Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:23][CH:21]([CH3:22])[CH2:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(N)CN
Solvent: CCO
Product: CC1CN=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=N1
Yield: 86 %

Procedure:
First, with ethanol as a solvent, 5.31 g of 4,4′-difluorobenzil (by Tokyo Chemical Industry Co., Ltd.) and 1.60 g of 1,2-diaminopropane (by Tokyo Chemical Industry Co., Ltd.) were mixed, and the mixture was refluxed for three hours. After reaction, a reaction solution was condensed by using an evaporator, and an obtained residue was recrystallized by using ethanol; thus, 2,3-bis(4-fluorophenyl)-5-methyl-5,6-dihydropyrazine was obtained (light yellow powder, yield: 86%).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH:18]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Solvent: CN(C)C=O
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][S:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CS(=O)(=O)OC1CCSCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCSCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 257.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)c(N)nc3c2)c1

Procedure:
3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo-[1,2-b]-pyridazin-7-yl]-N-methyl benzamide (1 eq, 0.146 mmol, 79 mg) and phenyl boronic acid (1.5 eq, 0.219 mmol, 27.5 mg) are dissolved in DME (1.5 ml) and water (0.4 ml) and Na2CO3 (3 eq, 0.438 mmol, 46.4 mg) are added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.12 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-(2-Amino-3-(2-phenyl-pyridin-4-yl)imidazo [1,2-b]pyridazin-7-yl]-N-methyl-benzamide as a yellow solid; [M+H]+=421
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)CC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(O)ccnc2c1
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: COc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 7-methoxyquinolin-4-ol (5.0 g, 28.5 mmol) and propionic acid (50 mL) was heated to reflux. Nitric acid (3.2 mL of 70%, 50 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was refluxed for 2 hrs and then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with cold ethanol followed by hexanes and then dried to provide 3.9 g of 7-methoxy-3-nitroquinolin-4-ol as a gray solid.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:11][C:12]1[C:21]([N+:22]([O-])=O)=[C:20]([NH:25][CH2:26][C:27]#[CH:28])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(O)C.C(#N)C>[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:25][CH2:26][C:27]#[CH:28])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: C#CCNc1c(N)c(Cl)nc2ccccc12
Yield: 62 %

Procedure:
An aqueous solution (1.5 L) of sodium dithionate (265 g, 1.52 mol) was added to a solution of 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine (79.3 g, 0.303 mol) in ethanol (750 mL) and acetonitrile (950 mL). A fine white precipitate formed within seconds. The reaction was worked-up after thin layer chromatography (TLC) analysis of the reaction mixture indicated that the reaction was complete. The solids were removed by filtration and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure to remove the volatiles, leaving an aqueous solution that was extracted with several portions of dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield 2-chloro-N4-prop-2-ynylquinoline-3,4-diamine (43.5 g) that was approximately 60% pure and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[O:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2cc(Cl)cc(B(O)O)c2O1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2OC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 5-chloro-2,2-dimethylbenzodioxolan-7-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(5-chloro-2,2-dimethylbenzodioxolan-7-yl)pyridine.
Reaction SMILES: CC[O:3][C:4]([C:6]1([CH3:17])[N:10]([C:11](=[O:13])[CH3:12])[CH:9]([C:14]([OH:16])=[O:15])[CH2:8][S:7]1)=[O:5].[OH-].[Na+]>C(O)C>[C:11]([N:10]1[CH:9]([C:14]([OH:16])=[O:15])[CH2:8][S:7][C:6]1([CH3:17])[C:4]([OH:5])=[O:3])(=[O:13])[CH3:12]
Reactant: CCOC(=O)C1(C)SCC(C(=O)O)N1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1C(C(=O)O)CSC1(C)C(=O)O
Yield: 72 %

Procedure:
The crude product (10.19 g) of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, which was obtained by a method similar to that in Synthetic Example 13, was dissolved in ethanol (20 ml), and 4N NaOH was added thereto. The mixture was stirred under an argon atmosphere, and ethanol was added thereto to give a pale-yellow solid. The obtained solid was collected by filtration to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2Na salt (trans form) as crystals (9.09 g, about 72%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].C(N(C(C)C)CC)(C)C.O>C1COCC1>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)C[C@H](C)N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](C)CC(=O)OC
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of methyl (3S)-3-aminobutanoate (1.47 g, 12.5 mmol) in THF (30 ml) were added at 0° C. allyl chloroformate (1.60 ml, 15.1 mmol) and diisopropylethylamine (2.62 ml, 15.0 mmol), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and extracted twice with ethylacetate. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give methyl (3S)-3-{[(allyloxy)carbonyl]amino}butanoate (2.06 g, 81%).
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].P(=O)(O)(O)O>>[CH2:1]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1(O)CCCCC1
Agent: O=P(O)(O)O
Product: CC(C)CC1=CCCCC1
Temperature: 145 °C
Yield: 253.2 %

Procedure:
In a flask equiped with a Vigreux-distillation apparatus, crude 1-isobutylcyclohexanol (200 g, 1.28 mol) was treated with phosphoric acid (100 g) and heated at 145° C. under vacuum (170 mbar). While 1-isobutylcyclohex-1-ene and water distilled (boiling point 60° C.), a second fraction of 1-isobutylcyclohexanol (492 g, 3.15 mol) was added dropwise in the reaction flask. At the end of the addition, the thick reaction mixture was diluted with paraffin oil (100 ml) and additional phosphoric acid (50 g) and heated further (vacuum from 170 to 40 mbar). The distillate was decanted and the water phase extracted with pentane (100 ml). The combined org. phases were dried (MgSO4) and the solvent evaporated to give 1-isobutylcyclohex-1-ene (448 g, 78%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[OH-].[Na+]>C(O)=O>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCCC2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A solution of 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.00 g) and 37% HCHO (6.0 mL) in HCO2H was heated to 90° C. and stirred for 4 h. The reaction mixture was cooled to rt and poured into ice-water. The mixture was adjusted to pH 10 with 2M NaOH aqueous solution and extracted with CH2Cl2 (70 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as pale yellow oil (0.95 g, 45.00%), HPLC: 85.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 231.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[C:7]([CH3:22])[C:8]([C:12]([CH:14]3[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]3=[O:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:24])(=[O:23])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(Cl)Cl>[C:33]1([C:32]([O:20][C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:21])[C:14]=2[C:12]([C:8]2[C:7]([CH3:22])=[C:6]3[C:11]([C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][S:5]3(=[O:24])=[O:23])=[CH:10][CH:9]=2)=[O:13])=[O:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(C(=O)C2C(=O)CCCC2=O)ccc2c1S(=O)(=O)CCC2(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)C2=C(OC(=O)c3ccccc3)CCCC2=O)ccc2c1S(=O)(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 g (2.2 mmol) of 2-(4,4,8-trimethyl-1,1-dioxothiochroman-7-yl)carbonyl-1,3-cyclohexanedione was dissolved in 10 ml of methylene chloride, and 0.17 g (2.2 mmol) of pyridine and 0.31 g (2.2 mmol) of benzoyl chloride was added. The mixture was stirred at room temperature for 2 hours, water was added, and the organic phase was separated off, extracted with 2 N hydrochloric acid and dried. The solvent was subsequently distilled off and the residue was chromatographed over silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C-]#N.[Na+].[CH3:15][N:16](C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CS(=O)(=O)c1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(Cl)n1
Temperature: 170 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of 2-chloro-6-methylsulfonylpyridine (13.0 g, 67.8 mmol), sodium cyanide (6.69 g, 136 mmol) and DMF (150 ml) was stirred at 170° C. for 18 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v) to give 2-chloro-6-cyanopyridine (6.67 g, 71%) as crystals (mp. 82.9-83.1° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1)(=[O:28])=[O:27]
Reactant: CN1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 419 %

Procedure:
3,4-Dihydro-6-amino-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (5.6 g, 0.0027 mol) was stirred in methylene chloride (50 ml) and pyridine (16 ml) at room temperature under a nitrogen atmosphere as methanesulfonyl chloride (2.7 ml, 0.035 mol) was added dropwise over several minutes. Some gum separated so additional pyridine (25 ml) was added. The mixture was stirred at ambient temperature for 16 hours. The methylene chloride and pyridine were removed in vacuo and the residue was taken up in saturated NaHCO3 (150 ml) and methylene chloride (150 ml). The methylene chloride layer was separated and the aqueous phase was again extracted with methylene chloride. The combined extracts were washed with sodium bicarbonate, dried filtered and concentrated in vacuo. The residual mixture was chzomatographed on silica gel (500 g) using 15% methanol/chloroform to yield 3.67 g (50%) of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH2:42][CH2:43][OH:44]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH2:42][CH2:43][OH:44])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: NCCO
Solvent: CCO
Product: CN(CCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.036 mmol) and 2-aminoethanol (13 μL, 0.22 mmol) were combined in EtOH (2 mL) and heated for 15 min. at 125° C. in a microwave vessel. Additional 2-aminoethanol (50 μL, 0.84 mmol) was added and the reaction was heated at 150° C. for 20 min. The mixture was evaporated in vacuo and partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, evaporated in vacuo and triturated with Et2O to provide the product as a white solid: 1H NMR (d6-DMSO) δ 10.37 (1H, b), 8.54 (1H, s), 7.93-8.03 (1H, m), 7.17-7.40 (7H, m), 7.11 (2H, t, J=9 Hz), 4.89-5.09 (3H, m), 4.12-4.22 (4H, m), 3.52-3.58 (2H, m), 3.40-3.45 (2H, m), 3.29 (3H, s), 2.81-2.88 (2H, m), 1.78 (b, 2H); ES+ MS: 563 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 92.8 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)-methylidene]-cyclopentane-1,3-dione (0.14 g, 0.44 mmol) in methanol (3 ml) is added 10% palladium on carbon (1.5 mg), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(4-fluoro-2,6-dimethylphenyl)-4-[tetrahydropyran-4-ylmethyl)-cyclopentane-1,3-dione (0.13 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:37]([CH3:39])[CH3:38])[C:12]([C:14]1[NH:15][C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Br:36])=[N:17][C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:37]([CH3:39])[CH3:38])[C:12]([C:14]1[NH:15][C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Br:36])=[N:17][C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
5-Benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (69) (0.75 g, 1.22 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (10 ml). HCl (915 μl, 1.83 mmol, Eq: 1.5) was added and the resulting mixture was stirred at room temperature. After 30 minutes the solvent was mostly removed. The residue was partitioned between ethyl acetate and 1M NaOH. The aqueous layer was washed with ethyl acetate, the organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated. The remaining brown oil was triturated in ethyl acetate/ether. The solid was collected by filtration, washed with a little ethyl acetate and dried to afford 5-benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (70) (0.21 g, 420 μmol, 34.4% yield) as an off-white solid. The mother liquor also showed clean product (0.43 g, 68% yield) of brown solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16](=O)[CH3:17].[CH3:19][CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:29]=1)=[O:24])[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH:33][C:16](=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=3)[N:5]=[C:4]2[CH3:15])[CH3:17])=[O:31])=[CH:28][CH:29]=1)=[O:24])([CH3:21])[CH3:19]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Reactant: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)NC(C)C)s1
Temperature: 90 °C
Yield: 43 %

Procedure:
1-(5-Hydroxy-3-methyl-1-(3,4-dimethylphenyl)-1H-pyrazol-4-yl)-ethanone (30 mg, 0.123 mmol, synthesized in accordance with patent document 25), 5-hydrazinocarbonyl-thiophene-2-carboxylic acid 2-propylamide prepared in Reference Synthetic Example 1 and p-toluenesulfonic acid monohydrate (2 mg) in isopropanol (1 mL) were heated at 90° C. overnight under reflux. After cooling, chloroform-ether was added, and the resulting crystals were collected by filtration, washed with chloroform-ether and dried to give 24 mg of the desired product (yield 43%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:48][O:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:46][O:47][CH2:48]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Yield: 73.5 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amide (362) (290 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammoniumfluorid (1M in tetrahydrofuran, 1.3 mL, 13 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1.5 h (silica TLC, ethyl acetate:hexane=1:1/SiO2/UV, Rf=0.3.) The tetrahydrofuran was removed in vacuum and the crude mass was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and brine (25 mL). The organic phase was thereafter dried and concentrated in vacuum to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to obtain pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (363) (175 mg, 73%) as a white solid.