Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1>[Pd].CO>[F:26][C:2]([F:1])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Temperature: 50 °C
Yield: 94.9 %

Procedure:
10% Palladium on carbon (0.563 g, 0.53 mmol) and tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carboxylate (1.97 g, 5.29 mmol) were stirred in MeOH (30 mL) under an atmosphere of hydrogen at atmospheric temperature and pressure for 3 days. The catalyst was removed by filtration and the solvents evaporated. The residues were re-dissolved in MeOH (50 mL), 5% palladium on carbon (0.4 g, 0.09 mmol) was added and the mixture was stirred under an atmosphere of hydrogen at 50° C. and 5 Bar pressure until complete conversion was obtained. The catalyst was removed by filtration, washed with MeOH then DCM/MeOH and the solvent was evaporated to afford tert-butyl 4-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carboxylate (1.880 g, 9%) as a solid.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:36])[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.15 g (0.59 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.31 mL (1.8 mmol) DIPEA were combined in 1.5 mL DMF and stirred first of all overnight at RT then for 2 h at 50° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 25 mg (0.0577 mmole) of 5-n-butyl-2,4-dihydro-4-[4-(methoxycarbonyl)benzyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 26) in 0.25 mL of THF was treated with 0.25 mL of 1N sodium hydroxide in methanol, and the resulting solution was stirred overnight at 60° C. Volatiles were removed by evaporation, and the residue was taken up in 1 mL of methanol and acidified to pH 1.5 by addition of 1N HCl in methanol. The mixture was concentrated to dryness. The residue was leached with chloroform. The CHCl3 solution was dried over anhydrous sodium sulfate, filtered through Celite, and concentrated in vacuo to give 23 mg (96%) of the title compound as a colorless, glassy solid; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 420 (M+1)+.
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][N:5]([CH3:28])[C:6](=[O:27])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([NH:25][CH3:26])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:9]=1.[OH-].[Na+]>C(O)=O>[CH3:28][N:5]([CH3:4])[C:6](=[O:27])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([N:25]([CH3:1])[CH3:26])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:9]=1
Reactant: C=O
Reactant: CNC(CCc1ccc(OC)cc1)c1cccc(OC(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1ccc(CCC(c2cccc(OC(=O)N(C)C)c2)N(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Formic acid (10 ml) and 35% aqueous formaldehyde solution (10 ml) were added to 3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyl dimethylcarbamate (500 mg, 1.4 mmol) obtained from Example 2 and the mixture was stirred at 90° C. for 2 hours. After cooling the reaction mixture to room temperature the mixture was neutralized with 1N aqueous sodium hydroxide solution. The neutralized mixture was extracted with ether and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol=80:20 as the eluent to give 3-[1-dimethylamino-3-(4-methoxyphenyl)propyl]phenyl dimethylcarbamate. The product was treated with 1N hydrogen chloride/ethyl acetate solution to afford the title compound as an amorphous solid.
Reaction SMILES: [Na+].C([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=O)C.[OH-].[Na+].Cl>O>[SH:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9]
Reactant: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)C(CS)Cc2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-fluorophenyl)propionyl]amino]benzoic acid sodium salt (compound- of Example 40) (1.2 g) is dissolved in water (20 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 2.5 with 10% hydrochloric acid. The mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and ethyl acetate is distilled off. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-dioxane). The fractions containing the desired compound are collected and lyophilized to give the title compound (0.6 g).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH:22]1([C:28]2[N:32]3[CH:33]=[C:34]([O:37][C@H:38]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[C@@H:41]([NH2:48])[CH2:40][CH2:39]4)[CH:35]=[CH:36][C:31]3=[N:30][N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.CO>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:48][C@@H:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:38]([O:37][C:34]3[CH:35]=[CH:36][C:31]4[N:32]([C:28]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[N:29][N:30]=4)[CH:33]=3)[CH2:39][CH2:40]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(C4CCCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C5CCCCC5)n4c3)c3ccccc32)n(CCO)n1
Yield: 50.4 %

Procedure:
A brown solution of Intermediate 26a (94.2 mg, 0.263 mmol), Intermediate 34c (90.6 mg, 0.250 mmol), and DIPEA (0.054 mL, 0.31 mmol) in dry dioxane (3 mL) was stirred at 75° C. for 16 h. The cooled solution was concentrated in vacuo, suspended in water (3 mL) and extracted with DCM (2×3 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a dark brown oil. Flash chromatography (silica gel, 3-9% MeOH in DCM) gave a pale yellow solid. MDAP (Method 7) gave an off-white solid (72 mg, 50%). LCMS (Method 5): Rt 3.98 min, m/z 572.4 [MH+].
Reaction SMILES: O.C(O)(O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[N:17]=[CH:18][C:19]=2[O:20]C)[CH:10]=[CH:11][C:12]=1[Cl:13].[OH-].[K+].Cl>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[N:17]=[CH:18][C:19]=2[OH:20])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COc1cnn(C)c(=O)c1-c1ccc(Cl)c(Cl)c1
Agent: CC(O)O
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cn1ncc(O)c(-c2ccc(Cl)c(Cl)c2)c1=O
Yield: 10 %

Procedure:
4 ml of water/ethanediol (1:1) were added to 1.0 g (7.4 mmol) of 4-(3,4-dichlorophenyl)-5-methoxy-2-methyl-2H-pyridazin-3-one and 0.4 g of potassium hydroxide (2 eq), and the mixture was reacted at 150° C. overnight. The reaction mixture was added to 50 ml of water and adjusted to pH 1 using concentrated hydrochloric acid, and the resulting precipitate was filtered off. Recrystallization from isopropanol gave 0.2 g of pure product.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 43 h
Yield: 90.5 %

Procedure:
To a solution of (2R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-2H-chromene (120 mg, 0.361 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.361 g, 1.084 mmol) and the reaction mixture stirred at room temperature for 43 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 100 mg (90%) of {[(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (2 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.326 mL, 0.326 mmol) was added followed hexane (7 mL). The resulting white precipitate was filtered to afford 100 mg (80%) of {[(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl}amine hydrochloride as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccnc1NCC1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1NCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To a solution of 3.5 g (18.1 mM) of N-(cyclopropylmethyl)-3-nitropyridin-2-amine in 36 ml of methanol, were added 700 mg of palladium on carbon at 5%. The reaction mixture was stirred for 3 h at room temperature under hydrogen atmosphere at room pressure. The catalyst was filtrated on Celite and the filtrate was evaporated under vacuum to give 3.1 g of N2-(cyclopropylmethyl)pyridine-2,3-diamine as a solid. Yield: 99.5%.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)([CH3:8])[O:5][C:4]1=[O:19].CN(C)C=O>C(OC(C)C)(C)C>[CH2:2]=[C:3]1[O:7][C:6]([C:9]23[CH2:16][CH:15]4[CH2:17][CH:11]([CH2:12][CH:13]([CH2:14]4)[CH2:18]2)[CH2:10]3)([CH3:8])[O:5][C:4]1=[O:19]
Reactant: CC1(C23CC4CC(CC(C4)C2)C3)OC(=O)C(CBr)O1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
A mixture obtained by dissolving 16.4 g (0.05 mol) of 5-bromomethyl-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one in 58 g of isopropyl ether was placed in a flask equipped with an agitator, a thermometer, a condenser and a dropping funnel. 36.5 g (0.5 mol) of N,N-dimethylformamide was added by drops thereto, followed by intensively stirring at room temperature for 4 hours. After completion of the stirring, insoluble products were removed from the reaction solution by filtration, and the obtained filtrate was transferred into a 500 ml separatory funnel. The solution was left at rest, so as to separate it into two layers, and the lower N,N-dimethylformamide layer was removed. The upper isopropyl ether layer washed with water to remove N,N-dimethylformamide dissolved therein. Thereafter, isopropyl ether was removed, so as to obtain white crystals. The obtained white crystals were recrystallized from hexane, so as to obtain 6.6 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (hereinafter referred to as AdMDO) (yield: 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:8]1[N:9]=[C:10]([C@@H:12]3[CH2:16][C@H:15]([CH3:17])[CH2:14][NH:13]3)[NH:11][C:7]=1[CH:6]=[CH:5]2.[CH3:21][O:22][C:23]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27]([N:13]1[CH2:14][C@@H:15]([CH3:17])[CH2:16][C@H:12]1[C:10]1[NH:11][C:7]2[CH:6]=[CH:5][C:4]3[C:18](=[CH:19][CH:20]=[C:2]([Br:1])[CH:3]=3)[C:8]=2[N:9]=1)=[O:28])[CH:30]([CH3:32])[CH3:31]
Reactant: C[C@@H]1CN[C@H](c2nc3c(ccc4cc(Br)ccc43)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(Br)ccc32)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of 7-bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole (1.05 g, 3.2 mmol; Preparation 12) in DCM (20 mL) was added (S)-2-Methoxycarbonylamino-3-methyl-butyric acid (672 mg, 3.84 mmol), DIPEA (825 mg, 6.4 mmol), and HATU (1.82 g, 4.8 mmol). The reaction mixture was stirred at RT for 4 h and extracted with DCM (3×250 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (1.2 g) (m/z): [M+H]+ calcd for C23H27BrN4O3 487.13, 489.12 found 489.2.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)OCc1ccc2ccccc2c1)C(F)(F)F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, dired (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10](I)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9])[CH3:11]
Reactant: CCI
Reactant: O=C1CSC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CSC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.188 g, 0.00470 mole) was taken in DMF (2.0 ml). Thiazolidine-2,4-dione (0.5 g, 0.00427 mole) in DMF (3 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 1 hr at 50° C. The reaction was then cooled to 0° C., followed by drop wise addition of ethyl iodide (0.41 ml, 0.00512 mole) at 0° C. The reaction mixture was warmed up to RT and stirred for 1 hr. After completion of the reaction, the reaction mixture was poured in water and aq. layer was extracted with ethyl acetate. Organic layers were combined and washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was purified using column purification by eluting the compound with 5% ethyl acetate in hexanes to yield 0.5 g of 3-ethylthiazolidine-2,4-dione.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[C:22]([F:23])=[CH:21][C:10]2[O:11][C:12]([F:20])([F:19])[C:13](=[O:18])[N:14]([CH2:15][C:16]#[CH:17])[C:9]=2[CH:8]=1.[C:24](Cl)(Cl)=[S:25].C(=O)(OCC)N>C(O)C>[F:20][C:12]1([F:19])[O:11][C:10]2[CH:21]=[C:22]([F:23])[C:7]([N:6]=[C:24]=[S:25])=[CH:8][C:9]=2[N:14]([CH2:15][C:16]#[CH:17])[C:13]1=[O:18]
Reactant: S=C(Cl)Cl
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Agent: CCOC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=S)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sodium bicarbonate (4.10 g, 48.8 mmol) was added to a stirred solution of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 1.6 above, 5.0 g, 19.52 mmol) in absolute ethanol (100 ml) at 0° C. under nitrogen. Thereafter thiophosgene (1.795 ml, 23.42 mmol) was added dropwise under ice-bath cooling, keeping the temperature of the reaction mixture below 10° C. After the addition was complete, the reaction mixture was stirred for 1 h at room temperature, by which time, according to TLC analysis, the reaction was complete. The salts were removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to yield 6.55 g of crude product, containing ca. 30% ethyl carbamate. Recrystallisation from dichloromethane afforded 3.84 g of the desired product (>90% purity), which was used without further purification.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([NH:19][S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[O:18])[CH:5]=2.[Li+].[Cl-].[C:28]([O-:31])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([NH:19][S:20]([N:23]([CH3:24])[CH3:25])(=[O:22])=[O:21])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:28]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)[nH]c2c1
Yield: 210.5 %

Procedure:
A mixture of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (950 mg, 2.22 mmol), LiCl (370 mg, 4.44 mmol), tetrakis(triphenylphosphine)palladium(0) (130 mg, 0.11 mmol) in toluene (30 mL) and ethanol (30 mL) containing aqueous 1 N Na2CO3 (15 mL, 15 mmol) was stirred under reflux for 18 hr. The mixture was diluted with ethyl acetate and washed with 1 N HCl (3×) followed by brine (3×). The solution was dried over Na2SO4 and concentrated to dryness to afford the titled compound as a yellow solid (1.06 g, 106%) which contained some triphenyl oxide. The product was used in the following step without additional purification. MS m/z 454 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]([NH2:28])([CH3:27])[CH2:25][NH2:26]>CN(C=O)C>[NH:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[C:2]([NH:26][CH2:25][C:24]([CH3:27])([NH2:28])[CH3:23])[CH:3]=[CH:4][CH:5]=2)=[N:9]1
Reactant: Brc1cccc(-c2n[nH]c3ncccc23)n1
Reactant: CC(C)(N)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(N)CNc1cccc(-c2n[nH]c3ncccc23)n1
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of 3-(6-bromo-2-pyridyl)-1H-pyrazolo[5,4-b]pyridine (50 mg,), potassium carbonate (150.6 mg, 1.09 mmol) and 2-methylpropane-1,2-diamine (40.1 mg, 0.45 mmol) in DMF (0.7 mL) was heated at 150° C. for 24 hours. The mixture was allowed to cool, filtered and the resultant filtrate purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (33.5 mg, 36% Yield).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([CH3:26])[CH:31]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3)c2cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(3-methylisoxazol-5-yl)carbamate (81 mg) were added to toluene (5 ml), diisopropylethylamine (0.88 ml) was added and the mixture was heated and stirred at 100° C. for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate:toluene (1:1) mixed solvent to obtain the title compound (102 mg).