Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=O)[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[ClH:31].[O:32]([NH2:34])[CH3:33]>C1COCC1>[ClH:31].[CH3:33][O:32][N:34]=[CH:27][C:22]1[N:23]([CH2:25][CH3:26])[CH:24]=[C:20]([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:8]=3)[C:4](=[O:29])[N:3]([CH3:30])[C:2]([NH2:1])=[N:6]2)[CH:21]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=NOC
Yield: 64 %

Procedure:
A stirred suspension of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25 mmol), in THF (5 mL), was added methoxylamine hydrochloride (0.021 g; 0.25 eq). The mixture was stirred at reflux temperature for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The dichloromethane solution was dried over MgSO4, filtered and evaporated. The resultant residue was crystallized from ethyl acetate and hexane to yield the title compound, 0.069 g (64% yield), mp 190-193° C., MS (ES) m/z 433.1; [M−H]
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1C(C(OO)=[O:29])=CC=CC=1>C(Cl)(Cl)Cl>[O:29]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]1[C:1]([O:20][CH3:21])=[O:19]
Reactant: CCCCCCCCCCCCCCC/C=C/C(=O)OC
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC1OC1C(=O)OC

Procedure:
For preparation of racemic dihydrosphingosines, K. Sisido, et al., report in J. Org. Chem., Vol. 29, No. 9, pp. 2783-2784 (1964) a process comprising, for example, reacting methyl trans-2-octadecenoate with perbenzoic acid in chloroform to obtain methyl 2,3-epoxyoctadecanoate having formula (V'): ##STR3## whose planar structure is the same as that of the compound represented by formula (V) hereinafter described, hydrolyzing the ester (V'), cyclizing the resulting acid by reaction with benzylamine to obtain 2-benzylamino-3-hydroxyoctadecanoic acid (cyclization yield: 68%), converting the acid to a methyl ester, and reducing the ester in an ether solvent with lithium aluminum hydride (LiAlH4) (reduction yield: 71%). Reduction of such a carboxylic acid as 2-benzylamino-3-hydroxyoctadecanoic acid to an alcohol has generally been carried out by once esterifying the carboxylic acid and using LiAlH4 as a reducing agent as in the above report. However, LiAlH4 is a reagent unsuitable to industrial use because it is not only expensive but difficult to handle on account of reactivity with moisture in air.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]([C:6]([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[C:4]([F:22])[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O.C1COCC1>[NH2:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([CH:17]=1)[C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:7]
Reactant: Cc1ccccc1N(C)C(=O)c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1N(C)C(=O)c1cc(N)c(Cl)cc1F

Procedure:
To 4-chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide (6.6 g, 20.3 mmol) was stirred vigorously in a mixture of water (30 mL) and THF (30 mL) containing Na2S2O4 (17.6 g, 101.2 mmol) for 12 hrs. The organic layer was then separated and the water layer was further extracted with ethyl acetate. The combined organic solutions were washed with brine and dried over MgSO4. Concentration yielded 5-amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide as a crude solid which was washed with ether to give a light yellow product (3.3 g). MS: 292.9 (M+H)+: tR=1.90 min (method 1)
Reaction SMILES: Cl.Br[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][C:10]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:9][C:8]1=[O:18].[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:12](=[O:13])[CH2:11][C:10]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:9][C:8]3=[O:18])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CCCC1(C)CC(=O)N(CCCCBr)C(=O)C1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CCCC1(C)CC(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)C1

Procedure:
Title product hydrochloride--Reaction of N-(4-bromobutyl)-3-methyl-3-n-propylglutarimide with 3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base to the hydrochloride salt according to the procedure of Example 3 affords 1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4-methyl-4-propyl-2,6-piperidinedione hydrochloride, m.p. 163°-165° C.
Reaction SMILES: [CH2:1]([CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[O:13]1CCC[CH2:14]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:13]=[C:14]1[NH:12][CH:8]([CH2:7][CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:9](=[O:11])[O:10]1
Reactant: NC(CCCCC(=O)O)C(=O)O
Reactant: C1CCOC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC1NC(=O)OC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 1.752 g of DL-2-aminopimelic acid, 55 ml of tetrahydrofuran and 16 ml of 1.93M phosgene in toluene is heated, in an oil bath, at 50° C. for 1 hour. Argon is bubbled through the reaction to remove the excess phosgene and the solvents are removed under house vacuum. The resulting oil is dissolved in 14 ml of ethyl alcohol, diluted with 14 ml of petroleum ether and the solution stored overnight at room temperature. The formed crystals are collected and dried to give 1.6 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)[C:6]=2[CH:5]=[C:4]([Br:24])[CH:3]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl.O>[Br:24][C:4]1[CH:3]=[C:2]([NH:1][CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[C:10]2[N:9]=[CH:8][N:7]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:19][CH2:20]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)[C:6]=2[CH:5]=1
Reactant: Cc1cc(-n2cnc3c(N)cc(Br)cc32)ccc1C(=O)NC1CC1
Reactant: O=CCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(Br)cc32)ccc1C(=O)NC1CC1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a stirred solution of 4-(4-amino-6-bromo-1H-benzimidazol-1-yl)-N-cyclopropyl-2-methylbenzamide (5.00 g, 12.98 mmol) in DCE at rt was added 3,3,3-trifluoropropanal (4.36 g, 38.93 mmol, 3 eq), sodium triacetoxy borohydride (13.75 g, 64.89 mmol, 5 eq) and acetic acid (14.9 mL, 259.56 mmol, 20 eq) and the mixture was stirred for overnight. Water and DCM was added, and the organic phase was separated and washed with water After addition of DCM, the organic phase was washed with water and evaporated to yield 4-{6-bromo-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-N-cyclopropyl-2-methylbenzamide (50%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:26])[CH2:9][C:10](=[O:25])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:3]([O:7][C:8](=[O:26])[CH2:9][CH:10]([OH:25])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(O)CCc1ccc(-c2ccccc2)cc1
Yield: 93.4 %

Procedure:
Sodium borohydride (51 mg, 1.4 mmol) was added in one portion to a stirred solution of 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 2, 400 mg, 1.23 mmol) in methanol (5 mL) at 0° C. under nitrogen. Stirring was continued for 30 mrrinutes then 1 M hydrochloric acid (5 mL) was added. The crude reaction mixture was extracted with diethyl ether (3×20 mL) and the resulting organic phases were combined, dried (MgSO4) then the solvent removed by evaporation under reduced pressure to give the title compound (375 mg, 93%) as a colourless oil. LC/MS: 3.67 min; z/e 344, calcd (M+NH4) 344.1H NMR (400 MHz: CDCl3): 7.55 (2 H), 7.50 (2 H), 7.43 (2 H), 7.38 (3 H), 4.01 (1 H), 3.25 (1 H), 2.80 (2 H), 2.44 (2 H), 1.82 (2 H), 1.45 (9 H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5][N:4]=1.O.[NH2:16][NH2:17]>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:16][NH2:17])[N:8]=1
Reactant: CSc1ncnc(-c2ccccn2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncnc(-c2ccccn2)n1

Procedure:
A stirred solution of the product of step 2 (0.763 g, 3.74 mmol) and hydrazine hydrate (0.22 mL, 3.9 mmol) in ethanol (8 mL) was heated at reflux for 30 minutes. The reaction was cooled in an ice bath and the precipitate was filtered off. Vacuum oven drying afforded crude product as light brown solid. This material was used without further purification in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[N:12]2.[BH4-].[Li+]>O1CCCC1>[CH3:24][C:21]1[O:20][C:19]([CH2:18][NH:17][C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[N:12]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)CCCc1cccc2nc(NCc3ccc(C)o3)ccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(CCCCO)cccc3n2)o1

Procedure:
4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-butyric acid methyl ester (100 mg, 0.3 mmol) was dissolved in 10 mL dry tetrahydrofurane. Lithiumborohydride (100 mg, 4.5 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched by addition of IN hydrochloride solution and refluxed for 30 minutes. The mixture was then adjusted to pH 10 by addition of 25% solution of ammonium hydroxide and extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→0:100 gradient). The title compound was obtained as a light yellow oil (67 mg, 73%), MS: m/e=311.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].B(F)(F)F>O1CCOCC1>[CH2:19]([O:18][C:16]([C:15]1[O:11][N:10]=[C:8]([C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:9]=1)=[O:17])[CH3:20]
Reactant: NC(=NO)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: FB(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzamide oxime (4 g) and ethyl chlorooxoacetate (3.01 g) in dioxane (200 ml) was refluxed for 1 hour, and then borontrifluoride (1 ml) was added thereto. The whole mixture was refluxed for 12 hours. After being cooled to room temperature, the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate (100 ml), washed with a saturated potassium carbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and hexane (1:1) as eluent. The fractions containing the object product were collected and evaporated in vacuo to afford 5-ethoxycarbonyl-3-(4-nitrophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After dissolving 4-aminomethylpiperidine (5.754 ml, 50 mmol) in acetonitrile (200 ml), potassium carbonate (13.82 g, 100 mmol) and benzyl chloride (17.13 g, 150 mmol) were added and the mixture was stirred at 60° C. overnight. Upon completion of the reaction, the reaction mixture was filtered and the solvent was distilled off. A developing solvent (CH2Cl2/MeOH/NEt3 90/5/5) was used for purification by silica gel column chromatography to obtain (1-benzyl-4-piperidyl)methylamine. The compound was identified by LC-MS.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH:16]=[N:17][NH:18][C:10]=12>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]3[CH:16]=[N:17][NH:18][C:10]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC2CCCCC2)c2[nH]ncc2n1
Yield: 16.2 %

Procedure:
Cyclohexylamine (1.14 ml, 0.01 mole) and 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (0.5 g, 0.003 mole) were heated at reflux in dry xylene (3 ml) for 48 h. The solvent was removed under reduced pressure and the residue crystallised from ethyl acetate/ether/pentane to give the title compound as a white solid (112 mg, 16%), m.p. 287°-289° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[OH-].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O.C(Cl)Cl>[Cl:26][CH2:27][C:28]([N:3]([CH2:4][CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:2])=[O:29]
Reactant: CNCC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(CC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To 55 g of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propylamine hydrochloride dissolved in 770 ml of distilled water there was added at room temperature 185 ml of 2 N NaOH and 200 ml of CH2Cl2. At 0° C., slow dropwise addition was made to the mixture of 16.7 ml of chloroacetyl chloride dissolved in 350 ml of anhydrous CH2Cl2. The solution was stirred at room temperature for 3 hours. The organic phase was separated and washed with an aqueous solution of bicarbonate, then with a saturated solution of NaCl, then dried and evaporated to dryness. There was obtained 60 g (Yield 97%) of N-chloroacetyl-N-methyl-3-phenyl-2-hydroxy-3-(2-nitro-phenoxy)-propylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:39]1[C:36]2[CH:37]=[CH:38][C:33]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:34][C:35]=2[O:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1N
Reactant: Ic1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1Nc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(4-(methanesulfonamido)phenyl)benzoate 0.12 g and cesium carbonate 0.27 g were added 1-iodo-3,4-methylenedioxybenzene 0.16 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.9 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and palladium acetate 1.5 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.9 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and palladium acetate 1.5 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoate.
Reaction SMILES: [CH3:1]CCCCC.C([Li])CCC.[C:12]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CI>O1CCCC1>[CH3:1][CH:13]([CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCC
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 1.7 g. of n-isopropylcyclohexylamine in 15 ml. of tetrahydrofuran, at -78°, is added 5.5 ml. of a 2.4 N n-butyl lithium n-hexane solution. Then 3 g. of ethyl arachidonate in 150 ml. of tetrahydrofuran is added dropwise, over a 2-hour period, at -78°. Then 1.5 ml. of methyl iodide is added and the mixture is allowed to warm to room temperature. The solution is concentrated by evaporating tetrahydrofuran, then extracted with ether to yield ethyl 2-methylarachidonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])=[CH:6][CH:7]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Into 10 ml of pyridine were dissolved 0.50 g of 5-(4-amino-phenyl) thiazolidine-2,4-dione, and after added 0.46 g of p-toluenesulfonyl chloride, the mixture was stirred for 1 hour at room temperature. After the completion of reaction, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from benzene to obtain 0.65 g of title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:36])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:20][C:19]=1[Cl:35])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:36])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[CH:20][C:19]=1[Cl:35])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@](C)(CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Yield: 98.8 %

Procedure:
To a solution of the compound of Example 12 (1.00 g) in THF (14 mL) was added under ice cooling lithium borohydride (229 mg), and then ethanol (1.4 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the target product (910 mg) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:10][C:11]([OH:13])=O)[O:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH:14][C:15]1[CH:20]=[C:19]([CH3:21])[O:18][C:17](=[O:22])[CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1.[Na].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(O)C>[O:2]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:5]=[C:1]1[CH2:10][C:11]([C:16]1[C:17](=[O:22])[O:18][C:19]([CH3:21])=[CH:20][C:15]=1[OH:14])=[O:13]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=C(O)Cc1occ2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)Cc2cc3ccccc3o2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.76 g (10.0 mmol) of the 2-benzofuranacetic acid, 1.26 g (10.0 mmol) of 4-hydroxy-6-methyl-2-pyrone and 2.27 g (11.1 mmol) of DCC were suspended in 50 ml of chloroform, then 130 mg (1.06 mmol) of DMAP added and stirring carried out overnight at 60° C. The reaction liquid was cooled to room temperature and the insoluble material filtered off. The mother liquor was concentrated and the residue purified by column chromatography. The solid obtained was recrystallized from ethanol and Compound 15 (614 mg, 2.16 mmol, 21%) obtained. This was converted to the sodium salt with an equivalent quantity of sodium hydrogen carbonate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12]C(C)(O)C)[CH:8]=[CH:9][CH:10]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=1)#[CH:12]
Reactant: CC(C)(O)C#Cc1cccc(CCCO)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(CCCO)c1

Procedure:
To a solution of 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (10) (0.750 g, 3.4 mmol) in toluene (50 mL) was added powdered KOH (0.390 g, 7 mmol). The resulting mixture was heated to reflux for 45 min, concentrated under reduced pressure to 10-15 mL and diluted with EtOAc (100 mL). The solution was washed with water (2×100 mL) and brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography gave 3-(3-ethynylphenyl)propan-1-ol (11) as a light brown oil. Yield (0.272 g, 49%): 1H NMR (400 MHz, DMSO-d6) δ 7.24-7.32 (m, 4H), 4.49 (t, J=5.2 Hz, 1H), 4.15 (s, 1H), 3.39 (dt, J=6.4, 5.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.66-1.73 (m, 2H).