Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].P(Br)(Br)[Br:17]>ClCCl.N1C=CC=CC=1>[Br:17][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:13]([O:14][CH3:15])[C:6]=2[C:7]=1[CH3:12]
Reactant: COc1c(Cl)ccc2oc(CO)c(C)c12
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Cl)ccc2oc(CBr)c(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a 0° C. solution of (5-chloro-4-methoxy-3-methyl benzofuran-2-yl)-methanol (0.29 g; 1.3 mmol) in dichloromethane (5 mL) was added neat phosphorus tribromide (0.18 mL; 0.52 g; 1.9 mmol; 1.5 eq) and pyridine (3 drops). The ice bath was removed and the reaction was allowed to warm to room temperature overnight. Additional phosphorus tribromide (0.09 mL; 0.26 g; 0.95 mmol; 0.75 eq) was added and stirring continued at room temperature. After two hours, the reaction was quenched with ice and extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate, followed by drying over magnesium sulfate, filtration and concentration in vacuo to give essentially pure 2-bromomethyl-5-chloro-4-methoxy-3-methyl benzofuran (0.37 g; 99%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39]1[O:40][C:41]([CH2:44][CH3:45])=[CH:42][N:43]=1>CN(C=O)C>[CH2:44]([C:41]1[O:40][C:39]([CH2:38][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:43][CH:42]=1)[CH3:45]
Reactant: CCc1cnc(CCl)o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (800 mg; compound B50) in DMF (15 ml) are added potassium carbonate (520 mg) and 2-(chloromethyl)-5-ethyl-1,3-oxazole (270 mg; compound D1). After stirring for 1 h at 100° C. further 2-(chloromethyl)-5-ethyl-1,3-oxazole (200 mg; compound D1) and potassium carbonate (400 mg) are added to the reaction mixture. The mixture is stirred for additional 30 min at 100° C. Afterwards all volatile materials are removed in vacuo and the residue is purified by flash chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)] to give the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3Cl)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(n3c(Cl)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Reactant: CN1CCNCC1
Product: Cc1c(C(=O)N2CCC(n3c(N4CCN(C)CC4)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 22 %

Procedure:
A mixture of 20 mg (0.041 mmol) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (the preparation of which is described in example 1) and N-methyl-piperazine was heated in a sealed tube at 90° C. for 8 hours, cooled to RT and then concentrated in vacuo. Flash chromatography (CH2Cl2/MeOH 9/1) afforded 5 mg (22%) of (1-benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazin-1-yl)-benzoimidazol-1-yl]-piperidin-1-yl}-methanone as white solid. ES-MS m/e (%): 547.5 (M+H+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:36]([OH:38])=[O:37])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:35])[NH:20]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N[C@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:36]([OH:38])=[O:37])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reaction time: 2 h

Procedure:
In 5 ml of mixed solution of trifluoroacetic acid-thioanisole (9:1) was dissolved 400 mg of Boc-Tyr-Arg(Mtr)OH and the resulting mixture was allowed to stand at room temperature for 2 hours. The trifluoroacetic acid was distilled off under reduced pressure, ether was added to the residue and the resulting precipitate was collected by filtration. The precipitate was dissolved in a small amount of water, passed through a column (1×10 cm) of Amberlite IRA-410 (acetate-form) and lyophilized. The lyophilizate was dissolved in a small amount of water, chromatographed on a carboxymethyl-cellulose column (2.2×8 cm) and eluted by the linear gradient method using water (300 ml) and 0.1 M ammonium acetate (300 ml). The fractions from 100 to 150 ml were pooled and lyophilized. Yield 175 mg, [α]D21 -17.4° (c=0.5, H2O); amino acid analysis (acid hydrolysis): Arg 1.00(1), Tyr 0.94(1); average recovery 86.5%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:12].[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH:17][C:26]([C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[NH:27])[CH:18]=[CH:19][CH:20]=1)[CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cccc(NC(=N)c2ccc(F)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.48 g (4.0 mmol) of 4-fluorobenzonitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 259.2 (M+1).
Reaction SMILES: [Cl:1]C1C(C(OCC)=O)=NNC=1C.[CH2:13]([N:17]([CH2:34][CH2:35][CH2:36][CH3:37])[C:18]([C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[NH:22][N:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]>>[CH2:34]([N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[C:18]([C:20]1[C:24]([Cl:1])=[C:23]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[NH:22][N:21]=1)=[O:19])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)C(=O)c1cc(CCOC2CCCCO2)[nH]n1
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1n[nH]c(CCOC2CCCCO2)c1Cl
Yield: 79 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, N,N-dibutyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxamide (355 mg, 1.01 mmol) was converted to the title compound (327 mg, 79%). 1H NMR (CD3OD) δ 4.60 (t, J=3.4 Hz, 1H), 3.94 (td, J=9.7, 6.5 Hz, 1H), 3.79-3.61 (m, 2 H), 3.59-3.41 (m, 3H), 3.39-3.25 (m, 2H), 3.04-2.91 (m, 2H), 1.87-1.34 (m, 12H), 1.27-1.09 (m, 2H), 0.99 (t, J=7.3 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 386.3 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[C:5]=1[C:25]([O:27][CH3:28])=[O:26].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:3]([C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[C:5]=1[C:25]([O:27][CH3:28])=[O:26])=[O:2]
Reactant: CCCOC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Reaction time: 5.5 h
Yield: 28.5 %

Procedure:
To a solution (132 ml) of n-propyl 6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (13.28 g) in acetone was added dropwise 6N hydrochloric acid (13.2 ml) at 12° C. with stirring, and the stirring was continued for 5.5 hours. The resultant mixture was adjusted to about pH 7 with an aqueous sodium bicarbonate solution. The acetone was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with an aqueous sodium chloride solution, water and petroleum ether, successively, and then recrystallized from a mixture of benzene and n-hexane. The crystals were collected by filtration and washed with diethyl ether to give n-propyl 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (3.37 g), mp 137.5°-141.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
A mixture of ethyl 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (10.00 g), 2N aqueous sodium hydroxide solution (40 mL), tetrahydrofuran (100 mL) and ethanol (40 mL) was stirred overnight at room temperature. The reaction mixture was acidified by adding hydrochloric acid and concentrated. The residue was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, v/v). The organic layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol-diisopropyl ether to give 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoic acid as a white solid (3.93 g, yield 44%). melting point: 219-220° C.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][CH2:18][C@@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:14][N:13]=1)=[CH:7][CH:6]=2.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:31][C@@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=1)[CH2:18][NH:17][C:15]1[S:16][C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[N:3][C:2]([F:1])=[CH:11]3)=[N:13][N:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of tert-butyl (S)-1-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.047 g, 0.086 mmol) in TFA/DCM (1:1, 4.0 mL) was stirred at room temperature for 30 minutes. The solvent was evaporated to provide the product as an off-white solid (50.3 mg, 100%). LCMS (API-ES) m/z: 449 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.05 (d, J=6.85 Hz, 2H), 3.54-3.65 (m, 2 H), 7.57 (d, J=8.02 Hz, 2 H), 7.72 (d, J=7.82 Hz, 3 H), 7.76 (s, 1 H), 8.03 (s, 3 H), 8.11 (dd, J=8.61, 1.57 Hz, 1 H), 8.28 (d, J=8.80 Hz, 1 H), 8.33-8.39 (m, 2 H).
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[CH:27]1([B-](F)(F)F)[CH2:29][CH2:28]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:27]1([C:2]2[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])=[CH:11][C:10]=3[O:23][CH3:24])=[N:6][CH:7]=2)[CH2:29][CH2:28]1
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1C1CC1
Temperature: 140 °C
Yield: 25.3 %

Procedure:
To a microwave tube was added (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (56 mg, 0.13 mmol), potassium cyclopropyltrifluoroborate (39 mg, 0.27 mmol), cesium carbonate (0.13 g, 0.40 mmol), toluene (1.8 mL) and water (0.2 mL). The mixture was degassed by nitrogen bubbling for 15 mintues. XPhos (6.4 mg, 0.013 mmol) and palladium acetate (2 mg, 0.01 mmol) was then added. The reaction was heated in a Biotage microwave at 140° C. for 20 minutes. The reaction mixture was filtered and concentrated. The crude product was purified by RP-HPLC to give the desire product (12.6 mg, 25%).
Reaction SMILES: C1(N2C(C3C=CC(OCC4C=CC=CC=4)=CC=3)=CC(/C=C/C(O)=O)=N2)CCCCC1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[N:48]=[C:47](/[CH:56]=[CH:57]/[C:58]([O:60]C)=[O:59])[C:46]=2[Br:62])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[N:48]=[C:47](/[CH:56]=[CH:57]/[C:58]([OH:60])=[O:59])[C:46]=2[Br:62])=[CH:43][CH:44]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Agent: O=C(O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Product: O=C(O)/C=C/c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Yield: 98.4 %

Procedure:
Acid 8.5 was prepared from 8.4 according to the procedure described above for the preparation acid 2.4. Thus, 8.4 (47 mg, 0.095 mmol) was saponified to yield 45 mg (99%) of 8.5. HRMS (ESI) calc'd for C25H26BrN2O3 481.1127, found 481.1105 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=16.1,1H), 7.49–7.34 (m, 5H), 7.27 (d, J=8.8, 2H), 7.12 (d, J=8.8, 2H), 6.88 (d, J=16.1, 1H), 5.14 (s, 2H), 4.04–3.96 (m, 1H), 2.00–1.83 (m, 6H), 1.26–1.24 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.[C:20]([C:26](OC)=[O:27])#[C:21][C:22]([O:24][CH3:25])=[O:23]>CO>[C:22]([C:21]1[N:3]2[C:4]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH2:8][C:2]2=[N:1][C:26](=[O:27])[CH:20]=1)([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CO
Product: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Yield: 16.3 %

Procedure:
A mixture of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (13.5 g.; 0.05 mole), dimethyl acetylenedicarboxylate (7.1 g.; 0.05 mole) and 250 ml. of methanol were refluxed for 2 hours and evaporated. The residue was dissolved in 50 ml. of methylene chloride and chromatographed on 2 kg. of silica gel using 60% ethyl acetate 40% cyclohexane. Fractions 1-6 (4.5 l.) gave no material. Fractions 6-51 were discarded. Fraction 52-54 gave 6.3 g. of solids which were crystallized from methylene chloride ether to give 1-carbomethoxy-9-chloro-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one 3.1 g. of melting point 214°-215° C. dec., raised to 216°-217° C. on recrystallization from methanol-ether.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([O:39]CC5C=CC=CC=5)=[O:38])[C:34]4([CH3:48])[CH3:47])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.[OH-].[Na+]>CO.C1COCC1>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([OH:39])=[O:38])[C:34]4([CH3:48])[CH3:47])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)O)C3(C)C)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
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of (1S,3R)-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylate (Example 2, about 0.140 g, 0.196 mmol) in MeOH:THF (2:1) (6 ml) at 0° C., 2N NaOH (2 ml) was added and allowed to stir at room temperature for about 6 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated and acidified with 2N HCl, the aqueous layer was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 50% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.105 g: Yield: 92%. 1H NMR (300 MHZ, CDCl3): δ 5.64 (d, 1H, J=7.8 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.15 (q, 1H, J=9.3 Hz), 3.18 (dd, 1H, J=5.1, 10.8 Hz), 3.14-3.08 (m, 1H), 2.71-2.64 (m, 1H), 2.52-2.41 (m, 1H), 2.40-2.28 (m, 1H), 2.10-1.88 (m, 4H), 1.78-1.64 (m, 9H), 1.62-1.51 (m, 3H), 1.49-1.41 (m, 4H), 1.39-1.32 (m, 7H), 1.28-1.22 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.81 (s, 3H), 0.75 (s, 3H); Mass: [M+1]+ 582 (10%), [M+Na]+ 604 (100%); IR (KBr, cm−1): 3454, 3407, 2949, 2869, 1716, 1709, 1642, 1459, 1243, 1191, 1009, 885, 787; M.R: 174.6° C.-187.0° C.; HPLC: 90.33%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([N+:13]([O-])=O)=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(N)c(N)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A mixture of 4,5-dinitro-2-ethoxy-benzoic acid methyl ester (320 mg) and 10% Pd/C (40 mg) in MeOH (8 mL) was stirred under an atmosphere of hydrogen gas for 4 h at r.t., filtered through a plug of Celite and reduced in vacuo to give the title compound (234 mg) as a black gum. 1H NMR (300 MHz, MeOD) δ 7.30 (s, 1H), 6.40 (s, 1H), 4.00 (q, 2H), 3.80 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31]>>[CH3:33][O:32][C:30]([C:29](=[O:34])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: COC(=O)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: COC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].[Cl:35][C:36]1[CH:41]=[C:40](Cl)[N:39]=[CH:38][N:37]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21])[C:40]1[CH:41]=[C:36]([Cl:35])[N:37]=[CH:38][N:39]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ncn1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
{2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (2.0 g), 4,6-dichloropyrimidine (1.19 g) and N-ethyldiisopropylamine (2.09 ml) are dissolved in toluene (10 ml) and the mixture is heated under reflux for 3 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give (3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-(6-chloropyrimidin-4-yl)-amine (1.8 g). MS (m/z): 613 [M+H]+
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C(O)C>[C:12]([CH2:13][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
In 560 ml of ethanol was dissolved 25 g (1.08 eq.) of sodium and a mixture of 135.6ml (146 g; 1 mol) of diethyl oxalate and 116.7 ml (120 g; 1 mol) of acetophenone was added thereto dropwise at 40° C. One hour later, reflux was begun and it was continued for 30 minutes. The solvent was distilled off. The residue was neutralized with sulfuric acid (55 g/water 200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane 1:1), to give colorless plates. The crystals were recovered by filtration with ethyl acetate/hexane. Yield: 114.6 g.