Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:4][CH3:5].Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)[CH2:4][CH3:5]
Reactant: CCCc1ccc(S)cc1
Reactant: CCCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
1.6 g (0.033 mole) sodium hydride (50% dispersion in mineral oil) was added to a solution of 5.0 g (0.033 mole) 4-propylthiophenol in 25 ml anhydrous dimethylformamide. After 15 minutes, 8.8 g (0.033 mole) ethyl 2-bromononanoate (prepared according to J. Labelled Compounds Radiopharm. 14, 713 (1978)) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with 150 ml ethyl acetate and the resulting mixture was washed with 5--60 ml water and then with 60 ml saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on 600 g silica gel, eluting with 7:3 hexane/methylene chloride to yield 9.0 g (81% yield) of the desired product as an oil.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
2-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[Br:58][C:59]1[CH:71]=[CH:70][CH:69]=[CH:68][C:60]=1[O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Br:58][C:59]1[CH:71]=[CH:70][CH:69]=[CH:68][C:60]=1[O:61][CH:62]1[CH2:67][CH2:66][N:65]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:64][CH2:63]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.08278 g, 0.00032 mol) in DMF (2 mL) was added, DIPEA (0.104 g, 0.00081 mol), HOBt (0.0437 g, 0.00032 mol) and EDCI.HCl (0.0619 g, 0.00032 mol) at ambient temperature. After 2 minutes 4-(2-bromo-phenoxy)-piperidine trifluoroacetate (0.1 g, 0.00027 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC [(column-Zorbax XDB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/acetonitrile (B), gradient: (Time): (% B)-0:50; 2:50; 5:80)]) to afford 0.033 g (22%) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 493.1 (M+1)+, 98.35%, 1H NMR (DMSO-d6): δ 8.65 (t, 1H), 8.0 (d, 2H), 7.8 (m, 4H), 7.6 (dd, 1H), 7.52 (t, 2H), 7.4 (m, 2H), 7.24 (m, 1H), 6.95 (m, 1H), 4.8 (m, 1H), 4.3 (m, 2H), 3.7 (m, 2H), 3.55 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][C:18]([NH2:20])=[O:19])=[C:8]1[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH3:21])=[C:9]2[CH2:17][C:18]([NH2:20])=[O:19])[CH3:32]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Reaction time: 1 h
Yield: 53 %

Procedure:
1-Hexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (230 mg, 0.8 mmol) was dissolved in 10 mL of DMF and 26 mg (0.8 mmol) of 60% NaH/mineral oil added. The mixture was stirred for 1 hour, 0.115 mL (0.8 mmol) of ethyl 4-bromobutyrate added and stirring continued for 96 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with water and dried (Na2SO4). The solution was concentrated at reduced pressure and the residue chromatographed on silica gel (eluted with 3% MeOH/methylene chloride) to give 170 mg (53% yield of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 69-71° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCOC3)c2n1
Reaction time: 16 h
Yield: 63.7 %

Procedure:
2-Butoxy-8-methoxy-9-[2-(tetrahydro-2H-pyran-3-yl)ethyl]-9H-purin-6-amine (108 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 16 h the reaction mixture was stripped, quenched with water then saturated sodium hydrogen carbonate added, when a solid precipitated. This was filtered, washed with water and dried. The solid was treated with hot methanol and was filtered after allowing to cool to yield 66 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[O:8].N1CCCCC1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:30][C:31]([OH:33])=[O:32])=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1

Procedure:
31.75 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-benzaldehyde (m.p. 115°-116° C.) and 1 ml. piperidine are added to 11.5 g. malonic acid in 100 ml. anhydrous pyridine. The reaction mixture is heated on a waterbath until the evolution of carbon dioxide is finished. After cooling, the reaction mixture is poured on to ice/concentrated hydrochloric acid and the precipitate formed is filtered off with suction, whereafter it is recrystallized from ethanol. There are obained 23.4 g. (about 65% of theory) 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 197°-198° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[OH:16][C:17]1[CH:41]=[CH:40][C:20]([C:21]([NH:23][CH2:24][C@H:25]([N:30]2[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:19][CH:18]=1>CN(C)C=O>[CH3:39][S:36]([N:33]1[CH2:32][CH2:31][N:30]([C@@H:25]([CH2:24][NH:23][C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:41][CH:40]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:35][CH2:34]1)(=[O:37])=[O:38]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2ccncc2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
1 g (3.2 mmol) of caesium carbonate and 280 mg (1.7 mmol) of 4-chloromethylpyridine hydrochloride are added to a solution of 560 mg (1.4 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate (prepared as described in example 4-4) diluted in 20 ml of dimethylformamide. The reaction medium is stirred at 80° C. for 24 h. The reaction medium is cooled, hydrolysed and extracted with ethyl acetate. The organic phase is washed once with water and once with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 30/70 heptane/ethyl acetate mixture+10% methanol. 430 mg (62%) of methyl (S)-2-(4-methane-sulphonylpiperazin-1-yl)-3-[4-(pyridin-4-ylmethoxy)-benzoylamino]propanoate are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:10])=[O:6].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH:8]([C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:10])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1cccc(Cl)c1)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1cccc(Cl)c1)C(=O)c1ccsc1
Yield: 62.6 %

Procedure:
11.0 g of N-(3-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 2.17 g of 50% sodium hydride and 7.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 9.0 g of ethyl 3-(3-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained. Yield: 62.5%
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.CC[O:28]C(C)=O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH:13]=[O:28])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: N#CC1(c2ccc(C(F)(F)F)nc2)CCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=CC1(c2ccc(C(F)(F)F)nc2)CCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of Example 85E (1.45 g, 6.45 mmol) in DCM (50 mL) was added dropwise a solution of DIBAL (7.74 mL, 7.74 mmol, IM in toluene) at −78° C. under nitrogen. After stirring for 3 hours at −78° C., the reaction was quenched with saturated NH4Cl (10 mL) and the resulting mixture was extracted with dichloromethane (30 mLx2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with petroleum ether:EtOAc=100:1-100:3 to provide the title compound (733 mg, 3.2 mmol, 49% yield) as colorless oil. LC-MS: m/z 230 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:20]>>[C:1]1([CH:7]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)COC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate I(3)) (2.58 g, 10.52 mmol) in ammonium hydroxide (28.7 mL, 736 mmol) was heated to 80° C. in a sealed tube and stirred overnight. The reaction mixture was then concentrated to dryness giving 8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione. The crude material was carried on as-is. LC-MS (M+H)+=245.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCc1ccncc1
Reactant: BrCCCCCCBr
Product: BrCCCCCCOCCCc1ccncc1

Procedure:
From 4-pyridinepropanol (2.0 g) and 1,6-dibromohexane (8 ml), with a reaction time of 30 min. FCC eluting with hexane→ether gave the title compound as a colourless oil (1.1 g), t.l.c. (ether) Rf 0.45.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16]>O1CCOCC1>[Cl:13][C:6]1[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride is added to a mixture of 2,6-dichloro-3-nitropyridine, methyl glycolate and 1,4-dioxane at 10° C. The mixture is stirred at room temperature for 2 hours, then, poured into ice water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7]1=[O:21])=O)C.[BH4-].[Na+]>C(O)C>[OH:3][CH2:4][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7]1=[O:21]
Reactant: CCOC(=O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1C(CO)CCN1c1cccc(C(F)(F)F)c1
Temperature: 12.5 °C
Reaction time: 3.5 h
Yield: 42.7 %

Procedure:
A mixture of 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester obtained in step 2 (0.5 g, 1.6 mmol) and ethanol were cooled to 10-15° C. Sodium borohydride (0.126 g, 3.3 mmol) was added portion wise over a period of 20 min and the reaction mixture was stirred for 3.5 hrs at 20-25° C. The organic volatiles were evaporated and the residue was taken into brine solution (15 ml). The aqueous layer was extracted with ethyl acetate, dried over Na2SO4 and evaporated to obtain brown semi solid which was purified by preparative TLC to afford 3-Hydroxymethyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one as a colorless oil (0.177 g, 43%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([CH:37]3[CH2:38][CH:39]=[CH:40][CH2:41][CH2:42]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(C(=O)NCCO)CC2)cc1C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)NCCO)CC3)cc2C2CC=CCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-amide (as prepared in the previous step, 95 mg, 0.16 mmol) in 3 mL of DCM was added 0.10 mL of EtOH followed by 1.0 mL of TFA. The resulting solution was stirred at RT for 6 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-8% MeOH/DCM) gave 68 mg (92%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.09 (d, 1H, J=8.4 Hz), 8.00 (s, 1H), 7.15 (dd, 1H, J=8.4, 2.2 Hz), 5.79 (m, 1H), 4.15 (dd, 2H, J=13.3, 1.1 Hz), 3.61 (t, 2H, J=5.9 Hz), 3.27-3.32 (m, 2H), 2.90 (ddd, 2H, J=13.0, 13.0, 2.5 Hz), 2.73 (dddd, 1H, J=12.1, 12.1, 2.6, 2.6 Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J=12.6, 12.6, 12.6, 4.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C25H30N6O3, 463.2 (M+H). found 463.2.
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-]>CO.[Pd]>[CH2:15]([N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[CH:4]([NH2:1])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC(CC)C(N=[N+]=[N-])c1nccn1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)C(N)c1nccn1Cc1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 5% Pd/C (200 mg) and 2-(1-azido-2-ethylbutyl)-1-benzyl-1H-imidazole (585 mg, 2.06 mmol) in methanol (25 mL) was shaken on a Parr apparatus for 1 h under 45 psi of H2. The mixture was filtered through a plug of Celite, washed well with methanol and concentrated in vacuo to yield the amine as an oil in 84% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([OH:7])=O.[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:28]1[C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=[CH:30][C:29]=1[S:33]([NH2:36])(=[O:34])=[O:35])=[O:7]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3c([N+](=O)[O-])cccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 32.6 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 3-nitrobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 7 mg (33%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:17]/[CH:18]([OH:28])[C:19]2[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:14][C:13]([CH3:30])([CH3:29])[C:12]1=[O:31])C.[OH-].[Na+]>CO>[OH:28][CH:18]([C:19]1[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=1)/[CH:17]=[CH:16]/[C@@H:15]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH2:14]1
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(O)c1ccc(C(F)(F)F)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C[C@H](/C=C/C(O)c2ccc(C(F)(F)F)o2)N(CCCCCCC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-{(R)-5-[(E)-3-hydroxy-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-3,3-dimethyl-2-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (89 mg, 0.2 mmol) was dissolved in methanol (3 mL) and the solution cooled in an ice bath. A 20% solution of sodium hydroxide (0.280 mL, 1.4 mmol) was slowly added and when the addition was complete, the reaction flask was left stirring overnight at room temperature. The reaction solution was concentrated under vacuum; the residue was suspended in 5 mL of 0.1 N solution of sodium hydroxide and it was washed twice with diethyl ether. The solution was then acidified with 1 N hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate giving after concentration 55 mg of 7-{(R)-5-[(E)-3-hydroxy-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-3,3-dimethyl-2-oxo-pyrrolidin-1-yl}-heptanoic acid (55) (80). MS: 432 [(M+H)+].
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-methylbenzenesulfonyl chloride (1.60 g, 8.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×40 mL). The organic phase was washed with brine (2×30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (2.1 g, 76%). 1H-NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 5.33 (s, 1H), 2.41 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[CH:7](=O)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10]>C1(C)C(C)=CC=CC=1>[CH:7](=[C:6]1[N:2]([NH2:1])[CH:3]=[N:4][NH:5]1)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10]
Reactant: Nn1cnnc1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1C
Product: NN1C=NNC1=Cc1ccccc1O
Yield: 94.7 %

Procedure:
4-amino-1,2,4-triazole (4.2 g.), salicylaldehyde (6.1g.) and xylene 140 ml. were heated at reflux for 3 hr. The reaction mixture was cooled and filtered to afford 9 grams of product, m.p. 210°-12°.
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[CH3:5][C:6]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].Cl>O>[Br:3][C:12]1[C:13]([CH3:15])=[CH:14][C:6]([CH3:5])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(C(=O)O)cc1Br
Reaction time: 0.75 h
Yield: 65 %

Procedure:
To the stirred solution of NaOH (60 g) in water (1152 ml) was added bromine (36 ml) dropwise at 0° C. and stirred the reaction mixture for 45 min. at same temperature. 2,4-dimethylbenzoic acid (12 g, 79.9 mmol) was added in above reaction mixture at 0° C. portion wise and stirred the reaction at room temperature for 3 h. After completion of reaction of reaction (TLC) reaction mixture was acidified using conc. HCl, solid was filtered through Buchner funnel and wash with water and dried to afford the desired compound (12 g, 65%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1>>[N:12]1([CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([N:19]3[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]3)=[CH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=c1cccn[nH]1
Reactant: Brc1ccc([C@H]2C[C@@H]2CN2CCCCC2)cc1
Product: O=c1cccnn1-c1ccc([C@H]2C[C@@H]2CN2CCCCC2)cc1

Procedure:
Following the general procedure, reaction of 7b (2.67 g assayed, 9.08 mmol) with 3(2H)-pyridazinone (1.14 g, 11.8 mmol) afforded a solution of the free base of 8b in an assayed yield of 2.61 g (93% assay yield, 95% peak area).