Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)=[O:21]>>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:17]([NH:16][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:18]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Cc1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cc1N
Product: COc1cc(C(=O)Nc2cc(C(=O)NCc3ccc(Cl)c(Cl)c3)ccc2C)cc(OC)c1OC

Procedure:
Using an analogous procedure to that described in Example 2, 3,4,5-trimethoxybenzoyl chloride was reacted with 3-amino-N-(3,4-dichlorobenzyl)-4-methylbenzamide to give the title compound which was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent; NMR Spectrum: (CDCl3) 2.28 (s, 3H), 3.87 (m, 9H), 4.48 (d, 2H), 7.13 (m, 5H), 7.36 (m, 2H), 7.52 (d, 1H), 8.01 (s, 1H), 8.13 (s, 1H); Mass Spectrum: M-H− 503.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 552.8 (M+H)+.
Reaction SMILES: C([NH:3]CC)C.C(OC([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](CCOS(C)(=O)=O)[CH:23]=2)[NH:18][C:17]=1C(F)(F)F)=O)C1C=CC=CC=1>>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[NH2:3]
Reactant: CS(=O)(=O)OCCc1ccc2[nH]c(C(F)(F)F)c(C(=O)OCc3ccccc3)c2c1
Reactant: CCNCC
Product: Nc1cc2ccccc2[nH]1
Yield: 20 %

Procedure:
Diethylamine (0.48 mL, 4.63 mmol, 3 eq) was added into the crude 5-(2-Methanesulfonyloxy-ethyl)-2-trifluoromethyl-1H-indole-3-carboxylic acid benzyl ester in dioxanes (20 mL) solution. The reaction mixture was heated to reflux overnight. After the solvent was removed, the residue was purified by gravity chromatography (SiO2, ethyl acetate-methanol-NH4OH) to yield the desire indole amine as pale yellow gel (20.0% yield). Elemental Analysis: C23H25F3N2O2.HCl: Calcd: C: 60.73; H: 5.76; N: 6.16. Found: C: 60.40; H: 5.83; N: 6.06. ESI-MS: m/z 419.73 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:23][CH:24]1[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[O:26][NH:25]1>ClCCl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([N:25]2[CH:24]([CH3:23])[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=3)[O:26]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(C2ONC(C)C=C2C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-N-acetylsulphanilyl chloride (1.14 g, 4.9 mmol) and triethylamine (0.82 g, 8.15 mmol) in dichloromethane (15 ml) was added a solution of 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine hydrochloride (0.88 g, 3.26 mmol) in dichloromethane (15 ml). The resulting solution was stirred at room temperature for 8 h then washed with water three times, aqueous sodium hydroxide (2M), water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to a foam. The crude product was purified on flash silica eluting with ethylacetate-hexane (3:2) to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3) δ 1.41(9H, m), 2.14(3H, s), 4.01(2H, q), 4.43(1H, m), 5.17(1H, s), 5.66(1H, d), 6.79(2H, d), 7.11(2H, d), 7.60(2H, d), 7.79(2H, d), 7.89(1H, bs).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[CH3:11])=[C:4]([C:12]4[O:13][C:14]([CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]5)=[N:15][N:16]=4)[CH:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)o2)CC1
Temperature: 110 °C
Yield: 41 %

Procedure:
6-Bromo-1-methyl-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (45 mg, 0.107 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26.1 mg, 0.107 mmol), sodium carbonate (34.1 mg, 0.322 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (7.85 mg, 10.73 μmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified firstly by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane then by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][CH:14]([O:21]CC)[CH2:15][C:16](OCC)=O)[CH3:12]>[N+](C)([O-])=O.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:16]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:21])[O:10][CH2:9][CH2:8]2
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: OCCc1cccc(Br)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)CC1OCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Titanium tetrachloride (1M in methylene chloride, 51 ml) is added over a period of 10 min to an ice-cooled mixture of 2-(3-bromophenyl)ethanol (XLV, 4.34 g, 21.6 mmol) and ethyl 3,3-diethoxypropionate (LXXXV, 4.93 g, 25.9 mmol) in nitromethane (5 ml). After stirring for 10 min, the ice bath is removed and the mixture is allowed to stir at 20-25° for 5 hr, at which time it is poured onto ice/aqueous hydrochloric acid (~1N). The mixture is extracted with dichloromethane and backwashed with hydrochloric acid (0.5N)/saline and saline. The organic phase is separated dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95). The appropriate fractions are pooled and concentrated to give ethyl (6-bromoisochroman-1-yl)acetate (LXXVII), NMR (CDCl3) 1.28, 2.66-2.87, 2.96, 3.768, 3.807, 4.11, 4.21, 5.19, 6.93 and 7.28 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:28]=[C:25]([CH3:26])[N:27]=[CH:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol was stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) of sodium methylate in one portion. After stirring for 10 min, 30 ml of methylene chloride was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride was repeated after another 2 hr and stirring at room temperature was continued overnight. After diluting with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization occurred when the residue was dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave a second crop of product. Recrystallization from hexane (charcoal) gave off-white crystals: mp 120°-122° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13]
Reactant: CC(C)c1ccc(O)c(C(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
To a solution of 2,4-diisopropyl-phenol (Intermediate 1, 10.0 g, 56 mmol) in acetic acid (20 mL) was added bromine (3.5 mL, 67 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min, quenched with water and extracted with EtOAc. The organic layer was washed successively with NaOH (4M, 85 mL), NaHSO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a light yellow oil (14.5 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[C:17]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(F)c1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 52 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,3-difluorophenylboronic acid (Aldrich; 529 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,3-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCCC1>[Pt]=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of ethyl (2E)-3-(2-fluoro-4-methoxyphenyl)acrylate (7.07 g, 31.5 mmol), tetrahydrofuran (50 mL), ethanol (5 mL) and platinum oxide (300 mg) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (5.97 g, yield 84%) as a colorless oil. 1H NMR (CDCl3) δ: 1.23 (3H, t, J=7.2 Hz), 2.58 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=7.6 Hz), 3.77 (3H, s), 4.12 (2H, q, J=7.2 Hz), 6.57-6.63 (2H, m), 7.07-7.13 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(=[O:17])[CH3:16].[OH-].[Na+]>CO>[C:15]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][S:14][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][C:9]=4[CH3:13])[N:4]=3)=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1)(=[O:17])[CH3:16]
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: CC(=O)OCCOc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)OCCOc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 56.5 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.888 g), 4-(4-acetoxyethoxybenzoyl)benzyl bromide (3.895 g) and 1N-aqueous sodium hydroxide solution (14.3 ml) in methanol (30 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and extracted with chloroform. The extract was washed with water, dried, and concentrated, and the residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (2.597 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:42]([OH:44])=[O:43])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[CH3:55][C:54]([CH3:57])([CH3:56])[C:53](=[O:58])[CH2:52][O:43][C:42]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1)=[O:44]
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 57.5 °C
Reaction time: 0.67 h

Procedure:
50 mL N,N-dimethylformamide, 5 g of 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester, 1.8 g of anhydrous potassium carbonate and 2.3 mL of 1-bromo-3,3-dimethylbutan-2-one are added into a 3 neck round bottomed flask. The reaction mixture is heated to 55-60° C. and stirred for 20-60 min. After completion of reaction, the mixture is cooled to 25-30° C. and 100 mL of ice water are added. The slurry is stirred at 25-30° C. for about 30 min and filtered. The product is washed with 50 mL demineralized water, then by 20 mL isopropyl alcohol and suck dried for about 30 mins. Finally the product is dried at 35-40° C. under vacuum to yield 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([O:13][CH3:20])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 4 h

Procedure:
A solution of 2 g (8 mmol) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl2 H-1-benzopyran-2-carboxylic acid (1) and 0.1 g of p-toluenesulphonic acid monohydrate in 40 ml methanol were stirred and re-fluxed for 4 hours. After cooling, the solution was diluted with water, extracted three times into ether that was subsequently washed with brine and aqueous sodium bicarbonate solution. The ether solution was washed, dried with MgSO4 and evaporated to give (R)-(+)-methyl 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2 H- 1-benzopyran-2 carboxylate (2).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[NH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([NH:20][C:21]([N:4]1[C:5]([CH3:8])([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]1)=[O:22])(=[O:18])=[O:19]
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CC1=NNC(C)(C)C1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=NN(C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)C(C)(C)C1

Procedure:
11.2 g of the 3,5,5-trimethyl-2-pyrazoline obtained according to example I(b) are added dropwise while stirring, cooling in cold water and under a nitrogen blanket to a solution of 25.2 g of the 2,6-dichlorobenzenesulphonylisocyanate obtained according to example I(a) in 200 ml of dry toluene. After stirring at room temperature for two hours, the precipitate is sucked off and washed successively with dry toluene and petroleum ether (40-60). The desired 1-(2,6-dichlorophenylsulphonylcarbamoyl)-3,5,5-trimethyl-2-pyrazoline is obtained in a yield of 20.07 g; melting-point 270° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=C(C=CC=2)C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CCCCCCCCC1C=CC=CC=1)[CH:31]([OH:36])[C:32]([O:34]C)=[O:33])([O:25]C)=[O:24]>>[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:42]=1)[CH:31]([OH:36])[C:32]([OH:34])=[O:33])([OH:25])=[O:24]
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC
Reactant: O=Cc1cccc(CCCCCCCCc2ccccc2)c1
Product: O=C(O)CCSC(c1cccc(CCCCCCCCc2ccccc2)c1)C(O)C(=O)O

Procedure:
Similarly, following the procedure of Example 7(b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8-phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a), (b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:10]([CH:13]=1)[CH2:11][NH2:12].[C:20]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:16][CH:17]([OH:19])[CH2:18]2)=[C:10]([CH:13]=1)[CH2:11][NH:12][C:29](=[O:30])[C@@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: NCc1cc(Cl)ccc1CN1CC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(O)C1
Yield: 9.4 %

Procedure:
EDC (1.51 g, 7.87 mmol) was added to a stirred mixture of 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzylamine (1.19 g, 5.25 mmol), N-Boc-L-proline (1.13 g, 5.25 mmol) and HOAT (0.36 g, 2.62 mmol) in DMF (9 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4)and evaporated. The residue was partitioned between EtOAc and 1M citric acid. The aqueous layer was made neutral with NaHCO3 and was extracted into CH2Cl2. The organic layer was evaporated and the residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 95:5) to give N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (210 mg) as a glass: MS: 424.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: Nc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CC#Cc1cncc(N)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a degassed solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) and N,N-dimethylprop-2-yn-1-amine (1.57 mL, 14.6 mmol) in TEA (26 mL) were added bis(triphenylphosphine)palladium(II)chloride (0.203 g, 0.29 mmol) and copper iodide (0.110 g, 0.58 mmol). The reaction mixture was allowed to stir under an atmosphere of argon at 80° C. for 14 h. The reaction mixture was allowed to cool to rt and then filtered through Celite. The filter pad was washed with EtOAc and the filtrate was concentrated. The residue was purified by column chromatography to give 5-[3-(dimethylamino)prop-1-yn-1-yl]pyridin-3-amine (0.55 g, 54%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([O:17]C)=[O:16])[O:8][N:7]=1)([CH3:5])=[CH2:4]>O.CO>[C:3]([C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([OH:17])=[O:16])[O:8][N:7]=1)([CH3:5])=[CH2:4]
Reactant: C=C(C)c1noc(C(=O)OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)c1noc(C(=O)O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
At 0° C., a solution of 3.6 g (0.09 mol) of sodium hydroxide in 75 ml of water was dripped into 20.0 g (0.09 mol) of dimethyl 3-isopropenylisoxazole-4,5-dicarboxylate (from stage A.1) in 150 ml of methanol, and the mixture was stirred for 14 hours at room temperature. 250 ml of water was added, the pH was adjusted to 8, extraction was effected with 200 ml of dichloroethane, and the aqueous phase was adjusted to a pH of 1-2 with 6N hydrochloric acid and extracted three times, each time with 250 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Yield: 97%; 1H-NMR (in CDCl3): δ=2.12 ppm (s; 3H), 4.07 ppm (s; 3H), 5.41 ppm (m; 2H); 8.00 ppm (bs; 1H).