Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16](Cl)=[N:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:16]2[N:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:13]([C:11](=[O:12])[NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:25])([F:24])[F:1])=[CH:5][CH:6]=3)=[CH:18][N:17]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)n2)CC1

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.8 g, 2.07 mmol, 1.0 equiv; commercially available from Maybridge, UK), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.62 g, 3.11 mmol, 1.5 equiv; commercially available) and triethylamine (0.43 mL, 0.32 g, 3.11 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.92 g (81%) of the title compound. MS (ISP): 550.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].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.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH2:72][CH2:73][NH2:74])=[CH:68][CH:67]=1>CN(C=O)C.O>[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH2:72][CH2:73][NH:74][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:31])=[CH:9][C:10]=3[CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[O:18])=[CH:68][CH:67]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)O)cc1)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1)S(C)(=O)=O
Yield: 17.6 %

Procedure:
To a stirred solution of 4-(4(2-tert-butoxy-2-oxoethyl)-2-((N-methylmethylsulfonamido)methyl)phenoxy)benzoic acid (50 mg, 0.111 mmol) and HATU (46.5 mg, 0.122 mmol) in DMF (1 ml) was added DIEA (23.2 μL, 0.133 mmol) followed by 2-(4-chlorophenyl)ethanamine (11.2 μL, 0.111 mmol). The reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((N-methylmethylsulfonamido)methyl)phenyl)acetate (0.0115 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:18])[F:17])=[O:12])[CH2:2][CH2:3]2)=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a stirred mixture of 3-(piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (3.07 mmol, 1.01 g), 4-aminobenzoic acid (3.07 mmol, 0.421 g) and triethylamine (6.13 mmol, 0.855 mL, 0.621 g) in dichloromethane (30.7 mL) was added 1-propanephosphonic acid cyclic anhydride (6.13 mmol, 3.63 ml, 3.90 g, 50% solution in ethyl acetate). After 2 hours stirring, dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (640 mg).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]([NH2:12])=O)[N:4]2[N:3]=1.S(Cl)(Cl)=O.O>CN(C)C=O>[CH3:1][C:2]1[C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]#[N:12])[N:4]2[N:3]=1
Reactant: Cc1nn2c(C(N)=O)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To the solution of 2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine-7-carboxamide (0.2 g, 0.498 mmol) in N,N-Dimethylformamide (DMF) (4 mL) was added thionyl chloride (0.055 mL, 0.747 mmol). The reaction was stirred at rt for 1 h. Additional thionyl chloride (0.055 mL, 0.747 mmol) was added in. The reaction was stirred at rt for 1 h. Water was added in. The solid precipitated. Filtration gave the crude product. The crude was purified on silica column (20˜50% EtOAc/Hexane) to give the product (0.06 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 3.58-3.72 (m, 8H) 4.34 (s, 2H) 7.30 (d, J=7.07 Hz, 1H) 7.36-7.45 (m, 1H) 7.46-7.54 (m, 2H) 7.58 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 7.83-7.95 (m, 1H) 8.40 (d, 1H); LC/MS: MS (ES+) m/e 384.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]1[C:15]([OH:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]1.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:16][C:15]2[N:11]([C:5]3[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:12]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: Oc1cc(C(F)(F)F)nn1-c1c(Cl)cccc1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(OCc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
At 0° C. NaH (60%, 400 mg, 10 mmol) was added to a stirred mixture of 1-(2,6-dichlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-ol (1.5 g, 5 mmol) and 4-bromobenzyl bromide (1.5 g, 6 mmol) in dry DMF (20 mL), the resulting mixture was stirred at ambient temperature for 1 h, then quenched with aqueous NH4Cl at 0° C., extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by column chromatography (30% EtOAc/hexanes) to give 5-(4-bromobenzyloxy)-1-(2,6-dichlorophenyl)-3-trifluoromethyl-1H-pyrazole as a white solid (2.2 g, 94%). 1H-NMR (CDCl3): δ 7.47-7.41 (m, 4H), 7.36-7.33 (m, 1H), 7.17 (d, 2H), 5.93 (s, 1H), 5.08 (s, 2H), MS (ESI): 467[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]#[CH:14]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]#[CH:14]
Reactant: C#CCOc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: C#CCOc1cc(N)ccc1C

Procedure:
As described above 1-methyl-4-nitro-2-(2-propynyloxy)benzene was made, mp 75°-77° C. This compound, (26 g) was reduced using iron in ethanol and water to give 4-methyl-3-(2-propynyloxy)benzenamine isolated as the hydrochloride salt mp >250° C. This amine salt was converted to the isocyanate analogue using phosgene in ethyl acetate as solvent, i.e. 4-isocyanato-4-methyl- 2-(2-propynyloxy)benzene, bp 78°-80° C./0.05 mm. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (19.6 g) was converted to its sodium salt using sodium hydride (4.6 g., 60%) in THF (100 ml). This solution was chilled to -62° C. and treated with a solution of the isocyanate (20 g) in THF (15 ml) over 2 minutes. The reaction warmed to -48° C. before cooling again. After stirring to ambient temperature and overnight the solvent was removed, water (250 ml) added, filtered to remove the precipitate and acidified whereupon a second precipitate was obtained. This solid was collected on a filter washed with water and re-extracted into aqueous sodium bicarbonate. After filtering the clear filtrate was acidified and the resulting cream precipitate was collected on a filter, washed with water and dried to give 3-[4-methyl-3-(2-propynyloxy)phenyl]-6- (trifluoromethyl)-2,4-(1H,3H)-pyrimidinedione, mp 202°-204° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([CH3:19])([OH:18])[CH3:17])=[N:12][CH:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](OB(O)O)=[CH:23][CH:22]=1>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([CH3:19])([OH:18])[CH3:17])=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(O)C#Cc1ccc(Br)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
Under an argon atmosphere 3 mL 2 M Na2CO3 solution and 173 mg (0.15 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 720 mg (3.0 mmol) 4-(5-bromo-pyridin-2-yl)-2-methyl-but-3-yn-2-ol and 593 mg (3.6 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and the reaction mixture is stirred for 18 h at 85° C. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with EtOAc, the organic phase is washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/EtOAc 1:1).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1>CO>[NH2:10][CH:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17]
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Solvent: CO
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
A mixture of carbamate 25 (170 mg, 0.30 mmol) and 10% Pd-on-carbon (wet, 100 mg, 0.09 mmol) in MeOH (20 mL) was stirred vigorously under 1 atm H2 for 2.5 h. The catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo to afford 125 mg (96%) of 26 as an oil which was carried on without further purification. Mass spectrum, m/z [437.9] (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:35][C:36]1[CH:37]=[C:38]([C:42]2[NH:43][O:44][C:45](=[O:47])[N:46]=2)[CH:39]=[CH:40][CH:41]=1.Cl.CCN(C(C)C)C(C)C>N1C=CC=CC=1.C(#N)C.CC(OC)(C)C.C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]4[NH:43][O:44][C:45](=[O:47])[N:46]=4)[CH:37]=3)=[O:16])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: Nc1cccc(-c2nc(=O)o[nH]2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2nc(=O)o[nH]2)c1

Procedure:
Preferably, the [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid is reacted with thionyl chloride in situ, in an organic solvent such as acetonitrile, THF, MTBE, and the like, preferably acetonitrile; and then reacted with 3-(3-amino-phenyl)-2H-[1,2,4]oxadiazol-5-one as its corresponding HCl salt, in the presence of an organic base such as TEA, DIPEA, pyridine, and the like, preferably DIPEA; wherein the base is preferably present in an amount greater than or equal to about 2 equivalents; in the same organic solvent; to yield the 2-[5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl )-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-acetamide, the compound of formula (Is).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1>B(F)(F)F.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:16][CH3:17])([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:21]=3)[CH2:18][CH3:19])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC=C(CC)c1ccc2sc(C(=O)OCC)cc2c1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2s1
Yield: 78 %

Procedure:
5-(1-Ethyl-propenyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (5.50 g, 20.0 mmol), o-cresol (4.33 g, 40.0 mmol), and BF3-Et2O (10 mL) are reacted analogous to Example 1C to afford the title compound (5.97 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CCCc1ccc(Cl)cc1
Temperature: 125 °C
Yield: 93.5 %

Procedure:
A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96%) as a white solid. UV λmax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm−1; MS (El ) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[BH4-].[Na+]>C(Cl)Cl.CO>[O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[CH2:10]2)[CH2:7][CH2:6]3
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)C2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Reaction time: 12 h

Procedure:
15 g (0.038 mole) of 2α,3α-epoxy-17-oxo-16β-N-Methyl-piperazino-5α-androstane (Example 9) are dissolved in the mixture of 45 ml of methylene chloride and 120 ml of methanol, whereafter 12 g (0.31 mole) of sodium borohydride are added at a temperature of below 30° C. When the addition is complete, the product of the reduction is crystallized. The crystalline solution is stirred vigorously for 12 hours, whereafter the solvent is distilled at reduced pressure at a temperature of below 40° C. The residue is triturated with water, the crystallized product is filtered, dissolved in chloroform and washed with 5% aqueous sodium hydroxide solution and with water until pH = 7. The layers are separated. The chloroform layer is dried on sodium sulfate, filtered and the filtrate is evaporated to dryness. The residue is recrystallized from acetonitrile. Yield: 11.7 g (77.2%) of 2α,3α-epoxy-17β-N-methyl-piperazino-5α-androstane; m.p. 149°-153° C; [α]D25 = +27.1° (c = 1 in chloroform).
Reaction SMILES: C([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])C.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[CH:13]=[CH:14][C:15]=1[Cl:16]>>[CH3:7][N:6]([C:18](=[O:20])[CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)[CH2:5][C:4]([OH:8])=[O:3]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CNC
Product: CN(CC(=O)O)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from commercially available sarcosine ethyl ester and 3,4-dichlorophenylacetic acid according to the procedure of Intermediate 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:5])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]3)[O:44][CH2:43][CH2:42][O:41]2)=[CH:36][CH:35]=1>O.ClCCl.C(N(CC)CC)C>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:45]3[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][NH:53][C:9]([C:8]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:14]=[CH:15][C:7]=4[NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])[CH2:49][CH2:50]3)[O:41][CH2:42][CH2:43][O:44]2)=[CH:36][CH:35]=1
Reactant: NCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reactant: CCOC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)NCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a stirred suspension of 19.6 parts of 2-[(ethoxycarbonyl)amino]-5-(phenylmethoxy)benzoic acid in 520 parts of dichloromethane were added 12.6 parts of N,N-diethylethanamine and the whole was stirred for 5 minutes. 15.9 Parts of 2-chloro-1-methylpyridinium iodide were added and stirring was continued for 90 minutes. A solution of 18.2 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidineethanamine in 390 parts of dichloromethane was added dropwise to the whole. Upon completion, stirring was continued for 2.50 hours at room temperature. 150 Parts of water were added to the reaction mixture. The organic layer was separated, washed with a sodium hydrogen carbonate solution 10%, dried, filtered and evaporated. The oily residue was purified by HPLC over silica gel using a mixture of methylbenzene and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24.7 parts (67%) of ethyl [2-[[2-[4[ 2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]aminocarbonyl]-4-(phenylmethoxy)phenyl]carbamate as a residue (25).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](=[O:32])([O:30][CH3:31])[NH2:29].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:29][C:28](=[O:32])[O:30][CH3:31])[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Reactant: COC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Temperature: 110 °C
Yield: 81.8 %

Procedure:
To a solution of 0.5 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 15 mL of dioxane are successively added, under argon, 146 mg of methyl carbamate, 1.6 g of caesium carbonate, 75 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 29 mg of palladium diacetate. The reaction mixture is heated at 110° C. for 1 hour, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume) to give 450 mg of methyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)carbamate, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: OCc1ccnc(F)c1
Reactant: CCOc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccc(OCc2ccnc(F)c2)cc1
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
To a solution of (2-fluoropyridin-4-yl)methanol (5.06 g, 39.8 mmol) in DMF (100 mL) were added triethylamine (8.30 mL, 59.7 mmol) and methanesulfonyl chloride (3.08 mL, 39.8 mmol) under ice-cooling. After stirring for 30 min, 4-ethoxyphenol (5.77 g, 41.8 mmol) and potassium carbonate (5.50 g, 39.8 mmol) were added thereto and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3). A mixture of the obtained product and 4-ethoxyphenol (starting material) was purified again by basic silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give the title compound (822 mg, yield 8.4%).