Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[C:7](=[O:11])([O:9][CH3:10])[NH2:8].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:10][O:9][C:7]([NH:8][C:2](=[CH2:4])[C:1]([OH:6])=[O:5])=[O:11]
Reactant: COC(N)=O
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=C(NC(=O)OC)C(=O)O
Reaction time: 2 h

Procedure:
A solution pyruvic acid (4.40 g, 50.0 mmol), methyl carbamate (3.75 g, 50.0 mmol), hydroquinone (used for a polymerization inhibitor, 0.05 g), and p-toluene sulfonic acid (50 mg) in 30 ml benzene is refluxed in a 100 ml round bottom flask to which is attached a Dean-Stark trap. The system is exposed to air during the reaction. After 2 hours, 25 minutes, 0.60 ml water (33 mmol) accumulates in the trap. The yellow solution is hazy while warm, but a small amount of gelatinous precipitate accumulated upon cooling. The suspension is filtered and is evaporated. Proton nuclear magnetic resonance spectrosopy confirms the presence of the title compound; (CDCl3, ppm) 10.0-10.5 (1H, broad singlet), 5.4 (1H, broad singlet), 5.1 (1H, broad singlet), 4.5-5.0 (1H, broad singlet), 3.9 (3H, singlet).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].[C-]#N.[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 40 h
Yield: 40 %

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenylhydrazono) succinonitrile (0.296 g, 1 mmol), sodium cyanide (0.196 g, 4 equivalents), water (1 ml) and acetic acid (5 ml) were added successively to a sealed tube. After reacting for 40 hours at 20° C., the mixture was added to saturated sodium bicarbonate solution, extracted (dichloromethane), washed (water), dried (magnesium sulfate) and evaporated to give a mixture which contained 40% of the desired title compound, NMR 3.1 (m, 2H), 4.5 (m, 1H), 5.89 (m, 1H), 6.94 (d, 1H), 7.71 (s, 2H), together with 60% of unchanged starting hydrazone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[O:11])=[CH:4][CH:3]=1.C(O)C.C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:11])[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:18]2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccc(Cl)cc2)Oc2ccccc21
Reaction time: 8 h
Yield: 29 %

Procedure:
4-Chloro-2'-hydroxychalcone (5.17 g) was boiled under reflux with a mixture of ethanol (250 ml.) and a solution or sodium acetate (anhydrous, 4.10 g) in water (25 ml.) for 5 hrs. The reaction mixture was diluted with water and allowed to stand overnight. The solid precipitate was filtered off, washed with water and dried. Recrystallisation from petroleum ether (b.p. 80°-100° C.) gave 4'-chloroflavanone (1.50 g.), m.p. 96°-98° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16](O)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1>>[F:30][C:31]1([F:35])[CH2:34][N:33]([C:16]([C@@H:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:23]3[CH2:26][C:25]([F:28])([F:27])[CH2:24]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:11]=2)=[O:13])[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:32]1
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7)) as starting materials. MS (EI): m/e=473.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[CH2:5][CH2:4]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:9](=[O:10])[CH:3]([CH2:2][O:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:4][CH2:5][C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]2=3)=[CH:17][CH:16]=1
Reactant: COc1ccc(CN2C(=O)C(CO)CCc3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)C(COS(C)(=O)=O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-hydroxymethyl-1-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.26 mmol) in 2 mL of anhydrous THF at 0° C. is added MsCl (0.39 mmol) and DIEA (0.47 mmol). After the addition, the mixture is allowed to warm up to room temperature and then stirred for 1 hour. The solvent is removed under vacuum and the residue is treated with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers are concentrated and the residue is purified by flash column chromatography (silica gel) to provide methanesulfonic acid 1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl ester as white crystals. Yield: 90%. MS: (ES+): 390[M+1].
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)(=[O:20])[CH2:18][CH3:19]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1CN(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:18]([CH3:19])[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])=[C:3]([CH3:10])[CH:4]=1
Reactant: CCC(=O)c1ccncc1
Reactant: COc1cc(C)c(Br)cn1
Agent: CN(C)Cc1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C)c(C(C)C(=O)c2ccncc2)cn1
Temperature: 120 °C

Procedure:
5-Bromo-2-methoxy-4-methylpyridine ([CAS Reg. No. 164513-39-7], 202 mg) was added to caesium carbonate (488 mg), 4-propionylpyridine ([CAS Reg. No. 1701-69-5], 165 mg) and chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II), ([CAS Reg. No. 614753-51-4], 11 mg) in dioxane (2 ml). The mixture was heated in a sealed tube to 120° C. over night. Purification by preparative HPLC (Phenomenex Gemini Axia-C18 column, solvent gradient 20-95% CH3CN in 0.1% HCOOH[aq]) gave the title compound (30 mg). MS (m/e)=257.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]#[N:6].[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:25](=[O:26])[C:24]2[CH:28]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=[CH:22][C:23]=2[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 3-Fluoro-4-piperazin-1-yl-benzonitrile [182181-38-0] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 471.4 MH+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([CH:30]=1)C(Cl)=O>C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:30]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(Cl)ccc1OC1CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
Acetonitrile (200 mL) was added to potassium 3-ethoxy-3-oxopropanoate (31.1 g, 182.7 mmol), in a 1000 mL 3-necked flask under N2 with stirring. The reaction mixture was cooled to 0° C., then triethylamine (38.8 mL, 278.4 mmol) was added, followed by MgCl2 (20.71 g, 217.5 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 2.5 h. The resulting slurry was cooled to 0° C. and 5-chloro-2-cyclopropoxybenzoyl chloride (18.5 g, 87 mmol) was added dropwise followed by the addition of more triethylamine (3.9 mL, 28 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo. 1 L of toluene was added, the mixture was cooled to 0° C., then 125 mL of HCl (13% aqueous solution) was added. The ice bath was removed, the mixture was stirred for 30 minutes, then the layers were separated and the organics washed with water and evaporated to dryness. The residue was purified by silica gel chromatography (Hexanes/EtOAc=3:1) to afford 21.8 g of ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=283.0; 1H NMR (400 MHz, CDCl3) δ: 7.81 (t, 1H), 7.44 (dd, 1H), 7.29 (d, 1H), 4.24 (m, 2H), 3.87 (s, 2H), 3.78 (m, 1H), 1.23 (t, 2H), 0.85 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C=O)C>[F:15][C:10]([F:16])([C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:4][C:3]=2[CH:6]=1)[C:11]([F:14])([F:13])[F:12]
Reactant: O=Cc1cc(C(F)(F)C(F)(F)F)ccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C(F)(F)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A mixture of 0.60 g of 2-hydroxy-5-(pentafluoroethyl)benzaldehyde, 0.41 g of 4-(chloromethyl)pyridine hydrochloride, 1.21 g of potassium carbonate, 0.41 g of potassium iodide and 10 ml of DMF was stirred at 80° C. for 2 hours and subsequently at 150° C. for 3 hours. Thereto was added 0.8 g of potassium carbonate, and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 4-[5-(pentafluoroethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 5”).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylic acid, (Compound 21, 0.03 g, 0.655 mmol) in ETCH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][N:24]([CH3:41])[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=[C:28]([S:25](=[O:26])(=[O:27])[N:24]([CH3:41])[CH3:23])[CH:29]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 90:10), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Light brown foam (13%). MS (ESI): m/z=598.104 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Li+].CCOCC>CO.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (52.5 g, 169.3 mmol), lithium hydroxide (4.86 g, 203.1 mmol) in methanol (546 mL) and water (273 mL) was stirred with a mechanical stirrer at room temp overnight. The methanol was evaporated, and to the aqueous solution, was added 1 N HCl (270 mL) to form the precipitate. Ether (350 mL) was added, and the mixture was stirred at 0° C. for 2 hours. The mixture was evaporated. To the residue, was added water (500 mL). The aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were separated, dried over magnesium sulfate, and concentrated to give 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil (21.0 g, 41% yield). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([CH:33]([CH2:37][CH2:38][CH3:39])[C:34](O)=[O:35])[CH2:31][CH3:32]>>[CH2:30]([CH:33]([CH2:37][CH2:38][CH3:39])[C:34]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:35])[CH2:31][CH3:32]
Reactant: CCCC(CCC)C(=O)O
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(CCC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 99.1 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (2.4 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 686 mg (4.8 mmol) of 2-propylvaleric acid, to provide 1.3 g of the title compound.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CCCCCCC>[CH3:2][C@@H:1]1[O:22][C@@:3]21[C@:11]1([CH3:12])[C@H:6]([C@@H:7]([OH:13])[CH2:8][CH2:9][CH2:10]1)[CH2:5][CH2:4]2
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@@H]1O[C@@]12CC[C@H]1[C@@H](O)CCC[C@@]12C
Temperature: 4.400000095367432 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
(Z,3aR,4S,7aS)-1-ethylidene-octahydro-7a-methyl-1H-indene-4-ol (Compound 6: 663.1 mg, 3.18 mmol) synthesized in accordance with the method described in J. Org. Chem. 2001, 66, 626-628 was dissolved in ethyl acetate (3.1 ml), and the solution was cooled to 4.4° C. Meta-chloroperbenzoic acid (913 mg, 3.44 mmol) was added to the reaction solution over 9 minutes. After stirring the reaction solution at 2° C. for 1 hour, aqueous sodium hydrogen carbonate solution (2 ml) and aqueous sodium sulfite solution (1 ml) were added thereto, and the mixed solution was stirred and separated. The obtained organic layer was washed with aqueous sodium hydrogen carbonate solution (2 ml) and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the obtained reaction mixture, seed crystals were added, and heptane (1.8 ml) was added thereto, followed by collecting the precipitated crystals by filtration to obtain (1R,3aR,4S,7aS,3′S)-3′,7a-dimethyl-4-hydroxyoctahydrospiro(indene-1,2′-oxirane) (382.8 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][C:32](C(OCC)=O)([C:38]([O:40]CC)=[O:39])[C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH:32]([C:33]([OH:35])=[O:34])[C:38]([OH:40])=[O:39])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC(C(=O)O)C(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.3 %

Procedure:
To a solution of triethyl 3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate (200 mg) in 1,4-dioxane (9 mL) and water (3 mL) was added lithium hydroxide (100 mg). After stirring the solution at room temperature for 7 hours, water was added thereto and it was concentrated under reduced pressure. Acetic acid (0.14 mL) was added to the residue, and the solution was further concentrated under reduced pressure and to dryness. The residue was purified by chromatography (DIAION HP20 manufactured by Mitubishi Chemical Corporation, methanol) to give the title compound (150 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (89%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]3)[C:9]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4].[C:30](Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O)(=O)/C=C\C(O)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.CC(C)=O.[OH-].[NH4+]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:28][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:21][CH2:20]3)[C:9]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(CCCC)cc32)CC1

Procedure:
In accordance with the general procedure described in the foregoing Examples, 4.1 grams of 8-(n-butyl)-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 3.2 grams of caprylyl chloride (octanoyl chloride) in a mixture of 18 milliliters of benzene and 7 milliliters of chloroform. A solution of 2.3 grams of maleic acid in 25 milliliters of acetone was then added to the mixture and the resulting 8-(n-butyl)-10-[4-(3-oxtanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin di(hydrogen maleate) which had a melting point of 113°-115°C, after recrystallization from acetone, was recovered. Its elemental analysis corresponded to the empirical formula C41H56N2O10S. The free base was obtained in the form of a colorless very viscous oil which was very soluble in vegetable oils by dissolving the salt in a dilute aqueous ammonium hydroxide solution and extracting the solution with benzene.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]4[N:26](COCC[Si](C)(C)C)[C:25]5[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=5[N:19]=4)[CH:15]=[N:14]3)[CH2:8]2)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]4[NH:26][C:25]5[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=5[N:19]=4)[CH:15]=[N:14]3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC4=NOC(Cc5ccc(F)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4=NOC(Cc5ccc(F)cc5)C4)c3)nc2n(CCC)c1=O
Yield: 158 %

Procedure:
To a solution of 8-{1-[5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (80 mg) in ethanol (5 ml) aq. HCl (2 N, 5 ml) was added and the reaction mixture was refluxed for 2 hrs. The volatiles were evaporated and the residue obtained was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain 8-{1-[5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (100 mg, 98%) as white solid.