Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)#[CH:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCCC1>O.CC(C)=O.[Pd](Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:22]#[C:21][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc2ccccc2c1Br
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCNCC1
Product: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)OC(C)(C)C)ccc3ccccc23)c1
Temperature: 60 °C

Procedure:
A mixture of (1-bromo-naphthalen-2-yloxy)-acetic acid tert-butyl ester (Intermediate 217; 500 mg; 1.48 mmol), 1-ethynyl-3-(propane-1-sulfonyl)-benzene (618 mg; 2.97 mmol) and PPh3 (39 mg; 0.15 mmol) in water (4.40 ml) and Acetone (5.6 ml) was treated with palladium(II) chloride (13 mg; 0.07 mmol) and piperidine (295 μl; 2.97 mmol) and heated at 60° C. for 2 days. The reaction mixture was extracted with EtOAc, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a yellow sticky solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[O:18][C:19]([CH3:25])=[CH:20][C:21]=1[C:22]([Cl:24])=[O:23]>C1C=CC=CC=1>[ClH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:22]([C:21]3[CH:20]=[C:19]([CH3:25])[O:18][C:17]=3[CH3:16])=[O:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)N2CCN(CCCc3ccccc3)CC2)c(C)o1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 1 from a mixture of 1-(3-phenylpropyl)piperazine, 2,5-dimethyl-3-furoyl chloride and benzene.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](=[O:23])[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:14][C:13]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][C:6]3=[O:12])=[CH:11][C:2]=2[O:1][C:21]=1[C:20](=[O:23])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: N#Cc1cc2c(cc1O)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C(=O)c2oc3cc4c(cc3c2N)C(=O)CCC4)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 24 %

Procedure:
To a solution of 3-hydroxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile from method II-6 (45 mg, 0.24 mmol) and 3-methoxyphenacyl bromide (60 mg, 0.26 mmol, 1.1 eq) in anhydrous N,N-dimethylformamide (2 mL) was added potassium carbonate (66 mg, 0.48 mmol, 2 eq). The reaction mixture was shaken at 90° C. for 17 h. The mixture was cooled to room temperature and poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. Combined the organic layers and evaporated in vacuo. The crude product was washed with methanol and gave 19 mg (24%) of 3-Amino-2-(3-methoxy-benzoyl)-7,8-dihydro-6H-naphtho[2,3-b]furan-5-one as a yellow solid. 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 7.68 to 7.42 (m, 5H), 7.18 to 7.14 (m, 1H). 6.33 (s, 1H), 3.84 (s, 3H), 3.07 (t, J=6.0 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H), 2.50 (m, 2H); MS LC-MS (MH+=336.2); Rf=0.62, 50% ethyl acetate-hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22]OCC)[C:17]([C:19]([OH:21])=[O:20])=O)[CH3:13].[C:27](O)(=O)[CH3:28]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:17]([C:19]([O:21][CH2:27][CH3:28])=[O:20])=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:26])[CH:22]=[N:11]1)([O-:3])=[O:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)O
Reactant: CC(=O)O
Reactant: NNc1ccccc1[N+](=O)[O-]
Product: CCOC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1C(=O)OCC
Reaction time: 24 h

Procedure:
5 g. of 2-nitrophenylhydrazine are dissolved in 50 ml. of glacial acetic acid and 7.9 g. of ethoxymethyleneoxalacetic acid ethyl ester in 50 ml. of glacial acetic acid are slowly added dropwise. After the addition has been completed, the reaction mixture is refluxed for at least 3 hours. After cooling, the solvent is distilled off first under water vacuum and then under oil pump vacuum. The dark, oily residue is dissolved in 20 ml. of tetrahydrofuran, 10 ml. of ether are added and the mixture is kept in the refrigerator for 24 hours. The product, 1-(2-nitrophenyl)-1H-pyrazole-4,5-dicarboxylic acid, diethyl ester, is obtained in the form of large crystals, yield 11.5 g. The product is recrystallized from cyclohexane and obtained as yellow crystals; yield 9.8 g., m.p. 45°-46°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:22])=[C:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=O)[CH3:24].[K+].C(OC(=O)C)(=O)C.[N:35](OCCC(C)C)=O>C1C=CC=CC=1>[C:23]([N:22]1[C:12]2[C:13](=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[C:15]([C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])=[N:35]1)(=[O:26])[CH3:24]
Reactant: CC(C)CCON=O
Reactant: CC(=O)[O-]
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)n1nc(C(=O)OC(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of isopropyl 5-benzyloxy-2-aminophenylactate (13.2 g) in benzene (140 ml) were added potassium acetate (4.33 g) and then acetic anhydride (13.5 g) and the mixture was heated under reflux for 20 minutes. A solution of isopentyl nitrite (7.76 g) in benzene (30 ml) was added dropwise over 5 minutes under reflux and then refluxing was continued for further 3 hours. After allowing to cool to room temperature, insolubles were filtered off with Celite and concentrated under reduced pressure. The resulting residue (16.9 g) was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to give the title compound (10.9 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20][CH2:21][C:22](=O)[CH3:23]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:22]([CH3:23])[CH2:21][S:20][CH3:19])=[O:14])[CH3:2]
Reactant: CSCC(C)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Temperature: 25 °C
Reaction time: 22 h
Yield: 86.1 %

Procedure:
To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfanyl-2-propanone (7-0-1) (0.23 g) were added and stirred at room temperature for 22 hours under a nitrogen atmosphere. Additional 1-methylsulfanyl-2-propanone (7-0-1) (0.12 g) was added thereto, and the mixture was further stirred at room temperature for 7 hours. Then, the reaction mixture was concentrated under reduced pressure. After the concentration, the residue was subjected to column chromatography (hexane: ethyl acetate=1:1) to gave 0.58 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([Cl:15])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:37].Cl.Cl>C(OCC)(=O)C>[ClH:15].[ClH:37].[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reactant: CN1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: COc1cccc(C(c2ccc(Br)cc2)N2CCN(C)CC2)c1
Temperature: 25 °C

Procedure:
The crude benzhydryl chloride from above (6.5 g, 21 mmole) was added to 8.3 g (83 mmole) of 1-methylpiperazine and the reaction was heated to reflux for four hours. After cooling to room temperature, the mixture was dissolved in 100 ml of ethyl acetate and washed with two 150 ml portions of 1.0 M sodium hydroxide, followed by two 150 ml portions of water and 100 ml of saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and the solvent removed to give 6.5 g of crude product as an oil. The product was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.2:0.1) to give a colorless oil. A portion was converted to the dihydrochloride salt with ethanolic hydrochloric acid and precipitated from ethanol with 1:1 hexane:diethyl ether to give 1-(α-(4-bromophenyl)-3-methoxybenzyl)-4-methylpiperazine dihydrochloride as a white powdery solid, mp. 195°-197° C. Calc. for C19H23BrN2O 2HCl: C, 50.91; H, 5.62; N, 6.25; Total halogen calc. as Cl, 23.73. Found: C, 51.00; H, 5.66; N, 6.23; Total halogen calc. as Cl, 23.78.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:30][C:31]1[N:32]=[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]2[CH:39]=1>CS(C)=O>[N:32]1[C:31]([CH2:30][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)=[CH:39][N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=12
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: ClCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (31 mg, 0.1 mmol) in DMSO (0.5 mL), Cs2CO3 (65 mg, 0.2 mmol) and 2-(chloromethyl)imidazo[1,2-a]pyridine (18 mg, 0.11 mmol) were added at RT. The mixture was stirred at RT overnight. The resulting crude product was purified by pre-HPLC (Mobile phase: A=0.01% TFA/H2O, B=0.01% TFA/MeCN; Gradient: B=10%-50% in 20 min; Column: C18) and then a silica gel column with (EtOAc/Hexane 16% to 100% EtOAc) to give 5-(1-(imidazo[1,2-a]pyridin-2-ylmethyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (4 mg, 10%). MS (ES+) C20H14F3N7O2 requires: 441. found: 442 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.53 (d, J=6.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.01 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.51 (d, J=9.1 Hz, 1H), 7.26 (dd, J=7.5, 8.2 Hz, 1H), 6.91 (t, J=6.8 Hz, 1H), 5.66 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][C@@H:21]1[CH2:22][OH:23]>CO>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:26][CH2:25][CH2:24][C@@H:21]3[CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: OC[C@H]1CCCN1
Solvent: CO
Product: COc1ccc(-c2cc(N3CCC[C@@H]3CO)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 148-160° C., [α]D20=−62.6° (c=0.51, methanol) and MS: m/e=334 (M+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and D-prolinol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11].[O:14]=[C:15]1[NH:24][CH:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:33])[CH2:20][CH2:19][CH2:18][C:17]=2[N:16]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1>CN(C)C=O>[CH3:13][S:10]([CH2:9][CH2:8][N:24]1[CH:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[C:22]2[C:21](=[O:33])[CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[C:15]1=[O:14])(=[O:12])=[O:11]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CS(=O)(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
Potassium carbonate (67 mg, 0.486 mmol) and 1-bromo-2-(methylsulfonyl)ethane (68 mg, 0.365 mmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethylformamide (3 mL). The mixture is heated at 50° C. for 3 d and then purified by reversed phase HPLC (first purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 22 mg; ESI mass spectrum [M+H]+=518; Retention time HPLC: 0.86 min (Z011_S03).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](Cl)=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 4.40 g, 21.0 mmol) is suspended in dry tetrahydrofuran (100 mL) in a 250 mL round bottom flask under an inert atmosphere. The dimethyl 5-aminoisophthalate suspension is cooled to 0° C. for at least 30 min., and an ice cold suspension of 2-decyltetradecanoyl chloride in of dry tetrahydrofuran (80 mL) is added slowly, dropwise. The reaction is then allowed to slowly warm to room temperature and stir overnight. Deionized water (10 mL) is added and the tetrahydrofuran is removed by rotary evaporation. The crude residue is then dissolved in 250 mL of ethyl acetate, and is washed with 3 successive 100 mL portions of deionized water. The ethyl acetate is then removed from the organic phase by rotary evaporation and the product is dried in vacuo to give crude dimethyl 5-(2′-decyltetradecanamido)isophthalate (12.56 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[CH:2].S(Cl)([Cl:14])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[CH:2]
Reactant: O=S(Cl)Cl
Reactant: C#Cc1cccc(C(=O)O)c1
Product: C#Cc1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 298 μl (7.35 mmol) of methanol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue and extracted with 35 ml of diethyl ether. The ether layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was dissolved in 15 ml of hexane at 70° C., insoluble matter was removed by filtration and the filtrate was cooled to obtain 0.74 g of ethyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 66E)
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29](Cl)(=O)[C:30]([CH3:33])(C)[CH3:31].[CH2:36](N(CC)CC)[CH3:37].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC(C)C)(=O)C.O>[CH2:36]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16](=[O:18])[C:30]([CH3:33])([CH3:31])[CH3:29])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)[CH3:37].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)CC
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
10 g (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=1-1, R3=Et) in isopropyl acetate (50 ml) is added to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate (50 ml). The mixture is then stirred for 40 min at room temperature. Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added over a period of 1 h. The resulting mixture is stirred for 16 h. Citric acid (7.5 g) dissolved in water (30 ml) is added and the phases are separated. The organic phase is washed twice with water (30 ml) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1=Piv, R2=H, R3=Et). 1H NMR (DMSO): 1.05 (9H), 1.09 (3H), 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H), 2.72 (2H), 3.97 (1H), 4.00 (2H), 7.15 (1H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H), 7.62 (2H).
Reaction SMILES: C([N:20]([CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[N:48]=2)=[CH:40][CH:39]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.[ClH:56]>C(Cl)Cl.CCO.CO>[ClH:56].[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:39][CH:40]=1
Reactant: c1ccc(CCCCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: c1ccc(CCCCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(4-phenylbutoxy)ethanamine (600 mg) is dissolved in a solution of CH2Cl2 (10 ml) and EtOH (10 ml) and treated with a solution of EtOH/HCl until acidic by pH paper. The solution is concentrated in vacuo, then purified by column chromatography using 5% MeOH/CH2Cl2. The residue is isolated, dissolved in methanol and acidified with acidic methanol. The solution is concentrated to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(4-phenylbutoxy)ethanamine hydrochloride (m.p. 121°-125° C.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O1[C:22]2C(OC)=C1C(CCC)=[C:20]([O:26][C:27]1[CH:32]=[C:31]3O[C:29](=[C:30]3[O:34][CH3:35])[C:28]=1CCC)[CH:21]=2.C([OH:45])(C)C>>[CH3:35][O:34][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:20][CH:21]([OH:45])[CH2:22][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCc1c(Oc2cc3c(OC)c(c2CCC)O3)cc2c(OC)c1O2
Reactant: CC(C)O
Product: COc1ccc(OCC(O)CN2CCC(c3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20 mmol) and 2, epoxypropyl-4-methoxyphenyl ether (3.7 g, 20.5 mmol) in isopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixture was cooled and the crystals were collected to yield 6.81 g (85%), m.p.=134-135° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[S:9][CH:10]=1)=[O:5])C.CO.[OH-].[Na+].Cl>O1CCCC1>[Si:22]([O:21][CH2:20][C@H:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[CH2:13][CH2:12][S:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1csc(SCCN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CCSc1nc(C(=O)O)cs1
Reaction time: 1 h

Procedure:
To a solution of 2-(2-((2R)-2-(t-butyldimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid ethyl ester (240 mg; the compound described in Reference Example 17 of WO03/74483) in tetrahydrofuran (4 mL)-methanol (2 mL) was added 2N aqueous sodium hydroxide solution (2 mL) at room temperature and the solution was stirred for 1 hour. The reaction solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (240 mg) having the following physical data.