Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.C(N(CC)C(C)C)(C)C.Cl.[NH2:44][C:45]([CH3:51])([CH3:50])[C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[CH3:49][O:48][C:46](=[O:47])[C:45]([NH:44][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:14])([CH3:51])[CH3:50]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 4.70 g 1-hydroxy-2-naphthalene carboxylic acid in 40 ml abs. DMF under inert atmosphere 3.72 g 1-hydroxybenzotriazole and 8.89 g N,N′-diisopropyl carbodiimide and 7 ml of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 4.22 g of methyl 2-aminoisobutyrate hydrochloride, followed by 5 ml of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl and brine. The organic layer was dried over magnesium sulphate, and concentrated and the resulting residue was crystallized from toluene to yield 4.18 g of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester. C16H17NO4 (287.12), LCMS (ESI): 287.97 (MH+).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:33])[CH2:6][N:7]1[C:12](=[O:13])[C:11]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.CO>[C:23]([O:22][C:20]([N:10]1[C:11]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:13])[N:7]([CH2:6][C:5]([OH:33])=[O:4])[C@H:8]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:9]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24 mg (1.0 mmol) lithium hydroxide in 1 ml of water were added to 0.22 g (0.5 mmol) (R)-tert-butyl 4-(2-methoxy-2-oxoethyl)-5-oxo-3-phenyl-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 10 ml MeOH. The reaction mixture was stirred overnight at RT and then the MeOH was distilled off. The residue was mixed with water and acidified with an aqueous 4N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:24]=[C:25]([CH3:27])[CH:26]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:28].N1C=CC([C:34]([NH2:36])=[NH:35])=N1>CN(C)C=O>[ClH:28].[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:24]=[C:25]([CH3:27])[CH:26]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH:23][C:34]([NH2:36])=[NH:35])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N=C(N)c1cc[nH]n1
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.4 %

Procedure:
To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyamine (100 mg, 0.25 mmol), as prepared in the preceding step, in N,N-dimethylformamide (4 mL) was added 1H-pyrazole-carboxamidine hydrochloride (150 mg, 1.0 mmol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (5 mL) was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was partitioned between water (20 mL plus 2 mL brine) and diethyl ether (10 mL). The water solution was extracted with diethyl ether (10 mL). The combined diethyl ether extracts were extracted with pH 5 water. The combined water solution was basified (pH 8-9) by using 2 N NaOH and extracted with ethyl acetate (3×30 mL). The ethyl acetate solution was washed with pH 7 buffer solution (2×20 mL) and brine (20 mL) then dried over Na2SO4. After removing the solvent, 0.6 N HCl methanol (3 mL) was added, and the solution was concentrated to give the title compound as colorless foam (95 mg, 81%). 1H-NMR (300 MHz, DMSO-d6) δ11.16 (br s, 1H), 9.75 (s, 1H), 8.89 (d, J=6.3 Hz, 1H), 8.73 (d, J=8.3 Hz, 1H), 8.46 (m, 4H), 7.93 (t, J=7.9 Hz, 1H), 7.72 (br s, 4H), 6.71 (s, 1H), 6.33 (s, 1H), 6.27 (s, 1H), 3.88 (m, 4H), 2.13 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H22N4O5S: 431.1 (M+H), 453.1 (M+Na). Found: 431.2, 453.3.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K+].[Br-]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:24]2)=[O:3])=[CH:6][CH:7]=1
Reactant: c1ccc(CCCCN2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Cl)cc1)N1CCN(CCCCc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 86%. White crystals, m.p. 230–232° C.; 1H NMR (DMSO-d6): δ 11.43 (br,1H), 7.51–7.43 (d-like m, 2H), 7.33–7.15 (m, 7H), 4.33–3.95 (br, max at 4.21 and 4.10 ppm; 2H), 3.72–3.36 (br m, 4H), 3.22–2.96 (br, max at 3.10 ppm, 4H), 2.62 (t, J=7.54 Hz, 2H), 1.84–1.69 (m, 2H), 1.69–1.54 (m, 2H) ppm; IR (KBr): ν 1736, 1720 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][CH2:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (8.50 g, 41.8 mmol), 60% sodium hydride (1.67 g, 41.8 mmol) and N,N-dimethylformamide (150 ml) was stirred at room temperature until the reaction mixture became transparent. Subsequently, ethyl 4-bromobutyrate (8.16 g, 41.8 mmol) was added dropwise to the aforesaid mixture and the resulting mixture was stirred at 27°-29° C. for another 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 3/97) to obtain ethyl 1-(3-ethoxycarbonylpropyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](C=O)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(/[CH:43]=[C:44]2/[C:45]([NH:47][C:48]([S:50]/2)=[NH:49])=[O:46])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:43]=[C:44]4/[C:45](=[O:46])[N:47]=[C:48]([NH2:49])[S:50]/4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(C=O)cc23)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(3-cyano-6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester, pseudothiohydantoin, sodium acetate and acetic acid to give 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-3-cyano-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 480 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[C@@H:10]([C:22]([O:24]C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[C@H:9]1[C@@H:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F)OCc1ccccc1
Yield: 59.9 %

Procedure:
A suspension of methyl β-[(2-aminophenyl)thio]-N-[(benzyloxy)carbonyl]-2,5-difluorophenylalaninate (4:1, Z:E) (4.3 g) and p-toluenesulfonic acid (catalytic) in xylenes (100 mL) was heated to reflux for 2 h, using a Dean-Stark apparatus to remove water. The mixture was then cooled, resulting in precipitation of the crude product as a white solid (3.3 g, 4:1, cis:trans). This was recrystallized from ethyl acetate/ether to afford the title compound (2.4 g, 60%). 1H NMR (300 MHz, d6-DMSO) δ 4.63 (t, 1H), 4.96 (s, 2H), 5.47 (d, 1H), 7.00 (d, 1H),7.23-7.34 (m, 9H), 7.49-7.53 (m, 2H), 7.70 (d, 1H), 10.57(s, 1H). MS APCI, m/z=441 (M+1). LC/MS: 2.74 min.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(C(=O)C(C)C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added isobutyryl chloride (0.013 mL, 0.124 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, warmed to 23° C. and stirred for an additional 15.5 h. The reaction mixture was concentrated via rotary evaporation and partitioned between EtOAc (4 mL) and NH4Cl (2 mL). The layers were separated and the organic phase was washed with brine (2 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.25 g), and purified via medium pressure chromatography using a 50% to 100% gradient of EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (39.3 mg, 66.9%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.99 (d, J=6.8 Hz, 2.7H), 1.03 (d, J=6.8 Hz, 3H), 1.11-1.22 (m, 6H), 2.58 (br s, 3.8H), 2.69 (t, J=5.4 Hz, 1.2H), 2.88-3.13 (m, 5H), 3.58 (s, 2H), 3.75 (dt, J=10.9, 5.6 Hz, 2H), 4.05-4.17 (m, 1H), 4.41 (s, 1.1H), 4.49 (s, 0.9H), 5.29-5.42 (m, 1H), 7.08 (td, J=8.5, 2.4 Hz, 1H), 7.21 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+F]+ 473.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=C(N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Reaction time: 30 h

Procedure:
The crude methyl N-[(S)-1-(4-methoxyphenyl)ethyl]-3-amino-3-(3-pyridyl)propenoate, (40.6 g, 130 mmol) was dissolved in methanol (200 mL) and mixed with 20% Pd(OH)2/C (4.1 g). The mixture was hydrogenated under atmospheric pressure for 30 h. The mixture was diluted with ethyl acetate (50 mL) and filtered through celite (20 g) to remove the catalyst. The celite was washed with hot (70° C.) ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure to near dryness to an oily residue. Crude amine (27.5 g) was dissolved in hot ethyl acetate (40 mL). The resulting hot yellow solution was filtered and rinsed with 15 mL of hot ethyl acetate. The clear solution was concentrated to <50 mL and allowed to stand at room temperature overnight. The resulting white crystalline solid was collected by filtration and washed with cold ethyl acetate (EtOAc) (˜15-20 mL), then air dried. Yield of isolated solid: 15.5 g. HPLC analysis showed >99% desired diastereomer. A second crop was obtained from the filtrate after concentration to about 20 mL. Yield: 1.7 identical by HPLC to first crop; total yield: 17.2 g (62.5%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.Cl[CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][N:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 5-hydroxy-2-methylpyridine (8.46 g), 4-chloromethyl-5-methyl-2-phenyloxazole (15.20 g), potassium carbonate (15.98 g) and N,N-dimethylformamide (200 ml) was stirred at 80° C. for 3 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (19.68 g, yield 96%) as pale yellow crystals from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). This was recrystallized from acetone-hexane. Melting point: 103–104° C.
Reaction SMILES: F[C:2]([F:14])(F)[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].N=C=N.Cl.[NH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].CCN(CC)CC>C(Cl)Cl>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:19][C:10]([C:8]1[S:9][C:5]([C:3](=[O:4])[CH2:2][F:14])=[CH:6][CH:7]=1)=[O:12]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: Cl
Agent: N=C=N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc(C(=O)CF)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1, A1 in DCM was added Pol-supported carbodiimide (2 eq) and the suspension was stirred at RT for 30 min. A solution of 2-aminoacetophenone HCl (1.1 eq) and Et3N (1.1 eq) in DCM was added and the resulting suspension was stirred at RT overnight. The resin was filtered, washed with DCM, and the filtrate was evaporated at reduced pressure. Purification by flash chromatography on silica gel eluting with DCM gave the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22]C)=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reaction time: 14 h

Procedure:
Oxycodone (10.0 g) was suspended in chloroform (CHCl3, 150 mL) in a reactor A. Boron tribromide (BBr3, 10.0 mL) was added slowly and an exotherm was observed. The reaction temperature was maintained below 25° C. during the addition. Stirring of the mixture was continued at room temperature for 14 hours. The material was transferred to reactor B that was pre-filled with 85 mL of water. The temperature reached 50 to 55° C. and was maintained below 55° C. during the addition. After transfer of the mixture to reactor B, some solid residue still remained in reactor A. The mixture in reactor B was stirred at 50 to 55° C. to dissolve the solid (about 15 minutes) and then when stirring was stopped, the mixture separated into two clear layers. The aqueous solution in reactor B was transferred back to reactor A. The mixture was stirred at 50 to 55° C. for 15 to 30 minutes to dissolve all the solids. The organic layer in reactor B was extracted with H3PO4/H2O solution (2% wt/wt, 15 mL). The aqueous extraction was transferred to reactor A. The solution in reactor A was extracted with dichloroethane (30 mL) and then allowed to separate into two phases.
Reaction SMILES: Cl.[N:2]1([CH2:12][C:13]([OH:15])=O)[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCCC2CCCCC21
Agent: Cl
Product: O=C(CN1CCCC2CCCCC21)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(octahydroquinolin-1(2H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 45, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroquinolin-1(2H)-yl)acetamido)propanamide (20.1 mg, 44.9%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.84 (m, 1H), 7.59 (d, 2H), 7.28 (m, 7H), 7.02 (m, 4H), 4.69 (m, 1H), 4.51 (m, 2H), 3.73 (m, 2H), 3.34 (m, 2H), 3.33 (m, 2H), 2.97 (m, 1H), 2.75 (m, 1H), 2.17 (m, 1H), 1.42 (m, 11H). MS (EI) for C33H38FN3O4: 560.5 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[CH:29]=[CH:28][C:21]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:20][C:19]=3[O:30][CH3:31])[CH:14]=2)[N:9]=1.[C:32](O)(=[O:35])[C:33]#[CH:34].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>ClCCl>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[CH:29][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:32](=[O:35])[C:33]#[CH:34])[N:17]=[CH:16]4)=[C:19]([O:30][CH3:31])[CH:20]=2)[CH2:27][CH2:26]1
Reactant: C#CC(=O)O
Reactant: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3N)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3ccc(C(=O)NC4CC4)cc3OC)ccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A mixture of 4-(2-(((1R,2S)-2-aminocyclopentyl)amino)quinazolin-6-yl)-N-cyclopropyl-3-methoxybenzamide (0.11 mmol), propiolic acid (0.010 mL, 0.17 mmol), HATU (64 mg, 0.17 mmol) and DIEA (0.06 mL, 0.34 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 45 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-cyclopropyl-3-methoxy-4-(2-(((1R,2S)-2-propiolamidocyclopentyl)amino)quinazolin-6-yl)benzamide (Compound 13) (35 mg, 69%). MS (ES+) C27H27N5O3 requires: 469, found: 470 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:36]([O:38]C(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.[C:64](O)(=O)[CH2:65][CH2:66][CH2:67]C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:36](=[O:38])[CH2:64][CH2:65][CH2:66][CH3:67])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)OC(O)C(=O)[C@@]1(OC(=O)CC)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
307 mg (0.35 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3), 36 μl (0.33 mmol) of valeric acid, 52 mg (0.35 mmol) of N-hydroxy-benzotriazole and 74 μl (0.66 mmol) of N-methylmorpholine are dissolved in 40 ml of dichloromethane, mixed with a solution of 84 mg (0.41 mmol) of dicyclohexylcarbodiimide in 10 ml of dichloromethane and stirred for 4 hours at room temperature. For working-up, the precipitated urea is filtered off, the filtrate is diluted with 40 ml of dichloromethane and washed with 40 ml each of 0.5N NaOH, 0.5N HCl and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation i.vac. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography on 200 g of silica gel 60 (dichloromethane→dichloromethane/methanol 95:5) yields 180 mg (64%) of N-(N-(N-(N -(valeroyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien -21-yl] ester and, after recrystallization, 157 mg (56%) in crystalline form from dichloromethane/diisopropyl ether/hexane.