Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([C:11]1[C:12]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH3:29])[C:20]=2[CH3:30])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)(O)=[O:9].[CH2:31]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:45])[CH3:44])[CH:38]=1)[CH2:32][CH2:33][CH2:34][CH3:35].C1(C)C=CC=CC=1>CO>[CH3:44][N:43]([CH3:45])[C:39]1[CH:40]=[CH:41][C:42]([C:17]2([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][CH3:29])[C:20]=3[CH3:30])[C:12]3[C:11](=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8](=[O:9])[O:18]2)=[C:37]([O:36][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:38]=1
Reactant: CCCCCOc1cccc(N(C)C)c1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCOc1cc(N(C)C)ccc1C1(c2c(C)n(CC)c3ccccc23)OC(=O)c2cccnc21
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Into 75 ml of acetic anhydride, 9.2 g of (1-ethyl-2-methylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 7050 g of 1-n-pentyloxy-3-dimethylaminobenzene were added, and the resultant mixture was stirred for 4 hours at 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled reaction mixture was poured into 500 ml of ice water and the resultant mixture was treated with toluene and methanol by the same manner as in Synthetic Example 1. As a result, 11.9 g of the objective compound were obtained as pale blue crystals (melting point: 169° to 171° C.). The elementary analytical data of the product were as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])[CH:20]=[C:19]([CH2:27][O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.N#N>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:24]([NH:23][C:21]1[CH:20]=[C:19]([CH2:27][O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[N:18]=[C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Nc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NC(C)C)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 60.5 %

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (90 mg, 0.44 mmol), 2-chloro-N-isopropyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (63 mg, 0.22 mmol), cesium carbonate (145 mg, 0.44 mmol), palladium acetate (7.48 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)-biphenyl (11.68 mg, 0.03 mmol) in dioxane (1.5 mL) were mixed in a vial under N2 atmosphere. The mixture was heated at 120° C. in a microwave reactor for 90 minutes. The mixture was filtered through diatomeous earth and the filter plug was washed with methanol. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a solid 60 mg (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:36])([F:35])[F:34])[CH2:13][CH2:12][N:11]([C:14]3[CH:28]=[CH:27][C:17]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:16]([C:29]([F:32])([F:31])[F:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:36])([F:35])[F:34])[CH2:13][CH2:12][N:11]([C:14]3[CH:28]=[CH:27][C:17]([CH2:18][NH2:19])=[C:16]([C:29]([F:30])([F:31])[F:32])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture comprising t-butyl {4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-pyrrolidin-1-yl]-2-(trifluoromethyl)benzyl}carbamate (6.0 g), concentrated hydrochloric acid (20 mL) and ethanol (100 mL) was stirred at 50° C. for three hours. After cooling the mixture to room temperature, the reaction solution was diluted by adding water (150 mL) and ethyl acetate (150 mL). By adding sodium carbonate in small portions, the solution was neutralized. After the extraction using ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure to obtain the title compound (5.2 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13](C=O)[CH2:12]1)[N:10]=2.C[O-:41].[Na+].O>CO>[F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:41])[CH2:12]1)[N:10]=2
Reactant: C[O-]
Reactant: CC(C)c1csc(CCc2cc3nc(N4CCCC(C=O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)c1csc(CCc2cc3nc(N4CCCC(O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 65.4 %

Procedure:
The tert-butyl (E)-3-{7-fluoro-2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (147 mg, 0.258 mmol) obtained in (L) was dissolved in methanol (3ml), added with sodium methoxide (33.6 mg, 0.618 mmol), and then stirred at room temperature for 9 hours. The reaction mixture was added with distilled water and extracted with chloroform (twice). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by preparative TLC (chloroform:methanol=100:5) to obtain the title compound (91.6 mg, 65%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([C@@H:22]([OH:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=O)C.[CH2:43]([O:50][CH2:51][N:52]1[C:60]2[C:59]([O:61][CH3:62])=[N:58][CH:57]=[N:56][C:55]=2[C:54]([CH:63]=O)=[CH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>ClCCCl.C(Cl)Cl.CCOC(C)=O>[CH2:43]([O:50][CH2:51][N:52]1[C:60]2[C:59]([O:61][CH3:62])=[N:58][CH:57]=[N:56][C:55]=2[C:54]([CH2:63][NH:15][C@@H:16]([C@@H:22]([OH:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Reactant: CCOC(=O)[C@@H](N)[C@@H](O)C(=O)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)[C@@H](O)C(=O)OCC
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Sodium triacetoxyborohydride (0.545 g, 2.57 mmol) was added to a solution of (2S,3R)-diethyl 2-amino-3-hydroxysuccinate (0.406 g, 1.978 mmol), the latter prepared from diethyl-L-tartrate by known methods (A. Breuning, R. Vicik and T. Schirmeister, Tetrahedron Asymm., 2003, 14, 3301 and Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, J. Am. Chem. Soc., 2005, 127, 9285) and 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.588 g, 1.978 mmol) in 1,2-dichloroethane (30 ml) and the mixture stirred at rt for 1 h. Tlc (EtOAc) showed all amine to have gone (ninhydrin) but still some aldehyde present and a new main product in between. More (2S,3R)-diethyl 2-amino-3-hydroxysuccinate (121 mg) added. The mixture was stirred a further 3 h then diluted with CH2Cl2 and washed with aqueous sat. NaHCO3, dried and evaporated. The residue was chromatographed (EtOAc-hexanes, 9:1 then EtOAc) to give (2S,3R)-diethyl 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-hydroxysuccinate (0.668 g, 1.373 mmol, 69.4% yield) as a pale yellow gum. [α]D21 −5.9 (c 0.54, EtOH). 1H NMR (CDCl3, 300 MHz), δ ppm, 8.55 (s, 1H), 7.34 (s, 1H), 7.33-7.23 (m, 5H), 5.70 (s, 2H), 4.62 (d, 1H, J 3.4 Hz), 4.48 (s, 2H), 4.23-4.15 (m, 5H), 4.10 (s, 3H), 3.99 (d, 1H, J 13.8 Hz), 3.85 (d, 1H, J 3.3 Hz), 2.25 (br. s, 2H, exchanged to D2O), 1.26 (t, 3H, J 7.1 Hz), 1.25 (t, 3H, J 7.1 Hz). 13C NMR (CDCl3, 75.5 MHz), δ ppm, 171.9 (C), 171.1 (C), 156.2 (C), 150.0 (CH), 149.8 (C), 136.9 (C), 130.9 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 116.1 (C), 77.0 (CH2), 72.0 (CH), 70.2 (CH2), 63.8 (CH), 61.4 (CH2), 61.3 (CH2), 53.5 (CH3), 42.6 (CH2), 14.1 (CH3). +ESMS Found 487.2174 (M+H)+ C24H31N4O7 requires 487.2193.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Yield: 57.2 %

Procedure:
{1-Benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.318 g, 0.680 mmol), and potassium hydroxide (0.123 g, 2.19 mmol) in THF (3 mL) and water (3 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from isopropanol and drying for 12 hours at 80° C. yielded the title compound as a white solid (0.171 g, 57%), mp: 177-178° C. Mass spectrum (−ESI, [M−H]−) m/z 438; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.65 (s, 1H), 8.35 (dd, 1H, J=7.9 Hz and 1.1 Hz), 7.35 (t, 1H, J=7.6 Hz), 7.2-7.25 (m, 4H), 7.1 (t, 1H, J=7.3 Hz), 7.0-7.05 (m, 3H), 6.25 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.Cl.[CH3:10][O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].N12CCCN=C1CCCCC2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH2:15][CH:12]([O:11][CH3:10])[CH2:13]2)=[CH:4][N:3]=1
Reactant: Brc1ccc(I)cn1
Reactant: COC1CNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC1CN(c2ccc(Br)nc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
A mixture of 2-bromo-5-iodopyridine (1.00 g), 3-methoxyazetidine hydrochloride (0.435 g), tris(dibenzylideneacetone)dipalladium(0) (0.106 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.204 g), sodium tert-butoxide (0.846 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.531 mL) and toluene (30 mL) was stirred at room temperature for 3 days under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (625.1 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Cl.[CH3:25][NH:26][CH3:27]>ClCCl.O>[CH3:25][N:26]([CH3:27])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(3-chloropropoxy)-4-nitrobenzene (2 g, 9.27 mmol), potassium carbonate (7.69 g, 46.4 mmol) and acetonitrile (15 ml) was prepared and stirred in a tube. To the stirring solution dimethylamine hydrochloride (3.78 g, 46.4 mmol) was added quickly. The tube was sealed and the mixture was stirred while heating overnight at 80° C. The mixture was cooled well before opening the pressure tube, then water and dichloromethane were added and the aqueous layer was extracted with dichloromethane. The combined organics were dried and evaporated giving the title product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:7]1[CH:8]=[C:9]([C:12]2[S:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: COC(=O)c1sc(-c2ccc(OCCCCl)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1sc(-c2ccc(OCCCCl)c(Br)c2)nc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A solution of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate ax60 (2 g, 6.15 mmol, 1 eq) in acetonitrile (50 ml) is treated with a solution of N-bromosuccinimide (1.8 g, 10 mmol, 1.5 eq) in acetonitrile (10 ml) and the resulting solution is stirred 2 h at room temperature and 2 h at 60° C. After cooling, the mixture is concentrated to dryness. The residue is taken up with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue over silicagel (eluent: dichloromethane/benzine) affords 0.6 g of methyl 2-[3-bromo-4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i91.
Reaction SMILES: C(OC(CCC(N[C@H](C(N[C@H](C([NH:37][C@H:38]([C:47]([NH:49][C@H:50](C(N[C@H](C(O)=O)CC(C)C)=O)[C:51]([CH3:54])(C)C)=[O:48])[CH2:39][C:40]1[CH:45]=CC=C[C:41]=1C)=O)CCC(=O)OC(C)(C)C)=O)CC(=O)OC(C)(C)C)=O)=O)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.FC(F)(F)C(O)=O.C(C([B:92]1[O:96][C:95]([CH3:98])([CH3:97])[C:94]([CH3:100])([CH3:99])[O:93]1)N)C>CN(C)C=O.ClCCl>[CH3:99][C:94]1([CH3:100])[C:95]([CH3:98])([CH3:97])[O:96][B:92]([CH:50]([NH:49][C:47](=[O:48])[C@H:38]([CH2:39][CH:40]([CH3:41])[CH3:45])[NH2:37])[CH2:51][CH3:54])[O:93]1
Reactant: CCC(N)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(NC(=O)[C@@H](N)CC(C)C)B1OC(C)(C)C(C)(C)O1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
0.25 g (0.27 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine was dissolved in 2 ml of dimethylformamide and 5 ml of dichloromethane. 0.15 ml (1.6 mmol) of N-methylmorpholine was added and the solution was cooled to -15° C. under a nitrogen atmosphere. 50 mg (0.38 mmol) of isobutyl chloroformate were added and the solution was stirred for 10 minutes at -15° C. 0.1 g (0.33 mmol) of α-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate was added and the mixture was stirred at room temperature for 18 hours. After evaporation the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was washed with 2M hydrochloric acid, water and saturated sodium chloride solution and then dried over anhydrous sodium sulphate. After evaporation there was obtained 0.26 g of N2-N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-L-leucinamide in the form of a solid; MS: m/e 1085 [M+H].
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:46]=[CH:47][C:48]=1[N:49]1[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]1)/[CH:25]=[C:26]1/[C:27](=[O:45])[N:28]2[C@@H:33]([CH2:34][CH2:35]/1)[CH2:32][CH2:31][CH2:30][C@H:29]2[C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=1.CNC.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:46]=[CH:47][C:48]=1[N:49]1[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]1)/[CH:25]=[C:26]1/[C:27](=[O:45])[N:28]2[C@@H:33]([CH2:34][CH2:35]/1)[CH2:32][CH2:31][CH2:30][C@H:29]2[C:36]1[CH:37]=[CH:38][C:39]([C:40]([N:4]([CH3:5])[CH3:1])=[O:42])=[CH:43][CH:44]=1
Reactant: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(C(=O)O)cc4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(C(=O)N(C)C)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
IPEA (0.03 mL), HOBT (10 mg), and EDC (14 mg) were sequentially added to a solution of (E)-4-{(4S*,9aR*)-7-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-oxooctahydroquinolizin-4-yl}benzoic acid (22 mg) and dimethylamine (2 M solution in THF, 0.12 mL) in DMF (2 mL), and the reaction solution was stirred at room temperature for two hours. Then, the reaction solution was further stirred at 100° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate:methanol=9:1) to obtain 19 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH:5]([CH3:8])[C:6]#[CH:7])[CH:3]=O.[Cl-].[P+]=O.[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:25])[CH:19]=2)=[CH:15][C:14]=1[C:28]([F:31])([F:30])[F:29].[OH-].[Na+]>ClCCl>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([N:24]=[CH:3][N:2]([CH3:1])[CH:5]([CH3:8])[C:6]#[CH:7])=[C:20]([CH3:25])[CH:19]=2)=[CH:15][C:14]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1N
Reactant: C#CC(C)N(C)C=O
Agent: O=[P+]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CC(C)N(C)C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
In a 25 ml single-necked round-bottomed flask, N-Methyl-N-(1-methyl-prop-2-ynyl)-formamide (223 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring a mixture of phosphorous oxide chloride (0.18 ml) in dichloromethane (1 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-4-methyl-pyridin-3-ylamine (303 mg) dissolved in 10 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 3 hours. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 3:2 (v:v) gives 198 mg of the compound as a brownish oil.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(=O)=O.[H][H].[ClH:27]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:27].[ClH:27].[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: [H][H]
Reactant: CON(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide (approximately 0.20 g, 0.8 mmol) in ethanol/ethyl acetate (1:1, 30 mL) and concentrated hydrochloric acid (1 mL) is degassed with dry ice. Palladium on carbon (10%, 35 mg) is added and the mixture is shaken for two hours under 40 psi of hydrogen. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 1-(4-amino-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide dihydrochloride (0.30 g, >100%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][CH2:6][C@@H:7]([CH3:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1.OO.[OH-:31].[Na+]>CO.ClCCl.O>[C:1]([OH:4])(=[O:3])[CH3:2].[O:31]1[C:15]23[C@:20]([CH3:21])([CH2:19][CH2:18][C:17](=[O:27])[CH:16]12)[C@@H:22]1[C@H:12]([C@H:11]2[C@:25]([CH3:26])([CH2:24][CH2:23]1)[C@@H:8]([C@H:7]([CH3:28])[CH2:6][OH:5])[CH2:9][CH2:10]2)[CH2:13][CH2:14]3
Reactant: [OH-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 122.5 %

Procedure:
To a solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one acetate (10.6 g, 28.3 mmole) in methanol (60 mL) and dichloromethane (15 mL) cooled to 15° C. in a cold water bath there was added 30% hydrogen peroxide (6.8 mL) and then, dropwise, a solution of sodium hydroxide (0.49 g) in water (3.2 mL). After 30 minutes, the cold bath was removed and the reaction was stirred for 4 hours at room temperature. The solvents were then removed under reduced pressure and the residue was dissolved in dichloromethane (300 mL) and extracted with brine (100 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to a solid which was purified by flash chromatography on silica gel to give (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one acetate (6.1 g, 55.6%) as a mixture of the 4α,5α- and 4,β5β-isomers.