Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>CN(C=O)C>[C:24]([NH:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:31]([OH:33])=[O:32])[NH2:18])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 210 %

Procedure:
The compound obtained in Example 23-1 (250.8 mg) was dissolved in DMF (5 ml). After the addition of diethylamine. (0.5 ml), the mixture was stirred for 2 hours at room temperature. After the reaction, the solvent was removed by distillation under reduced pressure and the residue was dried under vacuum to obtain the title compound (269.1 mg).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=[N:13]4)[N:10]=[C:9](S(O)(=O)=O)[C:8]=2S(O)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na][Na]>>[C:1]1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=[N:13]4)[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1nc2c(ccc3c(-c4ccccc4)ccnc32)c(-c2ccccc2)c1S(=O)(=O)O
Agent: [Na][Na]
Product: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1

Procedure:
4, 7-Diphenyl-1, 10-phenanthrolinedisulfonic acid, disodium salt
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH3:30])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
According to Scheme 7 Step 5: To a solution of 2-(3-acetamidophenyl)-4-(4-chlorobenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 11(D) (80 mg, 0.19 mmol) in MeOH (3 mL) was added dropwise at 0° C. a solution of trimethylsilyldiazomethane 2M (1.3 mL, 2.70 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with 100 mL of a saturated solution of NaHCO3 and the aqueous layer was extracted twice with 100 mL of DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel (AIT Flashmart prepacked column 7 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford a yellow solid. The solid was further triturated with diisopropylether and filtered to afford methyl 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (35 mg, 42%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:30][C:29]2[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:33][CH:32]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-methylsulphonylbenzyl bromide analogous to Example 1 to afford 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-(4-methanesulfonylbenzyl)-benzenesulfonamide: MS: m/e=507.2 (MH+), 524.1(MNH4+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:4](=[O:3])[CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccccc1C=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: COc1ccccc1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(trifluoromethoxy)phenyl)methanamine and commercially available 2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions H): tR=1.37 min.; [M+H]+: 379.75 g/mol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]=[CH2:16].[K].[C:19]([CH:27]=[C:28](O)[CH3:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>C(O)C>[C:19]([CH:27]=[C:28]([NH:2][CH2:3][CH:4]([OH:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]=[CH2:16])[CH3:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: CC(O)=CC(=O)c1cccnc1
Reactant: C=CCOc1ccccc1OCC(O)CN
Agent: Cl
Agent: [K]
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CNC(C)=CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.1 g of 1-amino-3-(o-allyloxyphenoxy)-propan-2-ol hydrochloride ##STR30## are suspended in 50 ml of ethanol, 4 g of the potassium salt of 2-nicotinoyl-1-methyl-vinyl alcohol ##STR31## are then added and the mixture is stirred for 24 hours at room temperature. The suspension is filtered off and the residue is washed with ethanol. The filtrate, together with the wash alcohol is concentrated in vacuo. An oil is left, which solidifies after a short time. The oil which has solidified, together with the residue left on washing with alcohol, is repeatedly triturated with water and then recrystallised from ethanol. 1-(2-Nicotinoyl-1-methyl-vinylamino)-3-(o-allyloxyphenoxy)-propan-2-ol of the formula ##STR32## is thus obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)=[CH:28][CH:27]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(-c2ccc(F)cc2)n1
Yield: 48.1 %

Procedure:
A mixture of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (150 mg, 0.43 mmol), 4-fluorobenzeneboronic acid (67 mg, 0.48 mmol), tetrakis-(triphenylphosphin)-palladium (20 mg, 0.02 mmol) and sodium carbonate (92 mg, 0.87 mmol) in 3 ml of dioxane was refluxed overnight. The mixture was diluted with water, extracted with ethyl acetate and purified by chromatography on silica gel using ethyl acetate as an eluent to give the title compound as a colorless solid (84 mg, yield=47%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][CH2:24][OH:25])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[C].[Pd]>[OH:25][CH2:24][CH2:23][C:19]1[N:18]([CH2:17][CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][N:20]=1
Reactant: OCCc1nccn1CCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Product: OCCc1nccn1CCCc1cccc(O)c1
Yield: 95.4 %

Procedure:
Using 2-(1-{3-[3-(benzyloxy)phenyl]propyl)-1H-imidazol-2-yl)-1-ethanol (2.42 g) and 10% palladium carbon (0.24 g), the same reaction as Reference Example 11-(v) was carried out to yield the titled compound (1.69 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-dichlorophenol and 4-fluoro-benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])(=O)C.[Na+].[N+:15]([C:18]1[CH:27]=[CH:26][C:21](/[CH:22]=[CH:23]/[CH:24]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]=[CH:24][CH:23]=[CH:22][C:21]2[CH:26]=[CH:27][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)nc(C=CC=Cc2ccc([N+](=O)[O-])cc2)c1
Yield: 50.6 %

Procedure:
2,4,6-Trimethylpyridine (2.24 mL, 16.9 mmol) and sodium acetate (0.92 g, 11.3 mmol) were added to a solution of trans-4-nitrocinnamaldehyde (1.0 g, 5.64 mmol) in acetic anhydride (20 mL). The reaction mixture was refluxed for 8 h, then brought to room temperature and quenched with 5% sodium bicarbonate solution (40 mL). The compound was extracted with ethyl acetate and the organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using 30% ethyl acetate in hexane as eluent to afford 2,4-dimethyl-6-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-pyridine (800 mg, 51%) as a yellow solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c(=O)c(C#N)c(O)c2ccccc21
Product: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Yield: 41 %

Procedure:
In 10 ml of phosphorus oxychloride was refluxed 1.0 g (4.1 mmol) of 1,2-dihydro-4-hydroxy-1-propyl-2-oxo-3-quinolinecarbonitrile for 1 hour. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure to obtain 0.44 g (41%) of the titled compound as a yellow crystal.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:24].[H][H]>[C].[Pd].C(O)C>[ClH:24].[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCNC2)cc1
Reaction time: 4.5 h

Procedure:
A mixed solution obtained by mixing 3.0 g of 100% pure (R)-1-benzyl-3-p-toluenesulfonyloxypyrrolidine with 3.0 ml of ethanol and adding dropwise 0.80 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 150 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 4.5 hours. Hydrogen absorption came to an end in 2.5 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 4 to give 2.51 g (yield: 86 mole percent) of (R)-3-p-toluenesulfonyloxypyrrolidine hydrochloride.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:27][C:16]1[C:17]([O:19][C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: Cc1ncccc1Oc1cc(NC(=S)NC(=O)c2ccccc2)ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ncccc1Oc1cc(NC(N)=S)ncc1Br
Temperature: 40 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
1-Benzoyl-3-(5-bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-yl)thiourea (2.8 g, 6.3 mmol) and potassium carbonate (0.57 mL, 9.5 mmol) were diluted in ethanol (50 mL). The reaction was stirred at 40° C. for 5 hours, then concentrated and purified using silica gel column chromatography (eluting with ethyl acetate) to give the title compound (1.58 g, 74% yield) as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][C:20](=O)[CH2:21][CH3:22])[C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:19][C:20]([CH2:21][CH3:22])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[C:9]2=[O:18])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CCC(=O)CN(C(=O)Cc1cccc(F)c1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1=C(c2cccc(F)c2)C(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1
Yield: 85 %

Procedure:
2.38 g (5.92 mmol) of N-(4-chloro-3-trifluoromethyl-phenyl)-N-(2-oxobutyl)-3-fluorophenylacetamide prepared in the same manner as in Example 3 were dissolved in 10 ml of ethanol, and 0.25 ml of a 10% aqueous sodium hydroxide solution was added at room temperature with stirring. The solution was stirred at the same temperature for 1 hour, and the reaction mixture was then poured into water, followed by extraction with ethyl acetate. Afterward, the resultant organic layer was dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The precipitated crystals were collected by filtration, and then washed with n-hexane to obtain 1.93 g of the desired product in the state of colorless crystals (yield 85.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH2:24][CH3:25])=[CH:18][C:17]=2[F:26])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][CH2:24][CH3:25])=[CH:18][C:17]=1[F:26]
Reactant: CCOc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1cc(F)c(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
0.25 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-ethoxyphenyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (stationary phase: silica gel, developing solvent: hexane/ethyl acetate=3/1), to obtain 0.16 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-ethoxyphenyl)-6-methylpyridazine (hereinafter, referred to as compound (vi) of the present invention).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:20])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:20][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1[C@H]1CC[C@@H](F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (3.2 g) in CH2Cl2 (10 mL) at −30° C., add 2.75 mL of DAST dropwise. Allow the resulting mixture to warm up to room temp and stand for 1 h. To the solution, add 10 mL of 5% aq NaHCO3 and allow to stand at room temp for 1 h. Extract the aqueous layer by CH2Cl2 twice (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography to yield 2.05 g of the title compound: mass spectrum (m/z): 186 (M+1).
Reaction SMILES: C(C1C=CC(NC([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH3:27])=O)=CC=1)(CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH3:27])=[O:38])=[CH:34][CH:35]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(C)c1ccc(NC(=O)N2CCN(c3ncccc3Cl)C[C@H]2C)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve Part A material of example 1 (0.2756 g, 1.3 mmoles) in toluene (1.5 mL) under nitrogen at room temperature. Add drop wise 4-trifluoromethylphenyl isocyanate (0.2431 g, 1.3 mmoles) dissolved in toluene (50 mL) to the mixture over a period of 30 mins and stir at room temperature for 3 hours. Evaporate the solvent from reaction mixture under vacuum to afford colorless oil. Crystallize the oil from 1:1 Et2O/hexane (2.0 mL) to afford white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2cc(Nc3ccc4[nH]ccc4c3)nnc2-c2ccccc2)cc1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-(4-tert-butylphenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (95 mg, 0.3 mmol) and 5-aminoindole (39 mg, 0.3 mmol, Aldrich) afforded the title compound as a light-yellow crystalline solid. MS (ESI, pos. ion) m/z: 419 (M+1). MP: 138-140° C.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:25])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.I[CH2:27][CH3:28]>O>[CH2:27]([N:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:13]2[CH:14]=[CH:15][C:10]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=[N:2]3)=[CH:11][CH:12]=2)[C:17]1=[O:25])[CH3:28]
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(-n2ncc3cccnc32)cc1
Reactant: CCI
Solvent: O
Product: CCn1c(=O)n(-c2ccc(-n3ncc4cccnc43)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) and iodoethane (10.5 μl) was stirred at 50° C. for 30 min, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with Hexane/AcOEt=2/1-1/2. The product was crystallized from AcOEt/hexane to give 1-ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (13 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5][C@:4]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([O:13][CH3:14])[CH2:3]1.[CH3:30]/[C:31](/[CH2:36][CH2:37][CH:38]=[CH2:39])=[CH:32]/[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:14][O:13][C@:4]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:3][C@H:2]([NH:1][C:33](=[O:34])/[CH:32]=[C:31](/[CH3:30])\[CH2:36][CH2:37][CH:38]=[CH2:39])[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5]1
Reactant: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCC/C(C)=C\C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.6 %

Procedure:
A solution of the title compound from Example 67 (155 mg, 0.368 mmol) in dichloromethane (5 mL) was treated with the title compound from Example 21 (58 mg, 0.42 mmol), HOBT (65 mg, 0.42 mmol), and EDC (78 mg, 0.41 mmol), and the mixture was stirred at room temperature for 4 days. The mixture was then concentrated and the residue was chromatographed on silica, eluting with ethyl acetate/hexanes, which afforded the title compound (133 mg, 67%) as a crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:40])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:40])=[O:35])[O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (1.53 g, 3.17 mmol) in THF (28 mL) was added NaIO4 (1.36 g, 6.34 mmol) followed by the addition of water (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then filtered through celite, and concentrated in vacuo. The residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo. To the intermediate aldehyde (˜1.4 g) was added 2-methylpropan-2-ol (17 mL) and 2-methylbut-2-ene (9 mL, 85.08 mmol) and the reaction mixture was cooled to 0° C. A solution of NaClO2 (938 mg, 8.29 mmol) and NaH2PO4 (1.15 g, 8.31 mmol) in water (17 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, then extracted with ethyl acetate (4×50 mL) and the combined organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo to give 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid as a white foam (1.48 g, 100%). ESI-MS m/z calc. 466.6. found 467.5 (M+1)+; Retention time: 1.27 minutes (3 min run).