Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.Br[C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[C:45]([NH:58][C:59](=[O:61])[O-:60])[CH:44]=[CH:43]2.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:36][O:35][C:34](=[O:37])[NH:33][C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]2[C:22]3[C:17]([CH:16]=[CH:15][C:13]=2[N:14]=1)=[CH:18][C:19]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH:58][C:59]([O:60][C:2]([CH3:38])([CH3:3])[CH3:1])=[O:61])[C:46]=2[NH:50][C:51]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:57])[CH:41]=1)=[CH:20][CH:21]=3)=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1c(NC(=O)[O-])ccc2cc(Br)ccc12
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)ccc5c4)ccc3c2[nH]1)C(C)C
Temperature: 120 °C
Yield: 151.7 %

Procedure:
To methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (190 mg, 0.36 mmol), tert-butyl 6-bromonaphthalene-1,2-diyldicarbamate (205 mg, 0.47 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol). DME (1.5 mL) was added and followed by 1.08 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide the desired product (205 mg, 75%). MS (ESI) m/z 752 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=3)[C:20]#[N:21])[N:11]=2)=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=3)[C:20]#[N:21])[N:11]=2)=[CH:8][CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(C#N)c3)no2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1C#N
Temperature: 60 °C
Yield: 101.8 %

Procedure:
5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol) and p-toluenesulfonic acid monohydrate (0.043 g, 0.227 mmol) were added in acetone (10 ml) to give a colorless solution. The reaction mixture was heated at 60° C. for 2 hr. The solution was cooled, the reaction mixture was concentrated, the residue was purified via silica gel chromatography (12 g, 50% EtOAc:Heptane) to afford 5-(5-(4-formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231 mmol, 102% yield) as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(OC(=O)C)(=O)C>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:1][C:2]2[N:3]=[N:4][C:5]([CH:8]=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Cc1ccc(C)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)nn2)cc1
Yield: 44.4 %

Procedure:
First, 24 g of 3,6-dimethylpyridazine and 60 g of p-nitrobenzaldehyde were dissolved in 1 liter of acetic anhydride, then heated under reflux so as to obtain 33 g of 3,6-di(p-nitrostyryl)pyridazine.
Reaction SMILES: [NH:1]([C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([NH:1][C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)[CH:14]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Reactant: O[C@H]1CCOC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Nc2cnc3cc(O[C@@H]4CCOC4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution at 0° C. under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S)-(+)-3-hydroxytetrahydrofuran (0.086 mL, 1.3 mmol), and triphenylphosphine (0.31 g, 1.2 mmol). DEAD (0.18 mL, 1.2 mmol) is added portionwise. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is concentrated and partitioned between EtOAc and H2O. The organic layer is washed with H2O, brine, dried (MgSO4), and concentrated. The resulting yellow oil is chromatographed (50% EtOAc/hexanes) and taken up in Et2O/IPA (isopropanol). HCl/Et2O solution is added dropwise and the resulting red-orange powder is dried in vacuo. The powder is free-based by stirring in MeOH with washed (3×H2O, 5×MeOH) basic ion exchange resin. The mixture is stirred 30 minutes, filtered, concentrated, and recrystallized from EtOAc/hexanes to provide, in two crops, the product (m.p. 173-175° C.). Anal. Calcd. for C18H17N3O2: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CCOC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 3 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-(tributylstannyl)pyridine: MS (m/z) 378.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:48])[C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:47])([F:46])[F:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:48])[C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:47])([F:45])[F:46])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)Nc3ccccc3C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(N(C)C(=O)Nc3ccccc3C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 5 from tert.butyl 4'-[(2-n-butyl-6-(N-(2-trifluoromethylphenyl-aminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=1.[OH2:11]>CC(C)=O>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:9])=[O:11])[CH:4]=1
Reactant: O
Reactant: O=C(Cl)c1cc(CBr)on1
Solvent: CC(C)=O
Product: O=C(O)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The distilled 5-(bromomethyl)-3-isoxazolecarbonyl chloride (1 g) is dissolved in 2 ml of acetone, cooled to 0° C. and 3 ml of water is added to the solution. The solution is allowed to stand at room temperature for one hour and then the solvent is removed under reduced pressure giving 0.9 g of the acid. It is dried over P2O5 for three days and has mp 143°-148° C.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:30]([C:31]([NH2:33])=[O:32])[C:29]=1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:31]([C:30]1[C:29]([OH:37])=[C:28]([CH:36]=[CH:35][CH:34]=1)[O:27][CH2:26][CH2:25][N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)(=[O:32])[NH2:33]
Reactant: COCCOc1ccc(OCC2CO2)cc1
Reactant: NC(=O)c1cccc(OCCNCc2ccccc2)c1O
Product: COCCOc1ccc(OCC(O)CN(CCOc2cccc(C(N)=O)c2O)Cc2ccccc2)cc1

Procedure:
By reacting 2.5 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene with 2.9 g of crude 3-(2-benzylaminoethoxy)salicylamide obtained according to Example (25c), analogously to Example (4a), 1-[N-[2-(3-carbamoyl-2-hydroxyphenoxy)ethyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is obtained as an oil which is further processed in this state
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]>CN(C=O)C>[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:39])[F:38])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]
Reactant: OCC(F)(F)F
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
2,2,2,-Trifluoroethanol (10 ul, 137 umol; CAS Reg. No. 75-89-8 99) and cesium carbonate (45 mg, 137 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (37 mg, 69 umol; example 388 g) in DMF (500 ul) under an argon atmosphere. The reaction mixture was stirred for 72 h at ambient temperature and partitioned between ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow foam which was purified by preparative chiral HPLC to give the title compound (13 mg, 21 umol; 31%) as colorless foam. MS (ESI): m/z=620.2 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:13]([C:10]2[CH2:9][C:8]3([CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:17][CH2:16]3)[O:12][N:11]=2)=[O:15])=[CH:27][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(NC(=O)C2=NOC3(CCC(C(C)(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (220 mg, 0.91 mmol), 4-tert-butylaniline (137 mg, 0.91 mmol), 4-methylmorpholine (279 mg, 2.76 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (528 mg, 1.20 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, ether/hexane 2:1), the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a diastereomer mixture in a yield of 80 mg (24% of the theoretical amount).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(S(C)(=O)=O)CC3)ncc1Cl

Procedure:
5-Chloro-N*2*-(3-methanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-methanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 318b. Product isolated as a pale yellow solid (60 mg, 37%). m.p.=204-206° C.; LCMS (m/e) 559 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H, J=8.8 Hz), 8.01 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.04 (d, 1H, J=7.9 Hz), 6.88 (s, 1H), 6.54 (s, 1H), 6.49 (d, 1H, J=9.0 Hz), 3.91 (s, 3H), 3.91-3.87 (m, 4H), 3.47-3.40 (m, 4H), 3.19-3.13 (m, 4H), 3.03-2.95 (m, 4H), 2.77 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH3:31]>ClCCl>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])=[CH2:29]
Reactant: CC(CBr)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1ccc(S(=O)(=O)N2CCN(CC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (549 mg) and triethylamine (0.836 ml) in dichloromethane (10 ml) was added dropwise a solution of 4-(2-bromo-1-methylethyl)benzenesulfonyl chloride (893 mg) in dichloromethane (2 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 6 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (20 ml), and to the solution was added 1N sodium hydroxide (2 ml). The mixture was stirred at 80° C. for 30 minutes, and to the reaction solution was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:11:1) and washed with water to give colorless crystals of 4-(4-isopropenylbenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (155 mg).
Reaction SMILES: [CH2:1]([C:3]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:8][CH2:7][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:52][C:53]1([CH3:60])[CH2:57][C:56](=[O:58])[O:55][C:54]1=[O:59]>C(OCC)(=O)C>[CH2:44]([O:43][C:41]([C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([O:33][C:56](=[O:58])[CH2:57][C:53]([CH3:60])([CH3:52])[C:54]([OH:59])=[O:55])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:7][CH2:8]1)=[O:42])[CH3:45]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ethyl 4-ethyl-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylate (Example 73, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Completion of the reaction was monitored by TLC, the reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753; (100%), [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([OH:19])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[CH:32]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([O:19][CH2:32][C:31]#[CH:30])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(O)nn1-c1ncc(Cl)cc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1cc(C(=O)OCC)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 60 °C
Yield: 38 %

Procedure:
To a 100 mL flask, ethyl 1-(3,5-dichloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylate (0.7 g, 2.32 mmol), acetonitrile (10 mL), potassium carbonate (0.32 g, 2.32 mmol) and 3-bromoprop-1-yne (0.27 g, 2.32 mmol) were added sequentially. The reaction mixture was heated to 60° C. for 2 hours. Then the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (2×100 mL). The organic layer was washed with saturated sodium carbonate solution (80 mL) and saturated brine (80 mL), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the compound (0.30 g) as yellow oil in 38% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([I:18])=[CH:13][C:10]=1[CH:11]=O>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([I:18])=[CH:13][C:10]=1[CH2:11][NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CN
Reactant: Cc1cc(I)cc(C=O)c1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNCc1cc(I)cc(C)c1N

Procedure:
A mixture of freshly prepared ethyl glycinate (2.58 g), 2-amino-5-iodo-3-methylbenzaldehyde (4.03 g) and 3Å molecular sieves (2 g "Fluka A.G." [Trade Mark] article No. 69828) was heated with stirring under reflux in chloroform (50 cm3) for 4 hours. The cooled solution was filtered, evaporated in vacuo, and the residue taken into ethanol (30 cm3) and treated with sodium cyanoborohydride (1.43 g). After stirring for 72 hours ethanol was removed in vacuo and the residue was partitioned between chloroform (50 cm3) and aqueous ammonia (50 cm3, S.G. 0.88). The aqueous phase was further extracted with chloroform (2×100 cm3) and the combined organic extracts were dried (MgSO4) and evaporated to give the title compound as a crude oil, (2.5 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:31][N:29]([CH2:28][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:20]1)[CH3:30]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CN(C)CC1CNc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 61.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 220 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of (2,3-dihydro-1H-indol-3-ylmethyl)dimethylamine and 210 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.14 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 206 mg of 2-[2-(3-dimethylaminomethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([Br:9])[N:6]=[C:5](Br)[C:4]1=[O:11])[CH3:2].[NH3:12]>O1CCOCC1>[CH2:1]([N:3]1[CH:8]=[C:7]([Br:9])[N:6]=[C:5]([NH2:12])[C:4]1=[O:11])[CH3:2]
Reactant: CCn1cc(Br)nc(Br)c1=O
Reactant: N
Solvent: C1COCCO1
Product: CCn1cc(Br)nc(N)c1=O
Reaction time: 15 h

Procedure:
A mixture of 4.6 g of 1-ethyl-3,5-dibromopyrazin-2-one, 9.6 ml of dioxane and 6.4 ml of 30% ammonia is stirred at 20°-25° C. for 15 hours. The product is filtered off and washed with alcohol and ether to give 1.3 g of 1-ethyl-3-amino-5-bromo-pyrazin-2-one with a melting point of 227°-230° C.