 (br. s., 3 H), 2.09 (br. s., 3 H). HRMS (ES+) calcd. for C21H19ClNO3 [(M+H)+] 368.1048, obsd. 368.1049.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[N:9]([CH3:17])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]2[N:9]([CH3:17])[C:8](=[O:18])[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:20]4[S:21][C:22]5[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)[CH2:4]3)[C:11]2=[N:12][CH:13]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncc(F)cc21
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccc(F)cc4s3)C2)c2ncc(F)cc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
3-(trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.100 g, 0.367 mmol), 2-chloro-6-fluorobenzothiazole (0.083 g, 0.440 mmol), and N,N-diisopropylethylamine (0.255 mL, 1.467 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.062 g, 0.160 mmol, 43.6% yield) as an off-white solid. M+1: 388.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40-2.49 (m, 2 H) 3.25-3.34 (m, 2 H) 3.36 (s, 3 H) 4.50-4.59 (m, 1 H) 5.21 (quin, J=8.36 Hz, 1 H) 7.08 (td, J=9.10, 2.74 Hz, 1 H) 7.41 (dd, J=8.80, 4.89 Hz, 1 H) 7.62-7.71 (m, 2 H) 8.05 (t, J=2.25 Hz, 1 H) 8.57 (d, J=6.26 Hz, 1 H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C=CC=C(N)C=1>C(O)(=O)C>[CH3:35][O:36][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: COc1cccc(N)c1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: COc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 83 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (70 mg, 0.30 mmol), triethyl orthoformate (0.57 ml), m-anisidine (0.063 ml, 0.56 mmol), and acetic acid (0.07 ml) were used to give 83 mg (0.25 mmol, 83% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]=O.Cl.[H][H]>CO.C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C

Procedure:
3-Methylpiperazine-1-carboxylic acid tert-butyl ester (5.70 g) obtained from Referential Example 82 was dissolved in methanol (100 mL). To the resultant solution, 10% palladium-carbon (0.59 g), 35% aqueous formalin (9.7 mL), and 1M HCl in ethanol (31.3 mL) were added at room temperature, followed by stirring in a hydrogen atmosphere for 15 hours. After the system was purged with nitrogen, insoluble matter was filtered off, and the solvent of the filtrate was evaporated under reduced pressure. To the residue, chloroform-methanol (9%) was added, and the resultant mixture was alkalinized through addition of aqueous sodium hydroxide, followed by partition. The aqueous layer was extracted with chloroform-methanol (9%). The organic layers were combined and washed with saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (3.10 g, 51%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[N:4][N:3]=1.C[Si](C)(C)[C:21]1[O:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[S:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:22]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)CC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([S:30][C:27]4[CH:26]=[CH:25][N:24]=[C:23]5[CH:22]=[CH:21][O:29][C:28]=45)=[CH:36][CH:35]=3)=[N:3][N:4]=2)=[N:13][CH:14]=1
Reactant: C[Si](C)(C)c1cc2nccc(Sc3ccc(N)cc3)c2o1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCC(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5ccoc45)cc3)c3ccccc23)nc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A resealable tube was charged with 1-chloro-4-(5-chloropyridin-2-yl)phthalazine (0.095 g, 0.34 mmol), 4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)benzenamine (0.090 g, 0.29 mmol) and 2-butanol (3.0 mL). The system was flushed with argon, and the tube was sealed. The mixture stirred at 100° C. for 2 h. LC-MS showed starting aniline and hydrolyzed phthalazine, so 90 mg of chlorophthalazine was added and the reaction was stirred for 1 h at 100° C. The reaction was concentrated, re-dissolved in THF, and TBAF (1.0 M in THF) (0.29 ml, 0.29 mmol) was added. The reaction was stirred at 60° C. overnight. The reaction was concentrated and purified via Gilson HPLC (gradient elution 10-90% MeCN:H2O). The clean fractions were partitioned between DCM and saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-2-yl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine as a yellow solid. MS: M+H+=482.1.