Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:15]=3[NH:16][N:17]=2)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:15]=3[NH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c2sc2ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2n[nH]c3c2sc2ccccc23)cc1
Temperature: 25 °C

Procedure:
Boron tribromide (3.0 ml of a 1.0M solution in dichloromethane) was added to a solution of the product from Example 60 (210 mg) in dichloromethane (10 ml) at −78° C. under nitrogen with stirring. The mixture was allowed to warm to ambient temperature slowly, and after stirring at this temperature for 2 days the mixture was quenched by the addition of aqueous ammonium chloride solution. The organic layer was separated, dried and evaporated to give a residue which was purified by flash column chromatography on silica using dichloromethane and then increasing amounts of methanol, up to 15% of methanol, in dichloromethane as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 3-(4-hydroxyphenyl)-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 137-1 39° C.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:21])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:10]=[C:9]([I:20])[CH:8]=1>O.C1COCC1>[I:20][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:10]=1)[C:6]([OH:21])=[O:5]
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(I)cc(C(=O)O)c2)nc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (526 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid (470 mg, 93%). MS (M+H)=340.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:44][O:45][CH2:46][CH:47](O)[CH3:48]>C1COCC1.O>[CH3:44][O:45][CH2:46][CH:47]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:48]
Reactant: COCC(C)O
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
To 2-methylquinolin-8-ol (1.0 g, 6.28 mmol) in THF (5 mL) was added PPh3 (6.92 g, 26.4 mmol), DEAD (1.58 ml, 10.1 mmol) and 1-methoxypropan-2-ol (0.736 g, 8.17 mmol). The reaction was stirred for 24 hours at ambient temperature and then water was added. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and purified by reverse chromatography (SP4, 40M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropan-2-yloxy)-2-methylquinoline (1.0 g, 68.8% yield) as a clear liquid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:29]#[C:28][C:26]([CH3:27])([OH:30])[CH3:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 2-Methyl-3-butyn-2-ol were converted to yield 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-2-methyl-but-3-yn-2-ol as light yellow semisolid, MS: 371 (M, 1Br).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:17][N:16]([CH3:18])[C:15](=[O:19])[CH:14]=2)=[C:8]([F:20])[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[CH:14]=[C:15]([O:19][CH:2]([F:4])[F:3])[N:16]([CH3:18])[N:17]=2)=[C:8]([F:20])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(F)cc1Cl

Procedure:
Gaseous chlorodifluoromethane was passed for 2 hours into a solution of 133 g (0.55 mol) of 5-(4-chloro-2-fluoro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one and 110 g (2.7 mol) of sodium hydroxide in 1 l of dioxane and 0.5 l of water at room temperature. The reaction solution was then poured into 2 l of water, whereupon the aqueous phase was extracted three times using ethyl acetate. The combined organic phases were dried over magnesium sulfate and then filtered and concentrated. The residue was purified by means of column chromatography on silica gel (eluent: cyclohexane/ethyl acetate=9:1) followed by preparative MPLC on silica gel (identical eluent). Yield: 43 g.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22](OS(C3C(C)=CC(C)=CC=3C)(=O)=O)=[N:23][C:24]([NH2:28])=[N:25][C:26]=2[CH3:27])=[C:16]([O:42][CH3:43])[CH:15]=1)(=O)=O.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH2:47][CH3:48]>O1CCOCC1>[NH2:28][C:24]1[N:25]=[C:26]([CH3:27])[C:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][C:16]=2[O:42][CH3:43])=[C:22]([NH:49][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[N:23]=1
Reactant: CCCCCN
Reactant: COc1cc(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(O)cc1OC

Procedure:
A mixture of the product from step (iv) (9.51 g) and pentylamine (12 ml) in dioxane (100 ml) was heated under reflux for 48 h. The solvent was evaporated and the residue partitioned between EtOAc/water. The organics were separated, washed with aq NaHCO3 soln, water, dried and evaporated under reduced pressure. The residue was dissolved in MeOH (200 ml) then aq NaOH (2M, 40 ml) added and the mixture heated under reflux for 6 h. The mixture was acidified to pH 7 with aq 2M HCl, the solvent evaporated under reduced pressure and the residue partitioned between DCM/water. The organics were separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate and filtered to afford the subtitle compound, 2.43 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([CH:25]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)O)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCCO)C.[OH-].[Na+]>O>[N:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([CH:25]=[CH:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(O)CCCN3CCCCC3)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCO
Solvent: O
Product: C(=Cc1ccc2c(c1)Cc1cc(C=CCCN3CCCCC3)ccc1-2)CCN1CCCCC1
Temperature: 80 °C

Procedure:
A mixture of 4.7 g (0.01 mole) of α,α'-bis(3-piperidinopropyl)-2,7-fluorenedimethanol, 25 ml of concentrated hydrochloric acid and 25 ml of ethylene glycol monoethyl ether is heated at 80°C. for 5 minutes. The solution is diluted with water, made alkaline with a 20% sodium hydroxide solution and the solution is extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from isopropanol resulting in the preparation of crystalline 2,7-bis(4-piperidino-1-buten-1-yl)fluorene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[CH2:22]([C:21]1[N:40]2[N:41]=[CH:42][N:43]=[C:39]2[N:38]([CH:35]2[CH2:34][CH2:33][C:32]3([O:28][CH2:29][CH2:30][O:31]3)[CH2:37][CH2:36]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[F:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.55 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (2.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (2.88 g, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1csc(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of 2-(4-hydroxyphenyl)-thiazole is added in one portion to a mixture, heated under reflux, of 5 ml of epichlorohydrin and 0.79 g of potassium carbonate and the reaction mixture is then heated under reflux for a further 20 minutes. After cooling, the mixture is filtered, the filtrate is concentrated by evaporation in a rotary evaporator and the residue is dissolved in 6 ml of dichloromethane; 100 mg of tetrabutylammonium hydrogen sulphate and 6 ml of 2N sodium hydroxide solution are added to the solution and the whole is stirred for 3 hours at room temperature. The organic phase is separated off, washed with water and dried over sodium sulphate and the solvent is then removed in a rotary evaporator. The residue is recrystallised from a mixture of ether/hexane, yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-thiazole having a melting point of 82°-93°.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:19]=[C:18]2[C:10]([CH:11]=[CH:12][C:13]3[O:14][C:15](=[O:22])[C:16]([CH3:21])([CH3:20])[C:17]=32)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].Cl>O>[CH3:21][C:16]1([CH3:20])[C:15](=[O:22])[O:14][C:13]2[CH:12]=[CH:11][C:10]3[C:18]([C:17]1=2)=[CH:19][C:7]([CH:2]([O:1][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:3]([F:4])([F:6])[F:5])=[CH:8][CH:9]=3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(C(O)C(F)(F)F)cc3c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(c2ccc3ccc4c(c3c2)C(C)(C)C(=O)O4)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8-(1-hydroxy-2,2,2-trifluoroethyl)-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone (0.04 g), pyridine (0.5 ml) and tosyl chloride (0.04 g) was stirred at room temperature for 18 h and then heated at 50° for 6 h. The mixture was cooled to room temperature, treated with water (10 ml) and the mixture was stirred at room temperature for 5 minutes and acidified with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness under reduced pressure to give the required starting material, 1,1-dimethyl-8-(2,2,2-trifluoro-1-tosyloxyethyl)-2(1H)-naphtho[2,1-b]furanone, which was used without further purification. ##STR3##
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26]C(C(O)=O)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1>ClCCl.CN(C=O)C>[N:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26][C:1]([C:2]([Cl:4])=[O:3])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2CCNCC2c2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2CCNCC2c2ccncc2)cc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.5 ml) was added to a stirred suspension of 4-((4-pyridyl)piperazin-1-yl)benzoic acid in dichloromethane (15 ml), followed by DMF (1 drop). The mixture was stirred for 2 hours and evaporated to dryness to give 4-[(4-pyridyl)piperazin-1-yl]benzoyl chloride which was used immediately.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1([CH3:22])[C:12]([CH3:14])([CH3:13])[O:11][B:10]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[O:9]1.Cl[CH2:24][C:25]1[C:26]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[N:27][O:28][C:29]=1[CH:30]([CH3:32])[CH3:31]>CN(C)C=O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:26]1[C:25]([CH2:24][O:21][C:18]2[CH:19]=[CH:20][C:15]([B:10]3[O:9][C:8]([CH3:22])([CH3:7])[C:12]([CH3:13])([CH3:14])[O:11]3)=[CH:16][CH:17]=2)=[C:29]([CH:30]([CH3:32])[CH3:31])[O:28][N:27]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
Cesium carbonate (1.96 g, 6.03 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (1.26 g, 5.74 mmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (1.75 g, 5.74 mmol) in N,N-dimethylformamide (57 mL) at room temperature. The resulting suspension was heated for sixty-nine hours at 60° C. The reaction was cooled and concentrated to remove the N,N-dimethylformamide, then water was added and the reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 2.24 g (80%) of 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole as an solid. 1H NMR (400 MHz, d6-DMSO): δ 7.62-7.59 (m, 2H), 7.55-7.48 (m, 3H), 6.76 (d, J=9 Hz, 2H), 4.82 (s, 2H), 3.44 (septet, J=7 Hz, 1H), 1.31 (d, J=7 Hz, 6H), 1.24 (s, 12H). ESI-LCMS m/z 488 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O:21][C:22]([N:24]1CC[N:27]([CH2:30][C:31]2[CH:39]=CC3OCOC=3C=2)[CH2:26][CH2:25]1)=O)(C)(C)C>>[N:27]1[CH:30]=[CH:31][CH:39]=[C:25]([NH:24][C:22]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:16][CH2:15]2)=[O:21])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-Benzo[1,3]dioxol-5-ylmethyl-piperazine. The title compound was prepared from 4-benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester in analogy with Example 6.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[C:11]2[CH2:15][CH2:14][CH2:13][C:12]=12)=[O:7].O[Li].O>C1COCC1.O>[Cl:31][C:29]1[CH:30]=[C:25]([C:19]2([C:21]([F:22])([F:24])[F:23])[O:18][N:17]=[C:16]([C:10]3[S:9][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:34])=[O:2])=[O:7])=[C:12]4[CH2:13][CH2:14][CH2:15][C:11]=34)[CH2:20]2)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2

Procedure:
Stir a mixture of ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid methyl ester (11 g, 18.6 mmol) and LiOH—H2O (1.56 g, 37.2 mmol) in THF (100 mL) and water (50 mL) at room temperature for overnight. After being checked with TLC, the solvent is removed under vacuum, dilute the residue with water (50 mL). Acidify the aqueous mixture with 2M HCl to pH=3, and extract the resultant mixture with EtOAc (100 mL×3), the combined organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum, the residue is purified by silica gel chromatograph (PE:EtOAc 1:1) to afford ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid as a white solid (10.2 g, 90.7% for two steps). MS (m/z): 525 (M+1).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[NH2:18][NH2:19]>>[C:2]1([C:1]2[NH:19][NH:18][C:10](=[O:12])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2)[nH][nH]1
Yield: 81 %

Procedure:
A vigorously stirred solution of ethyl benzoylacetate (30 g 150 mmol), of 5% aqueous sodium hydroxide (312 mL), and hydrazine hydrate (14.6 mL 468 mmol) was heated to 75° C. for sixteen hours. The resultant precipitate was filtered, washed with water and dried and gave 5-Phenyl-1,2-dihydro-pyrazol-3-one (20.3) in 81% yield as a white solid. C9H8N2O: 1H NMR (d6-DMSO): δ 7.62 (d, 2H, J=7.0 Hz), 7.36 (t, 2H, J=7.0 Hz), 7.26 (t, 1H, J=7.0 Hz), 5.85 (s, 1H) ppm.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[CH:34]([O:43][C:44](=[O:46])[CH3:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=1)[CH2:19][CH2:20][CH2:21][CH:22]=[O:23])(=[O:16])[CH3:15].C(O)(C)C>CC(C)=O.CCOCC>[C:14]([O:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[CH:34]([O:43][C:44](=[O:46])[CH3:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=1)[CH2:19][CH2:20][CH2:21][C:22]([OH:3])=[O:23])(=[O:16])[CH3:15]
Reactant: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC=O)OC(C)=O)c1)OC(C)=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC(=O)O)OC(C)=O)c1)OC(C)=O
Temperature: -30 °C

Procedure:
0.3 ml of Jones reagent (J. Chem. Soc. 1953., 2555) is instilled in a solution of 150 mg of the above-produced aldehyde in 11 ml of acetone with stirring at -30° C. and stirred for one hour at -30° C. Then, 0.23 ml of isopropanol is added, stirred for 15 minutes, diluted with ether, filtered, washed neutral with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-50% ethyl acetate, 52 mg of (5RS)-5-acetoxy-5-{3-[(1E,3E)-(5RS)-5-acetoxy1,3-tridecadienyl]-phenyl}-pentanoic acid is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH:18]=[O:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C[C@H]1OC[C@]2(c3cccc(F)c3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide, obtained in preparation example 1-(6), (4.20 g) was dissolved in DCM (60 mL) and the solution was cooled to 0° C. 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (5.50 g) was added portionwise over 10 min, and the reaction mixture was allowed to warm to RT. After stirring for 2 h, NaHCO3 (sat., aq., 100 mL) was added, and the mixture was extracted with DCM (3×150 mL). The combined organic portions were dried over MgSO4 and evaporated to afford the title compound (3.04 g, approx. purity 60%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.97 (dd, J=14.0, 4.2 Hz, 1H), 3.23 (d, J=11.6 Hz, 1H), 3.29-3.38 (m, 1H), 4.08-4.18 (m, 1H), 4.56-4.83 (m, 2H), 7.11-7.24 (m, 3H), 7.39-7.64 (m, 3H), 7.98-8.18 (m, 2H), 9.96 (d, J=1.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2([CH:17]([F:19])[F:18])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]2)[CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>CO.C1COCC1.[Pd]>[F:19][CH:17]([F:18])[C:8]1([C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[F:20])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]1
Reactant: CC1(C)OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OCC(c2ccccc2F)(C(F)F)NC1=O
Yield: 99.3 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-morpholin-3-one (3.14 g, 8.92 mmol) and sodium acetate (1.46 g, 17.83 mmol) were suspended in 100 mL methanol and 10 mL THF. Eventually, 10% Pd on charcoal (315 mg) was added and the reaction mixture was treated with hydrogen (balloon) at rt. After 60 minutes the reaction mixture was filtered over celite and evaporated. The residue was partitioned between aqueous Na2CO3 solution and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated to give 2.42 g of the title compound as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1.CCOCC>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiAlH4 (2.51 g, 66.3 mmol) was suspended in THF (60 mL) and then cooled in an ice-bath. To the suspension was added Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (11.357 g, 53.0 mmol) dissolved in THF (40 mL) dropwise and the reaction mixture was gradually warmed to room temperature over 1 h upon which LCMS indicated complete reduction of SM. The reaction mixture was diluted with ether (200 mL) and quenched with 2.5 mL water and then 5 mL (10% NaOH) and then 7.5 mL water. To this, anhydrous MgSO4 was added, which was then agitated for 30 min and filtered over Celite. The filtrate was concentrated in vacuo to afford the desired product in quantitative yield. LCMS (m/z): 173.1 (MH+), 0.41 min.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:22](=O)[CH2:21][O:20][C:17]2=[CH:18][N:19]=1>>[CH3:1][O:2][N:3]=[C:22]1[C:16]2[C:17](=[CH:18][N:19]=[C:14]([Cl:13])[CH:15]=2)[O:20][CH2:21]1
Reactant: CON=C1COc2nnccc21
Reactant: O=C1COc2cnc(Cl)cc21
Product: CON=C1COc2cnc(Cl)cc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 5-chlorofuro[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;