Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.CN1[CH:13]=[CH:12][N:11]=[CH:10]1.[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>CCOC(C)=O>[C:1]([C:12]1[N:11]=[CH:10][C:6]([C:1]2([CH2:2][CH3:3])[CH2:7][CH:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:13]=1)([CH3:7])([CH3:6])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1ccccc1
Reactant: Cn1ccnc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1(CC)c1ccc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a toluene (100 ml) solution of the compound of example 62B (1.89 g, 10 mmol), Co(TPP) (0.17 g, 0.25 mmol), 1-methyl-1H-imidazole (2.39 ml, 30 mmol), and ethyl diazoacetate (1.58 ml, 15 mmol) were added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 1.5 hours at 80° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel, eluting with hexane/EtOAc (1:10), to give the title compound (1.34 g, 49%, trans) as a brown oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1cccnc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyridin-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 247, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyridin-3-yl)acetamido)propanamide (3 mg, 50%). MS (EI) for C29H26FN3O4. found 500.5 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH2:4][CH2:3][O:2]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:11]
Reactant: O=C1OCCc2cnccc21
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccncc2CCO)cc1

Procedure:
3,4-Dihydro-1H-pyrano[4,3-c]pyridin-1-one (I-67e: 100 mg, (0.666 mmol) in THF (1 mL) was refluxed with p-methoxybenzylamine (0.9 mL, 6.66 mmol) to afford 220 mg of the crude product. LCMS: 95.54%, m/z=287.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH:10]=[CH:11][C:12]4=[O:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]4=[O:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)C=C[C@@H]12
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
0.5 g. of 3-methoxy-14α-estra-1,3,5(10), 8,15-pentaen-17-one in 25 ml. of ethanol is reduced catalytically with 50 mg. of 5% palladium-on-charcoal until a molar equivalent of hydrogen is taken up. The catalyst is filtered off and the filtrate evaporated to dryness to yield the known 3-methoxyestra-1,3,5 (10),8-tetraen-17-one which can be converted into estrone methyl ether by procedures outlined in Chemistry & Industry (London), 1022 (1960) or into 19-nor-Δ4 -steroids using the procedure of, for example, U.S. Pat. No. 3,318,922.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([N:9]2[CH2:13][CH2:12]C(C)(C)[C:10]2=[O:16])=[N:5][N:6]([CH3:8])[CH:7]=1.[C:17]([O:21][C:22]([N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:25]1[CH:30]=[C:29]([C:31]2[O:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:28]=[CH:27][N:26]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.C[N:46](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CC(N(C)C)=O.O.C(N(CC)CC)C>[CH3:8][N:6]1[CH:7]=[C:3]([NH:2][C:36]([C:34]2[N:35]=[C:31]([C:29]3[CH:28]=[CH:27][N:26]=[C:25]([N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:30]=3)[O:32][CH:33]=2)=[O:37])[C:4]([N:9]2[CH2:13][CH2:12][NH:46][C:10]2=[O:16])=[N:5]1
Reactant: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCNC2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 1-(4-amino-1-methyl-1H-pyrazol-3-yl)-3,3-dimethylpyrrolidin-2-one hydrochloride (3.09 g), 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylic acid (5.50 g), N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (3.27 g) and 1-hydroxybenzotriazole hydrate (2.39 g) in DMA (40 mL) was added triethylamine (3.96 mL), and the mixture was stirred at room temperature for 1 hr, and then at 50° C. for 3 hr. The reaction mixture was ice-cooled, and water was added thereto. The precipitate was collected by filtration, and washed successively with DMA/water (1/2), water and diisopropyl ether. The obtained solid was suspended in ethanol, and the suspension was stirred at room temperature for 15 min, and the solid was collected by filtration, and washed with ethanol to give the title compound (4.46 g).
Reaction SMILES: [Cl:1][Sb-:2]([Cl:7])([Cl:6])([Cl:5])([Cl:4])[Cl:3].[CH3:8][O+](C)C.[Cl:12][C:13]1[S:17][N:16]=[C:15]([Cl:18])[C:14]=1[Cl:19]>>[Cl:1][Sb-:2]([Cl:7])([Cl:6])([Cl:5])([Cl:4])[Cl:3].[CH3:8][N+:16]1[S:17][C:13]([Cl:12])=[C:14]([Cl:19])[C:15]=1[Cl:18]
Reactant: C[O+](C)C
Reactant: Clc1nsc(Cl)c1Cl
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Product: C[n+]1sc(Cl)c(Cl)c1Cl

Procedure:
Trichloroisothiazole (10 ml) and trimethyloxonium hexachloroantimonate (7.9 g, 0.02 mol) were heated at 90° for 30 min. After cooling either (150 ml) was added and the solid collected to yield 7.8 g (73%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (28.4 g) and anhydrous potassium carbonate (13.8 g) are dissolved in water (100 ml) and thereto is added benzene (10 ml). To the mixture is added dropwise methanesulfonyl chloride (15.6 ml) with stirring under ice-cooling and the mixture is further stirred for 1 hour. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate (300 ml). The extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (38.0 g; 86.3%), melting point: 79°-81° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[Br:18]Br>C(Cl)Cl>[Br:18][C:11]1[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)c2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
5-Acetylindane (6.3 g, 39 mmol) was dissolved in CH2Cl2 (150 mL) whereupon aluminium chloride (13.0 g, 97 mmol) was added during one minute and a vigorous generation of HCl gas was observed, which was conducted away by means of a tube. The mixture was stirred at room temperature for 5 min and then bromine (9.0 g, 56 mmol), dissolved in CH2Cl2 (50 mL) was added during 2 min. Additional stirring at room temperature for 2 h was followed by pouring the reaction mixture over ice (200 g). The flask was washed with additional CH2Cl2 (100 mL). The organic solution was washed twice with brine, dried and then the solvent was evaporated. There was obtained 8.8 g (93%) of 1-(7-bromo-2,3-dihydro-1H-inden-5-yl)ethanone as a solid material. 1H NMR (300 MHz, CDCl3): 2.1-2.2 (q, 2H), 2.6 (s, 3H), 2.9 (t, 2H), 3.1 (t, 2H), 7.7 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:45]1
Reactant: NC1CCCC(Oc2ccccc2F)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Oc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 74.3 mg), HCl salt of 3-(2-fluorophenoxy)cyclohexanamine (0.15 mmol, 37 mg), HATU (0.15 mmol, 57 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(2-fluorophenoxy)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[NH2:9][CH2:10][CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>C1COCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH2:11][NH:12][CH2:16][C:15]([N:9]2[CH2:19][CH2:18][CH2:17][C@H:10]2[C:11]#[N:12])=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccccc1B(O)O
Reactant: NCCN
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(NCCNCC(=O)N2CCC[C@H]2C#N)n1

Procedure:
This compound was obtained in analogy to example 36, steps A] to C] starting from 2,6-dibromopyridine, 1,2-diaminoethane, 2-methoxyphenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in THF and precipitated by treatment with methanesulfonic acid in tert-butyl methyl ether and ethyl acetate yielding a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:15]([O:17]C)=O)=[C:8]([C:12](Cl)=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][NH2:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7]3[C:15](=[O:17])[N:30]([C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:31]=[C:12]([OH:13])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN)cc1OC
Reactant: COC(=O)c1c(C(=O)Cl)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1OC
Temperature: 0 °C
Yield: 10.5 %

Procedure:
7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (7.00 g, 23.3 mM) was dissolved in tetrahydrofuran (210 mL) and added dropwise over 20 minutes to a cold (0° C.) solution of 3,4-dimethoxyphenylhydrazine (9.80 g, 58.3 mM) in tetrahydrofuran (420 mL)with stirring. The resulting brown suspension was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. Ice/water slurry (450 mL) was added to the reaction mixture followed by 1N HCl (1.2 L) and the brown suspension was stirred for 1 hour. The solids were separated by filtration and washed with water and then ether to provide7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimethoxyphenyl)hydrazide (15 g, wet). The combined filtrateand washes were partially concentrated to remove the THF whereupon a precipitate formed. This precipitate was collected and washed with water and then ether to give the crude title compound (2.00 g). Recrystallization of this crude from refluxing methanol (500 mL) gave the title compound (0.98 g, 10%) as a tan powder, mp=334°-336° C.; HS(CI): 400 (M+H).
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CNC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25 is used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][C:2](=[O:3])[N:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH3:6])[CH:8]=[CH:9]2)[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cl
Reactant: Cn1ccc2cc(Nc3ccncc3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(c1ccncc1)c1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl chloroformate (1.3 g) in 5 ml DCM was added to a solution of 1-methyl-5-(4-pyridinylamino)-1H-indole (2.5 g) in 120 ml DCM and 6 ml triethylamine (4.4 g). After stirring one hour at ambient temperature the reaction mixture was washed with water and saturated sodium chloride, dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 3.1 g of a solid. Recrystallization from methanol yielded 2.4 g of crystals, mp 157°-159° C.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)O

Procedure:
A total of 17.8 g of nicotinoyl chloride hydrochloride was dissolved in 150 ml of pyridine and 50 ml of dimethylformamide and the solution treated slowly with stirring at a temperature not over 15° with 22.2 g of benzyl-(R)-α-hydroxy-isovalerate (prepared from (R)-2-hydroxy-isovaleric acid and benzyl chloride in a manner analogous to that described for the preparation of the corresponding compound to Example 1). After stirring for two hours at room temperature, the mixture was evaporated under reduced pressure. The residue was taken up in ether, washed 3 times with water and extracted six times with ice-cold 3-N hydrochloric acid. The hydrochloride phases were immediately allowed to run into saturated sodium bicarbonate solution and the base which was thus released was extracted three times with ether. After washing and drying, it was evaporated under reduced pressure and there were obtained 27 g of a resin which contained benzyl-(R)-2-(nicotinoyloxy)-isocaproate. The resin was then hydrogenated in 200 ml. of ethanol with 2 g. of 5% palladium-on-charcoal until 2 equivalents of hydrogen had been taken up. After filtration and evaporation, the residue was taken up in 10% potassium bicarbonate, washed twice with ether and adjusted to pH 3 with citric acid. After extraction with ether, washing, drying and evaporation of the extract, there was obtained a crystallizing oil. Recrystallization from ethyl acetate/petroleum ether yielded 14 g of (R)-2-(nicotinoyloxy)-isocaproic acid; mp 101°-103°; [α]D25 = + 18.8° (c = 1.0 in methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:21](=[O:24])[CH2:22][CH3:23])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
400 mg (2 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide (Example 1b) are dissolved in 15 ml dichloromethane, cooled in the ice-bath and treated with 0.36 ml triethylamine. 185 mg (2 mmol) propionyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 489 mg (96%) of the desired product is obtained.
Reaction SMILES: CC1C(CN[C@@H]2C3N=CC=CC=3CCC2)=NC=C(C)C=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31](CBr)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[C:24]([C:23]([O:22][CH3:21])=[O:36])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Agent: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)OC)c1

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-bromomethyl-isophthalic acid dimethyl ester (Egbertson, M. S. et al. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524), DIPEA and KI in CH3CN gave 4-1[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-isophthalic acid dimethyl ester as a tan oily foam. 1H NMR (CDCl3) δ 1.64 (m, 1H), 2.01 (m, 2H), 2.14 (s+m, 4H), 2.27 (s, 3H), 2.68 (m, 1H), 2.79 (m, 1H), 3.89 (s, 6H), 3.92 (s, 2H), 4.09 (t, 1H, J=6.0 Hz), 4.26 (m, 2H), 6.97 (s, 1H), 7.03 (m, 1H), 7.30 (d, 1H, J=9.0 Hz), 7.89 (dd, 2H, J=7.5, 4.5 Hz), 8.02 (s, 1H), 8.25 (s, 1H), 8.50 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.1, 18.7, 22.2, 26.8, 29.7, 52.5, 54.7, 57.1, 63.3, 121.9, 128.0, 130.7, 131.4, 131.9, 133.3, 134.5, 136.7, 138.8, 146.3, 148.5, 166.8, 168.1. HPLC: 96%. ES-MS m/z 474 [M+H]+, 496 [M+Na]+. Anal. Calcd. for C28H31N3O4.1.1H2O: C, 68.30; H, 6.59; N, 8.53. Found: C, 68.23; H, 6.41; N, 8.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C[N+](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)([OH:12])[C:27]([F:29])([F:28])[F:26]
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of 6-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (1.17 g) in tetrahydrofuran (60 ml) was added a solution of (trifluoromethyl)trimethylsilane (703 mg) in tetrahydrofuran (10 ml) at 0° C. Tetramethylammonium fluoride (30 mg) was added and the mixture was stirred at 0° C. for 30 min and at room temperature for 15 min. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.26 ml) was added and the mixture was stirred for 20 min. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>7:3) to give the title compound (1.1 g) as a colorless solid. MS (m/e, ISP neg. ion)=428.4 [M−H+].
Reaction SMILES: C(O)(=O)C.N1CCCC1.[CH3:10][C:11]([CH3:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:32]2[C:37]([OH:38])=[C:36]([CH3:39])[C:35]([CH3:40])=[C:34]([CH:41]=O)[C:33]=2[CH3:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1>O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:32]2[C:33]([CH3:43])=[C:34]([CH:41]=[CH:10][C:11](=[O:12])[CH3:13])[C:35]([CH3:40])=[C:36]([CH3:39])[C:37]=2[OH:38])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=CC(C)=O)c(C)c(C)c1O
Reaction time: 6.5 h

Procedure:
To acetic acid (0.14 ml) were added pyrrolidine (0.2 ml) and acetone (0.26 ml). To this solution was added ethyl 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate (1.0 g) and the mixture was stirred for 6.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 7-(4-fluorophenyl)-7-[2-hydroxy-5-(3-oxobutenyl)-3,4,6-trimethylphenyl]heptanoate (0.95 g) (Compound 42). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=1)[C:10]([OH:12])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:45]([O:52][C:53](=[O:67])[NH:54][CH2:55][C@@H:56]([OH:66])[C@@H:57]([NH2:65])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:45]([O:52][C:53](=[O:67])[NH:54][CH2:55][C@@H:56]([OH:66])[C@@H:57]([NH:65][C:10]([C:9]1[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH:8]=1)=[O:12])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Reactant: CCCCCOc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
To a suspension of 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid (A13) (530 mg, 1.82 mmol, 1 equiv) in CH2Cl2 (20 ml) were added HOBT (300 mg, 2.2 mmol, 1.2 equiv) and EDAC.HCl (420 mg, 2.2 mmol, 1.2 equiv). After stirring for 5 min, 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid hydrochloride (D104) (570 mg, 1.82 mmol, 1 equiv) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2 (20 ml) washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give [(2R,3S)-2-hydroxy-3-({1-[3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-phenyl]-methanoyl}-amino)-4-phenyl-butyl]-carbamic acid benzyl ester (D105) (510 mg, 48%) as a white solid.