Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2].[H-].[Na+].C(C1C(C)=[C:29]([O:32][C:33](C2CC2)=[O:34])C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14][C:33]([O:32][CH3:29])=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(F)c(Cl)c2c(O)c1C
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2ccc(F)c(Cl)c2c(OC(=O)OC)c1C
Reaction time: 1 h

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoroquinoline (1.5 g) prepared as described in Example 7 was dissolved in 70 ml of methanol. To this solution was added 30 ml of a 10% aqueous sodium hydroxide solution. The mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.17 g of 0.2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 15 ml of dimethyl formamide was suspended 40.1 mg of 60% sodium hydride. Separately, 200 mg of 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) prepared above was suspended in 2 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 78.5 mg of methyl chloroformate (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated, brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 218.8 mg of 2-ethyl-3-methyl-4-methoxycarbonyloxy-5-chloro-6-fluoroquinoline (compound 36). 1H-NMR data are shown in Table 3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)nc1

Procedure:
N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (50 mg, 0.196 mmol, Description 3), copper(I) iodide (41.0 mg, 0.215 mmol), 2-bromo-5-methylpyridine (33.7 mg, 0.196 mmol), Cs2CO3 (191 mg, 0.587 mmol) and N,N-dimethylglycine (24.23 mg, 0.235 mmol), in dimethyl sulfoxide (2 ml) were heated under microwave conditions for 30 minutes at 190° C. The reaction mixture was partitioned between EtOAc (10 ml) and water (5 ml). Aqueous was further extracted with DCM (10 ml). The organic solution was dried (Na2SO4) and evaporated under reduced pressure to yield the impure product as a dark brown oil. The product was purified by reverse phase chromatography using MDAP to give the title compound as a solid (17 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:33])[C@@H:11]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([C@H]([C@H](O)COCC1C=CC=CC=1)C(O)=O)=[N+]=[N-].[Sn](Cl)Cl>CO>[CH2:1]([O:8][CH2:9][C@H:10]([OH:33])[C@@H:11]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](O)COCc3ccccc3)cc2)cc1
Agent: Cl[Sn]Cl
Agent: [N-]=[N+]=N[C@@H](C(=O)O)[C@H](O)COCc1ccccc1
Solvent: CO
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@@H](O)COCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,3S)-4-Benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid. To a solution of (2R, 3S)-2-azido-4-benzyloxy-3-hydroxy-butyric acid (50 mg) in methanol (1 mL) is added tin (II) chloride (60 mg) and the reaction mixture is stirred at room temperature for 2 hr. The volatiles are removed under vacuum and the residue is dissolved in dioxane-water (1.6 mL, 1:1, v/v). To the mixture is added triethylamine (0.1 mL) and (4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl chloride (110 mg) and the mixture is stirred at room temperature for 10 hr. The volatiles are removed under vacuum and the residue is treated with methanol (3 mL) and acetic acid (1 mL). The precipitate is filtered off, the filtrate is concentrated and a crude product is purified using RF HPLC to give (2R,3R)-4-benzyloxy-3-hydroxy-2-(4′-methoxy-biphenyl-4-sulfonylamino)-butyric acid as a white, crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Yield: 59.3 %

Procedure:
A solution of 1.25 g (3.15 mmol) of Compound 18 obtained in Example 17 and 40 mg (0.32 mmol) of iodine in 125 ml of toluene was heated under reflux for 6.5 hours. After cooling, a 0.1M aqueous solution of sodium thiosulfate and chloroform were added thereto, followed by stirring. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 740 mg (yield 59%) of Compound 19 as ocher needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])[C:11]([N+:25]([O-])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([OH:30])C>[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[C:11]([NH:25][C:28](=[O:30])[N:14]3[CH2:15][C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C(=O)CNc1nc(-c2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Reactant: CCO
Agent: O=[Pt]=O
Product: CCCN(CCC)C(=O)Cn1c(=O)[nH]c2cnc(-c3ccc(Cl)cc3)nc21
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(4-chlorophenyl)-5-nitro-4-pyrimidinylamino]-N,N-dipropylacetamide (9 g), platinum (IV) oxide (1 g) and ethanol (150 ml) is stirred under hydrogen atmosphere for four hours, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and to the resulting residue is added urea (2.1 g). The mixture is stirred at 200° C. for two hours. After cooling, water is added to the reaction mixture, and the precipitates are collected by filtration, washed with water, and recrystallized from ethanol to give the desired compound (7 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[C:14]#[N:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>O>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[C:14]([NH2:15])=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54.8 %

Procedure:
A solution of 8.9 parts of intermediate 13, namely 5-benzoyl-2-nitrobenzonitrile, 166 parts of sulfuric acid and 10 parts of water was heated at 90° C. for 13/4 hours. The reaction mixture was poured into ice-water. The precipitate was filtered off and recrystallized from methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 60°-70° C., yielding 5.23 parts (54.8%) of 5-benzoyl-2-nitrobenzamide; mp. 244.3° C. (intermediate 14).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:23][C:24]([NH:26][CH3:27])=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]=[C:24]1[N:26]([CH3:27])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC(=S)NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCOCC
Product: CN1C(=NCc2ccccc2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.7 g of 1-benzyl-3-methylthiourea were reacted as prescribed in Example 23 and the reaction mixture was introduced into 200 ml of diethyl ether while stirring. The hygroscopic crystals of the 2-benzylimino-4-(4-chloro-3-sulfamoylphenyl)-3-methyl-1,3-thiazolidine-4-ol-hydrobromide were rapidly filtered off, dissolved in 70 ml of water and converted into the end product according to the prescription of Example 28. Colorless solid body: decomposition beginning at 110° C., γC=N 1610 cm-1.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH:5]1[OH:13])([OH:3])=[O:2].[N:14]([O-])=[O:15].[Na+]>Cl>[C:1]([CH:4]1[N:9]([N:14]=[O:15])[CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH:5]1[OH:13])([OH:3])=[O:2]
Reactant: O=C(O)C1NCc2sccc2C1O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: O=NN1Cc2sccc2C(O)C1C(=O)O
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a magnetically stirred suspension of 20 g (0.1 mole) 5-carboxy-4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in 200 cc 3 N hydrochloric acid maintained at 10° C. is added dropwise a 10% aqueous sodium nitrite solution (200 cc; 2.9 equivalents) and the resulting mixture is stirred at room temperature for 3 hours. The reaction medium remains heterogeneous throughout this step and nitrous fumes are evolved. The resulting precipitate is filtered off, washed with water and dried in vacuo, to give beige crystals (paste melting from 100° C.) in a yield of 21.3 g (93%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C1(CCO)C=CC=CC=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:38])([F:40])[F:39])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OCCC1CC1
Solvent: OCCc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCC3CC3)nn2)CC1

Procedure:
Following the procedure set forth above in Example 5, only making variations using 2-cyclopropylethanol to replace 2-phenylethanol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (56 mg, 74.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.72, 7.60-7.63, 7.52-7.56, 7.35, 7.03, 6.87, 4.46, 3.91-3.98, 3.55, 3.46-3.50, 3.31, 1.68, 0.79-0.84, 0.43-0.46, 0.11-−0.79.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][O:13][CH2:14][CH2:15]Br.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:15][CH2:14][O:13][CH3:12])[CH:2]=[O:1]
Reactant: COCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1OC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a flask was added vanillin (3.28 g, 21.6 mmol) and 2-bromoethyl methyl ether (3.04 mL, 1.5 equiv) in a solution of DMF (20 mL). K2CO3 (5.5 g, 2 equiv) was then added to the solution and the reaction slurry was stirred at 90° C. for 16 h under N2. The reaction solution was diluted with EtOAc (100 mL), filtered, washed with sat NH4Cl, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was chromatographed (SiO2, Hex/EtOAc 100:D to 70:30) to afford the intermediate compound.
Reaction SMILES: [Li+].[OH-].Br[C:4]1[N:9]=[C:8]([NH:10][C:11]([C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:14]=2)=[O:12])[CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH2:16]([NH:15][C:4]1[N:9]=[C:8]([NH:10][C:11]([C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:14]=2)=[O:12])[CH:7]=[CH:6][CH:5]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Yield: 123.1 %

Procedure:
LiOH (120 mg, 5 mmol) was added to a solution of ethyl 5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate 3 (1.1 g 3.4 mmol) in THF/H2O (1:1, 5 ml). The reaction mixture was stirred over night. The clear solution was concentrated, and suspended in chloroform (25 ml), The solid was filtered off and dried under vacuum to give 5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 4 (987 mg, 99%) as a white solid. Mp. 188-190° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[C:30]([Br:32])[C:29]([OH:33])=[C:28]([Br:34])[CH:27]=1>C(OCCO)C>[Br:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[C:28]([Br:34])[C:29]=1[OH:33]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cc(Br)c(O)c(Br)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(Br)c(O)c(Br)c3)c2cc1OC
Yield: 89.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:13][CH3:14])[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([C:4]=1[CH3:3])[C:10]([OH:12])=[O:11]
Reactant: COc1cccc(C)c1C(=O)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of bromine (102 ml, 2.0 mol) and acetic acid (225 ml) is added to a mixture of 50A (304.0 g, 1.8 mol),), sodium acetate (164.0 g, 2.0 mol) and acetic acid (3.0 l) at a temperature of 10 to 15° C. The reaction mixture is stirred at room temperature for 16 hours. The solid material is collected by vacuum filtration, washed with water and dried yielding off-white crystals 321.0 g (72.6.%), mp 81-83° C.
Reaction SMILES: [OH:1][CH:2]([CH2:39][N:40]1[C:49]([CH3:51])([CH3:50])[CH2:48][C:43]2([O:47][CH2:46][CH2:45][O:44]2)[CH2:42][C:41]1([CH3:53])[CH3:52])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][C:25]3([CH3:37])[CH3:36])[CH2:16][CH2:15]2)([CH3:13])[CH3:12])[CH2:7][CH2:6]1.[C:54](SC1SC2C=CC=CC=2N=1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1C=CC=CC=1>[C:54]([O:1][CH:2]([CH2:39][N:40]1[C:41]([CH3:53])([CH3:52])[CH2:42][C:43]2([O:47][CH2:46][CH2:45][O:44]2)[CH2:48][C:49]1([CH3:51])[CH3:50])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][CH:22]([O:38][C:54](=[O:61])[C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:23][N:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:26][C:25]3([CH3:37])[CH3:36])[CH2:16][CH2:15]2)([CH3:12])[CH3:13])[CH2:7][CH2:6]1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(Sc1nc2ccccc2s1)c1ccccc1
Reactant: CC(C)(C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1)C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1
Solvent: c1ccccc1
Product: CC(C)(C1CCC(OCC(CN2C(C)(C)CC3(CC2(C)C)OCCO3)OC(=O)c2ccccc2)CC1)C1CCC(OCC(CN2C(C)(C)CC3(CC2(C)C)OCCO3)OC(=O)c2ccccc2)CC1

Procedure:
1.5 g of 2,2-bis{4-[2-hydroxy-3-(7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)propoxy]cyclohexyl}propane and 1.2 g of 2-benzoylthiobenzthiazole were refluxed in 30 ml of anhydrous benzene for 4.5 hours. After completion of the reaction, the reaction mixture was treated with an aqueous alkali and then extracted with benzene, giving crystals. The crystals were purified by column chromatography through silica gel eluted with a 4:1 by volume mixture of diethyl ether and ethyl acetate. The desired Compound No. 222 was obtained in the form of a white powder melting at 77°-79° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.N1C=CC=CC=1.S(Cl)([Cl:36])=O>C1(C)C=CC=CC=1.O>[Cl:36][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(CO)CC2)CC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(CCl)CC2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
The compound (41) (7.4 g), toluene (100 ml) and pyridine (0.5 ml) were put in a reaction vessel under a nitrogen atmosphere, and the mixture was stirred at 45° C. for 1 hour. Then, thionyl chloride (1.7 ml) was added in the temperature range of 45° C. to 55° C., and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate twice and with water three times, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 7.3 g of 4-chloromethyl-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-cyclohexane (42). The yield based on the compound (41) was 94.1%.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:24]=CC.N1C=CC=CC=1.Cl.O1CCOCC1>ClCCCl.C(O)(=O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:11](=[O:12])[C:4]2[C@@H:5]3[C:8]([CH3:10])([CH3:9])[C@@:2]([CH3:1])([CH2:7][CH2:6]3)[C:3]=2[NH:24]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC=NNc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 5.4 g, 25.15 mmol) in 1,2-dichloroethane (60 mL) was added over a period of 1 min to a cooled (0° C.) solution of N-(2,4-difluoro-phenyl)-N′-ethylidene-hydrazine (Intermediate 26; 3.92 g, 23.04 mmol) and pyridine (2.9 mL, 35.9 mmol) in 1,2-dichloroethane (30 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 40 min. The reaction mixture was cooled, and a solution of HCl in dioxane (4 M, 18 mL, 72 mmol) was added. The solution was stirred for 5 min at room temperature and then glacial acetic acid (30 mL) was added. The reaction mixture was stirred at 100° C. for 45 min. The solvent was evaporated and dichloromethane (200 mL) was added. The solution was washed with 50% saturated brine (2×50 mL), and the combined aqueous layers were back-extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL), dried (magnesium sulfate), filtered, evaporated and eluted through a plug of silica gel with 30% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (3.2 g, 45%) as an orange gummy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[CH:10]([CH3:9])[CH2:11][CH2:12][C:13]2=[O:14]
Reactant: Fc1ccc(F)cc1
Reactant: O=C1CCCCO1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CCC(=O)c2c(F)ccc(F)c21
Temperature: 110 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with □-valerolactone (4 ml, 42 mmol) and AlCl3 (28 g, 210 mmol) was added by portions to the stirred reaction mixture. The reaction mixture was then refluxed at stirring for 16 h (oil bath 110° C.). The reaction mixture was cooled down (ice/brine bath) and ice/conc. HCl was added and stirred until homogeneous mixture was obtained. The reaction mixture was then extracted into methylene chloride, washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml). The organic extract was dried over Na2SO4. Concentration by rotary evaporation gave 6.7 g of product as yellow powder. Yield 81%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CN(C)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)c1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a mixture of 306 mg (purity: 99.0%; 1.84 mmol) of 4-hydroxy-3,6-dichloropyridazine and 830 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added dimethylaniline (2.76 g) and 331 mg (5.62 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 381 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.