Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:23])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cn2ccnc2)c1
Yield: 16.5 %

Procedure:
3-((1H-Imidazol-1-yl)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), imidazole (0.034 g; 0.5 mmol) and sodium iodide (0.090 g; 0.6 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.009 g (16%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[C:11]([Cl:17])[C:10]=2[Cl:18])=[O:8])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](Br)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[Cl:17][C:11]1[C:12]2[O:16][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:15][C:13]=2[CH:14]=[C:9]([C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[O:8])[C:10]=1[Cl:18]
Reactant: Cn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 2.0 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 22 ml of dimethylformamide are added 2.12 g of powdered potassium carbonate and 3.7 g of ethyl dibromoacetate, and the mixture is stirred at 90° to 100° C. under argon gas atmosphere for 2 hours. After cooling, the mixture is poured into ice-water and the mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane-ethyl acetate) to give 1.64 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate. Yield: 63%
Reaction SMILES: Br[CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[I-:21].[Na+].O.CCOCC>CC(C)=O>[I:21][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(CC(O)(CBr)c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(CC(O)(CI)c1ccccc1)c1ccccc1
Yield: 31.1 %

Procedure:
1-Bromo-2-phenyl-3-phenylsulphonyl-2-propanol (1.3 g, 0.004 mole) is dissolved in acetone (30 cc). Sodium iodide (0.9 g, 0.006 mole) is added and heated under reflux for 15 h. The reaction mixture is poured into water (100 cc), reextracted with ether (3×50 cc), washed with a 15% strength NaHSO3 solution (50 cc) and then with water (50 cc) and is dried over MgSO4. The crystallized crude (0.9 g) is recrystallized from carbon tetrachloride to give yellow crystals of 1-iodo-2-phenyl-3-phenylsulphonyl-2-propanol (0.5 g, 31%). Mp=98° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]2[O:27][CH2:26][CH2:25][N:20]2[C:21](=[O:24])[C:22]=1[CH3:23].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[CH3:23][C:22]1[C:21](=[O:24])[N:20]2[CH2:25][CH2:26][O:27][C:19]2=[C:18]([N+:28]([O-:30])=[O:29])[C:17]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCO2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.8 %

Procedure:
Triflic anhydride (2.78 g, 9.9 mmol) was added dropwise to a stirred solution of 7-hydroxy-6-methyl-8-nitro-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (1.5 g, 7.0 mmol) and TEA (1.42 g, 14.060 mmol) in DCM (30 mL) at −78° C. over a period of 1 hour. The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was partitioned between DCM and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.5 g of the product (20.6% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22]C1C=CC(N)=CC=1>>[CH3:21][O:22][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
(RK1-1-27E) I This compound was prepared according to the procedure described for compound 11a except using p-anisidine to obtain the required product as a light brown solid. (278 mg, 100%) Mp=173-175° C. (lit 187-189° C., Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 6.36 (br s, 1H), 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[CH3:26][C:27]1([NH:31][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:22])[CH2:30][O:29][CH2:28]1
Reactant: CC1(N)COC1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1(C)COC1
Yield: 50 %

Procedure:
As described for example 97, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.29 mmol) was converted, using 3-methyl-3-oxetanamine instead of rac-3-aminotetrahydrofuran, to the title compound (60 mg, 50%) which was obtained as a white foam. MS: m/e=415.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][C@H:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16].Cl[CH2:24][C:25](O)=[O:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:14]([C@H:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])[C:25](=[O:26])[CH2:24][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)CCl
Reactant: C[C@H](N)C1CCCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1[C@@H](C)C1CCCCC1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-1,3-thiazolidin4-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]#[N:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(CC)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(CC)cc2)cc1

Procedure:
A solution of 2,3-bis(4-ethylphenyl)quinoxaline-6-carbonitrile (200 mg, 0.55 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), NaN3 (179 mg, 2.75 mmol, 5.00 equiv), and NH4Cl (146 mg, 2.75 mmol, 5.00 equiv) was stirred for 7 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 8×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting solution was concentrated in vacuo, and washed with methanol. This resulted in 98 mg (44%) of 2,3-bis(4-ethylphenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a white solid.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:11](Br)([CH3:13])[CH3:12]>CS(C)=O>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:11]([CH3:13])[CH3:12]
Reactant: Cc1ccccc1O
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 54.1 g (0.5 mole) of ortho-cresol in 150 ml of DMSO was added portionwise and with stirring 12 g of 57% sodium hydroxide. This addition was exothermic to 45° C. After 2 hours at ambient temperature, 61.5 g (0.5 mole) of isopropyl bromide in 50 ml of DMSO was added dropwise with stirring. After another 2 hours, the reaction mixture was poured into 1000 ml of ice water and extracted with ether. Distillation of the dried extract gave 53.9 g of product as a colorless liquid; b.p. 94°-96° C. (30 mm).
Reaction SMILES: [CH2:1]([CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24])[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH3:12].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].[ClH:30]>CO.Cl.Cl.NNC(N)=N>[ClH:30].[ClH:30].[C:25]([NH:28][N:29]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH2:1][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[N:29][NH:28][C:25](=[NH:26])[NH2:27])=[CH:17][C:16]=2[O:23][CH3:24])=[C:4]([O:11][CH3:12])[CH:5]=1)(=[NH:27])[NH2:26]
Reactant: N=C(N)NN
Reactant: COc1cc(C=O)ccc1OCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc(C=NNC(=N)N)ccc1OCCOc1ccc(C=NNC(=N)N)cc1OC
Yield: 98.4 %

Procedure:
4,4'-(ethylenedioxy)di-m-anisaldehyde (0.99 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.01 g) were heated in 95% methanol (10.5 mL) under nitrogen for 16 hr. Cooling and filtration gave 1.52 g of 4,4'-(ethylenedioxy)di-m-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 322-30° C. dec.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C=O.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>O.CCOC(C)=O>[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2NCCCC2C1
Agent: C#C[Si](C)(C)C
Agent: C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C1CC[C@@H]2NCCC[C@@H]2C1
Yield: 26 %

Procedure:
A solution of the cis/trans mixture of decahydroquinoline diastereomers (1.20 g, 3.48 mmol), formaldehyde (1.1 mL, 13.9 mmol) as a 37 wt % solution in H2O, trimethylsilyl acetylene (963 μL, 6.95 mmol), and AuBr3 (455 mg, 1.04 mmol) in H2O (2.0 mL) was heated at 75° C. overnight. LC/MS of an aliquot showed the reaction had not gone to completion. The reaction mixture was charged with a second portion of formaldehyde (1.1 mL, 13.9 mmol) as a 37 wt % solution in H2O and trimethylsilyl acetylene (963 μL, 6.95 mmol) and heated at 75° C. for an additional 72 hr. The reaction mixture was diluted with EtOAc and filtered through a Celite pad, washing with EtOAc (25 mL). The solution was concentrated and purified by chromatography, eluting with 0-20% EtOAc/hexanes to give 413 mg (26%) of the cis-decahydroquinoline trimethylsilyl acetylene as a colorless oil confirmed by MS (ESI+): cal'd [M+H]+ 466.6, exp. 466.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([O:38]CC)=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Ethyl 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (0.300 g, 0.546 mmol) was dissolved in a 3:1:1 mixture of THF/MeOH/water (10 ml) and charged with lithium hydroxide (0.065 g, 2.73 mmol). The reaction was stirred at rt for 1 h, at which time LC/MS suggested the reaction was complete. The reaction was acidified with 3 N HCl, and the resulting mixture concentrated to almost dryness (water left), diluted with 3 mL brine solution and extracted 3 times with DCM. The organic layers were combined, dried, filtered, and concentrated under vacuum to yield 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (285 mg, 0.546 mmol, 100% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(O)=O>O>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[O:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: O=CNc1ccccc1
Solvent: O
Solvent: O=CO
Product: CCN(CC)CCNc1ccc(CN(C=O)c2ccccc2)c2sc3ccccc3c(=O)c12
Temperature: 160 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.40 g, 9.59 mmol), formanilide (31g) and formic acid (3 mL) were heated to 160° C. for 2 hours. The mixture was cooled, poured into water (200 mL) and extracted with ether (3×150 mL). The aqueous layer was basified with 5N NaOH, extracted with CHCl3 (3×150 mL) and the combined organic extracts were dried over Na2SO4 and filtered through florisil eluting with CHCl3 (100%), then 5% isopropylamine/CHCl3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 0.5% to 1% isopropylamine/CHCl3 and then by recrystallization from benzene/hexane (2x) to afford 1.88 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][C@@H:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][C@@H:6]2[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: COC(=O)[C@H](C[C@@H]1CCC(F)(F)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(C[C@@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
(R)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid methyl ester (224 mg, 0.59 mmol) was dissolved in ethanol (8 mL) and treated with a solution of lithium hydroxide monohydrate (62 mg, 1.47 mmol) in water (2 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid (210 mg, 97%) as a mixture of two diastereomers as a clear colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:6]=1)C.[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:4](=[O:3])[C:5]1[CH:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[C:8]([O:19][CH2:20][CH2:21][OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2ccc(F)c(Cl)c2)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
N-Methyl-N-(8-phenyloctyl)-3,5-bis[m-chloro-p-fluoro-phenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.313 g, 78%) from 3,5-bis[(m-chloro)-(p-fluoro)-phenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.71-7.66 (dd, 2H); 7.52-7.45 (m, 2H); 7.36 (m, 2H); 7.30-7.12 (m, 7H); 3.52 and 3.28 (2bt, 2H); 3.27 (m, 4H); 3.04 (2s, 3H); 2.58 (m, 2H); 1.60 (m, 4H); 1.42-1.10 (m, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][NH:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:16][CH2:17][NH:18][CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1
Temperature: 50 °C

Procedure:
To a solution of Example 12B (160 g, 326 mmol) in methanol (652 mL) was added 4 M HCl in dioxane (408 mL, 1630 mmol) and the mixture was heated at 50° C. for 3 hours. The solvent was then evaporated and water was added. A solid precipitates. The water layer was decanted and washed once with ethyl acetate. The solid was dissolved in ethyl acetate and extracted with water once. The water layers were combined and treated with 1 N NaOH (1 L) until pH=10. The free amine was extracted twice with dichloromethane, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.34-7.20 (m, 5H), 3.57 (s, 3H), 3.42 (q, J=13.4 Hz, 2H), 2.96 (qd, J=2.7 Hz, 6.9 Hz, 1H), 2.78 (dt, J=2.9 Hz, 11.9 Hz, 1H), 2.69-2.60 (m, 2H), 2.55 (d, J=10.8 Hz, 1H), 2.30 (dd, J=3.2 Hz, 6.7 Hz, 2H), 1.92 (td, J=2.8 Hz, 10.6 Hz, 1H), 1.68 (t, J=10.0 Hz, 1H); MS (ESI) m/z 249.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:29])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([Cl:29])=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(ccn2-c2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c(Cl)cn2-c2ccccc2)c1O
Yield: 40 %

Procedure:
A mixture of 4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (223 mg, 0.789 mmol), NCS (117 mg, 0.869 mmol) and BzOOBz (10 mg, 0.039 mmol) in carbontetrachloride (4 mL) was refluxed for 30 min. Then the reaction was cooled and concentrated, the resulting mixture was purified by column to give the desired product (100 mg). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=11.8 (s, 1H), 8.44 (s, 1H), 7.6-7.4 (m, 5H), 7.35 (s, 1H), 4.53 (q, 2H, J=7.4 Hz), 1.49 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7])(=O)C>[OH-].[K+].C(O)C>[OH:4][C@@H:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCCCCCCC[C@H](OC(C)=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCC[C@H](O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(S)-(+)-2-Acetoxyhexadecanoic acid (0.5 g; prepared by the method described in Agric. Biol. Chem., 54(12), 3337-3338, 1990) was dissolved in a solution of potassium hydroxide (1.0 g) in 50% aqueous ethanol was stirred at 70° C. for 2 hours. After the ethanol was evaporated, the reaction mixture was acidified with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give (S)-(-)-2-hydroxyhexadecanoic acid (407 mg). The product was dissolved in DMF (20 ml), and N-hydroxysuccinimide (173 mg) and N,N'-dicyclohexylcarbodiimide (310 mg) were added to the solution. The mixture was stirred at room temperature for 12 hours and then filtered. 6-(4'-N-Glycyl-spicaminyl-amino)purine hydrochloride (0.60 g) and triethylamine (1.0 ml) were added to the filtrate, and the mixture was stirred for 12 hours, concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK271 in the yield of 97 mg. Substantially no contamination of the diastereomer was observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][C:13](=[O:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere 16.76 g of (3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F2) are dissolved in 300 ml of tetrahydrofurane, the solution is cooled to −78° C., and 75 ml of 1M solution of potassium tri-sec-butylborohydride in tetrahydrofurane is added dropwise. After stirring for further 1 h, a mixture consisting of 30% hydrogeneperoxide solution and phosphate buffer solution is added. Stirring is continued for further 10 min, the reaction mixture is diluted with 400 ml of ethyl acetate and the aqueous layer is extracted with ethyl acetate, the combined organic phases are concentrated to give a foam, which is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 1/1 to furnish 10.18 g (60% of theory) of the title compound.