Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[O:18][CH3:19])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br.C(COC1C=CC(N=NC2C=CC(CO)=CC=2)=CC=1)(OC)=O>CC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[CH:13][C:12]=2[O:18][CH3:19])=[CH:7][CH:8]=1
Reactant: COc1cc(O)ccc1N=Nc1ccc(CO)cc1
Reactant: COC(=O)CBr
Agent: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)c(OC)c1
Reaction time: 12 h

Procedure:
Compound 2 (0.375 g, 1.45 mmol) was dissolved in 20 mL anhydrous acetone to which K2CO3 (0.6 g, 4.35 mmol) was added, followed by methyl-bromoacetate (0.15 mL, 1.59 mmol) at room temperature and reaction mixture stirred for 12 hours. The remaining procedure was followed as described for compound 3 to obtain compound 4. Yield: 0.41 g (86%). 1H NMR (500 MHz, CD3SOCD3) δ 3.71 (s, 3H, H, (OMe)), 3.94 (s, 3H, aromatic-OCH3), 4.56 (d, 2H, J=6.0 Hz, Hf), 4.93 (s, 2H, Hl), 5.34 (t, 1H, J=6.0 Hz, —OH), 6.54-6.64 (m, 1H, Hb), 6.78-6.82 (m, 1H, Hc), 7.45-7.49 (m, 2H, He), 7.57-7.61 (m, 1H, Ha), 7.73-7.78 (m, 2H, Hd). 13C NMR (125 MHz, CD3SOCD3) δ 51.96 (Cm), 52.2 (aromatic-OMe), 62.5 (Cf), 64.8 (Cl), 100.0 (Cc), 106.4 (Cb), 117.2 (Ci), 122.1 (Cd), 127.0 (Ce), 136.2 (Ca), 145.3 (Ck), 151.4 (Cj), 158.4 (Ch), 161.7 (Cg), 168.8 (CO). ESI-MS: [M+H]+ C17H19N2O5 calcd 331.1294, obsd 331.11.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCOC(=O)c1cccc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 100 °C
Reaction time: 28 h
Yield: 23.4 %

Procedure:
Under a nitrogen atmosphere, 6.0 g (0.0176 mole) of 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 2.53 g (0.0176 mole) of 2-dimethylaminoethyl chloride hydrochloride were dissolved in 17 ml of N,N-dimethylformamide. To this mixture was added 4.9 ml (0.035 mole) of triethylamine and the reaction was heated at 100° C. for 25 hours. The reaction temperature was then raised to 120° C. and heating was continued for an additional 28 hours. The reaction mixture was diluted with 10 ml of diethyl ether, then filtered to remove triethylamine hydrochloride. The filtrate was diluted with additional diethyl ether and then shaken with cold 10% hydrochloric acid. A middle layer contained most of the product hydrochloride. It was diluted with water and ether, and basified with solid sodium carbonate. The ether extract was washed with saturated aqueous sodium chloride and then concentrated to give 1.7 g of a tan solid, m.p. 119°-120° C. This material was recrystallized first from 20 ml of cyclohexane and then from a mixture of 10 ml of ethanol and 3 ml of water to give 1.48 g of light yellow prisms of N,N-dimethyl-2-aminoethyl 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoate m.p. 123°-124° C. Analysis: Calculated for C25H36N2O3 : % C, 72.8; % H, 8.8; % N, 6.8. Found: % C, 73.0; % H, 8.8; % N, 6.7.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:10])[CH2:8][CH3:9].CN(C=O)C.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32](Cl)[C:31]([S:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]>CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32]([S:10][CH2:7][CH2:8][CH3:9])[C:31]([S:35][C:36]2[CH:37]=[CH:38][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:40][CH:41]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]
Reactant: CCCS
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
Cesium carbonate (65 mg, 0.2 mmol) was added to a solution of propanethiol (8 μl, 0.09 mmol) in acetone (0.5 mL). The reaction mixture was heated to 50° C. for 45 minutes then cooled to r.t. DMF (2 mL) and 2,4-Dichloro-N-{4-chloro-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyrimidin-2-yl}-benzenesulfonamide 11 (50 mg, 0.08 mmol) were added and the resultant mixture heated to 50° C. for 2 hours. The reaction was allowed to cool, filtered through celite and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (2% MeOH in DCM) to afford 2,4-Dichloro-N-{5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-4-propylsulfanyl-pyrimidin-2-yl}-benzenesulfonamide 32 (20 mg). 1H NMR (CDCl3): δ 1.00 (m, 3H), 1.27 (m, 2H), 1.66 (m, 6H), 2.88 (m, 2H), 2.99 (m, 4H), 7.26 (m, 2H), 7.45 (d, 1H), 7.55 (s, 1H), 7.66 (d, 2H), 8.27 (d, 1H), 8.5149 (s, 1H), 12.61 (br s, 1H) ppm. Mass Spectrum m/e=632.8 (M+1).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)pyridin-4-yl)propanoate (140 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate and hexane to give the title compound (123 mg) as a white solid.
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:22][CH3:23])=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[C:1]12([C:11]3[C:12]([O:22][CH3:23])=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=3)[C:16]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:25]=3[OH:24])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NCc1ccc(O)cc1O
Reactant: COc1cc(OC)c(C23CC4CC(CC(C4)C2)C3)cc1C(=O)O
Product: COc1cc(OC)c(C23CC4CC(CC(C4)C2)C3)cc1C(=O)NCc1ccc(O)cc1O

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2,4-dimethoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16][CH3:17])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[OH:19]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16]([CH3:17])=[O:19])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: OO
Reactant: CSc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 32.6 gm (0.1 mol) of 2-chloro-4-(2,5-dichloro-4-methylmercaptophenoxy)-pyridine, prepared analogously to Example 1, was suspended in 100 ml of glacial acetic acid. The mixture was warmed to 45° to 50° C., and 11 ml (0.11 mol) of 30% H2O2 were added dropwise at such a rate that the internal temperature did not exceed 50° C. The mixture was then stirred for 3 hours at 50° C., after which it was cooled and poured into 300 ml of water. The batch was stirred until crystallization was complete, and the product was recovered by suction filtration, washed with water, dried, and recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([O:15][CH2:16][CH2:17][CH3:18])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:20].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([O:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:19]([NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1)=[O:20]
Reactant: CCCOC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
0.18 g of methyl 3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2propoxypropanoate was dissolved in 2 ml methanol, and 2 ml of 1 N sodium hydroxide was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.15 g of 3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propoxypropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:9][OH:10])=O.FC1C=CC=C(F)C=1C(NC(C1C=CC(Cl)=CC=1)CCO)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]1[O:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1
Reactant: O=C(NC(CCO)c1ccccc1)c1c(F)cccc1Cl
Agent: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Product: Fc1cccc(Cl)c1C1=NC(c2ccccc2)CCO1
Yield: 66.6 %

Procedure:
The procedure is as for Example 85, but 3.5 g (11.4 mmol) of N-(2-chloro-6-fluorobenzoyl)-3-amino-3-phenyl-1-propanol are employed instead of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol. 2.2 g (66.8%) of 2-(2-chloro-6-fluorophenyl)-4-phenyl-5,6-dihydro(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: [CH2:1]1[S:9](=[O:11])(=[O:10])[O:8][CH2:7][CH2:6][O:5][S:2]1(=[O:4])=[O:3].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1>C(COC)OC.[OH-].[Na+]>[CH2:1]([S:9]([OH:8])(=[O:11])=[O:10])[S:2]([O:5][CH2:6][C:7]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)(=[O:4])=[O:3].[CH2:14]=[CH2:15]
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: C=C
Product: O=S(=O)(O)CS(=O)(=O)OCc1ccccc1
Yield: 34.7 %

Procedure:
To a solution of 2.6 g of ethylene methanedisulfonate in 50 mL of glyme and 1.0 g of NaH was added 3 g of benzyl chloride. After rotoevaporation of the glyme the residue was taken up in 25 mL of 0.5 M NaOH, filtered, and acidified to give 1.21 g of ethylene benzyl methanedisulfonate, m.p. 170-174° C. (90-3).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([N+:11]([O-])=O)[CH:10]=1)(=[O:4])=[O:3].NC1C=CC=CC=1.[N-]=[C:23]=[O:24]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([N:11]=[C:23]=[O:24])[CH:10]=1)(=[O:4])=[O:3]
Reactant: [N-]=C=O
Reactant: Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Solvent: Nc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)cc1N=C=O

Procedure:
5-Methylsulfonyl-2-methylphenyl isocyanate was prepared from the corresponding 5-methylsulfonyl-2-methyl-1-nitrobenzene via reduction to the corresponding aniline followed by conversion to the isocyanate as described previously.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[O:10][C:11]([CH3:32])=[C:12]([CH:14]([OH:31])[CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)[N:13]=1.O>CS(C)=O>[CH3:8][C:9]1[O:10][C:11]([CH3:32])=[C:12]([C:14](=[O:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[N:13]=1
Reactant: Cc1nc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)o1
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)o1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
Acetic anhydride (1.0 ml) was added to a solution of 5-{4-[2-(2,5-dimethyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione (0.5 g) in dimethylsulfoxide (10 ml), and the mixture was allowed to stand overnight and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concetrated. The oily residue was chromatographed on a column of silica gel (40 g), and from the fractions eluted with benzene-acetone (9:1 V/v), there was obtained 5-{4-[2-(2,5-dimethyl-4-oxazolyl)-2-oxoethoxy]benzyl}-2,4-thiazolidinedione (0.24 g, 48.3%). Recrystallization from ethyl acetate-hexane afforded colorless plates, m.p. 161°-162° C. Elemental analysis for C17H16N2O5S, Calcd.: C, 56.66; H, 4.47; N, 7.77. Found: C, 56.62; H, 4.38; N, 7.60.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([OH:36])[C:34]#[CH:35]>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:35]#[C:34][C:33]([OH:36])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:32]([F:43])([F:44])[F:31])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CC(O)(c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(O)(c3ccccc3)C(F)(F)F)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl)naphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 1,1,1-trifluoro-2-phenylbut-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (m, 3H), 7.67 (s, 1H), 7.55 (m, 4H), 7.46 (m, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 5.07 (s, 1H), 2.66 (s, 3H), 0.94 (s, 9H). LCMS-ESI+ (m/z): [M-OH]+ calcd for C31H32ClF3O3: 563.2. found: 563.1.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[OH-:19].[Na+].[CH2:21]1[CH2:25][O:24]CC1>C(OCC)(=O)C>[O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1/[CH:15]=[CH:21]/[C:25]([OH:19])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=Cc1cccn1CCOc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/c1cccn1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 1-(2-phenoxyethyl)-1H-pyrrole-2-carbaldehyde (0.68 g, 3.2 mmol) triethyl phosphonoacetate (0.76 mL, 3.8 mmol) in THF (20 mL) was added NaH (91 mg, 3.8 mmol. 60% wt.). The mixture was stirred for 2 hr at room temperature then diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated. The crude ethyl ester was stirred in MeOH (20 mL) and NaOH (0.9 g, 22 mmol/dissolved in 10 mL H2O) was added. After stirring at room temperature for 24 hr, the solution was concentrated and then diluted with H20 (50 mL) and extracted with ether (2×100 mL). The aqueous layer was acidified (1N HCl) to pH=2-3 and then extracted with ethyl acetate (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 0.47 g (58%) of (E)-3-(1-(2-phenoxyethyl)-1H-pyrrol-2-yl)acrylic acid as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([NH2:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[NH2:20]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(=O)C(N)Cc1ccccc1
Product: NC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 370 (M+1). 1H-NMR (400 MHz, DMSO-d6), δ (ppm) 3.02-3.07 (m, 1H); 3.17-3.22 (m, 1H); 4.90-4.95 (m, 1H); 7.09-7.24 (m, 6H); 7.49-7.62 (m, 3H); 7.96 (d, 2.4 Hz, 1H); 8.52 (d, 6.4 Hz, 1H); 8.72 (s, 1H).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=S.[Br:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]2[NH:13][C:2]([NH:1][CH3:4])=[N:12][C:10]=2[CH:11]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: CN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1nc2cc(Br)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+.
Reaction SMILES: [OH:1][CH:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH:3]1[CH3:19]>CO.[C].[Pd]>[CH3:19][CH:3]1[CH:2]([OH:1])[C:6]([CH3:8])([CH3:7])[CH2:5][NH:4]1
Reactant: CC1C(O)C(C)(C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1NCC(C)(C)C1O
Yield: 123.9 %

Procedure:
A suspension (20 mL) of benzyl (2RS,3SR)-3-hydroxy-2,4,4-trimethylpyrrolidine-1-carboxylate (842 mg) and 10% palladium carbon (50% water-containing, 110 mg) in methanol was stirred under a hydrogen atmosphere for 1.5 hr. The reaction mixture was filtered, oxalic acid (144 mg) was added to the filtrate, and the mixture was concentrated under reduced pressure to give the title compound as a colorless solid (yield: 512 mg, yield: 92%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:22](=[O:24])[C@H:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][CH3:13])[CH3:25])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Temperature: 4 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
0.37 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.41 g of (S)-2-(2-methoxyphenyl)-propionic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at 4° C. and then a solution of 0.75 g (3aR,4S,7aR)-7,7-diphenyl-4-perhydroiso-indolol hydrochloride is added. The reaction mixture is stirred at room temperature for 20 hours and then then washed twice with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm, height 37 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate and cyclohexane mixture (50/50 by volume) and collecting fractions of 50 cm3. Fractions 21 to 41 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in isopropyl oxide and then dried. 0.3 g of (3aR,4S,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol is obtained in the form of a white meringue.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC(=O)[NH:37][C:38]([CH3:50])([CH3:49])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1)(C)(C)C>>[NH2:37][C:38]([CH3:50])([CH3:49])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:43][CH:42]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 74.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (32 mg) was obtained.