Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:8][C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:18][C:13]2[C:12]([NH:11][C:9]([O:8][CH:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OC(c1ccncc1)C1CCNCC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: O[C:2]1[C:11](C)=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][C:3]=1C.C(C1C=CC([C:20]([O:22][CH2:23][CH3:24])=[O:21])=CC=1)#N>>[CH2:23]([O:22][C:20](=[O:21])[C:2]1[CH:3]=[CH:4][C:5]([C:6](=[NH:7])[NH:8][OH:9])=[CH:10][CH:11]=1)[CH3:24]
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Reactant: CCOC(=O)c1ccc(C#N)cc1
Product: CCOC(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 4,N-dihydroxy-3,5-dimethyl-benzamidine starting from ethyl 4-cyanobenzoate; LC-MS: tR=0.55 min, [M+1]+=209.05; 1H NMR (D6-DMSO): δ 1.33 (t, J=7.0 Hz, 3H), 4.32 (q, J=7.0 Hz, 2H), 5.94 (s, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.95 (d, J=7.8 Hz, 2H), 9.91 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][N:8]([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)c1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1nn(CCOC2CCCCO2)cc1I
Yield: 39 %

Procedure:
A suspension of Intermediate 74b (2.72 g, 10.2 mmol) in acetonitrile (27 mL) was treated with caesium carbonate (5.0 g, 15.3 mmol) then 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.70 mL, 11.2 mmol) and the mixture was stirred at 60° C. for 3.5 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, isolating the lower running spot to give the title compound as a colourless glass (1.57 g, 39%). LCMS (Method 3): Rt 3.67 min, m/z 417 [M+Na+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Brc1cccnc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 3-bromopyridine according to the general procedure C. Obtained as a yellow solid (587 mg).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>O1CCCC1>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-bromo-5α-pregnane-3,11,20-trione (500 mg) in dry tetrahydrofuran was treated at reflux with morpholine (0.5 ml) for 1/2 hour, and poured into water. The oily precipitate was extracted into ether and the extracts were washed with water, dried (Na2SO4) and evaporated to the crude product which was purified by preparative t.l.c. in ethyl acetate and crystallisation from ether to give the title compound (220 mg). m.p. 159°-164°C [α]D +98° (c=1.1%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=3[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.N1C=CC=CC=1>[CH3:30][O:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[C:22]=2[CH:23]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 0.6 ml methanesulphonyl chloride in 3 ml absolute dioxane is added dropwise to a solution of 2.1 g rac-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-hexahydro-2-methyl-benzo[c ][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at 60° C. for a further 3 h. After cooling, the mixture is poured onto 100 ml of an ice/water mixture, rendered alkaline with dilute sodium hydroxide solution and extracted with n-butanol. After the n-butanol has been evaporated off, the residue which remains is extracted with methylene chloride and the organic phase is dried over sodium sulphate and then concentrated. 2.4 g of the title compound are obtained as the residue and are converted into the dihydrochloride with ethereal HCl, and the product is recrystallized from non-dried methanol. Yield: 2.3 g of the title compound as the dihydrochloride hydrate. M.p. 239°-240° C. (decomposition).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)CNCN2
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CNc2ccccc2C1
Reaction time: 0.08 h

Procedure:
0.17 ml of methanesulfonyl chloride is added to a mixture of 300 mg of 1,2,3,4-tetrahydroquinazoline (prepared by the method described by R. F. Smith et al. in J.Heterocycl. Chem.2 (1965)) and 0.47 ml of triethylamine in 14 ml of methylene chloride at 0° C., while stirring. After 5 min, saturated sodium chloride solution is added, the mixture is subsequently stirred briefly and, after drying over sodium sulfate, the organic phase is concentrated. Purification of the crude product by means of FC over 30 g of silica gel (mobile phase P) gives 3-methylsulfonyl-1,2,3,4-tetrahydroquinazoline: Rf (K)=0.65; IR(KBr): 3360(m), 1600(m), 1500(m), 1320(s), 1145(s), 770(s).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26]O)=[C:11]([CH2:16][NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2].C(N(S(F)(F)[F:36])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26][F:36])=[C:11]([CH2:16][NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(CF)c1OCc1ccc(C#N)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 4-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (8) (1765 mg, 4.60 mmol) in dry dichloromethane (200 mL) was slowly added diethylaminosulfurtrifluoride (DAST) (741 mg, 4.6 mmol) in dry dichloromethane (50 mL) at −78° C. under nitrogen atmosphere. The reaction temperature was warmed to −40° C. and stirred for 30 minutes. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product was extracted with dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using dichloromethane:hexane:methyl alcohol (15:10:1) as an eluant to give 4-{[5-(4-cyano-benzyloxy)-4-fluoromethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (10) (650 mg, 37% yield) as a colorless solid.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:19]([O:20][CH3:21])=[CH:18][C:8]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])=[O:10])=[C:7]([N+:22]([O-])=O)[C:6]=1[O:25][CH3:26].[H][H]>CO.[Ni]>[NH2:22][C:7]1[C:6]([O:25][CH3:26])=[C:5]([CH3:4])[C:19]([O:20][CH3:21])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Hydrazine hydrate (1.26 g, 39.37 mmol) was added dropwise to a solution of 190 (2.13 g, 6.56 mmol) in methanol (50 mL) gently refluxing over Raney nickel (1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product as a brown glass (191) (1.91 g, 6.50 mmol) which was protected directly as the troc-carbamate.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[O:33][CH3:34])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CN(CC1CCCC1)C(=O)c1ccc2c(ccn2C)c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)N(C)CC4CCCC4)cc23)c(OC)c1
Yield: 13.2 %

Procedure:
Silver(I) oxide (0.30 g) was added to a solution of 5-[N-(cyclopentylmethyl)-N-methylcarbamoyl]-1-methylindole (G) (0.35 g) in dixoane (2 ml). The mixture was protected from light, stirred, and heated to reflux under an atmosphere of nitrogen for 2 hours. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (0.33 g) in dioxane (1 ml) was added and the mixture was heated to reflux for an additonal 18 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was evaporated to give an amber gum which was purified by flash chromatography on silica gel (223 ml), eluting with chloroform to give the title compound (75.2 mg, 13%) as a white foam; partial nmr (80 MHz, CDCl3): 3.01(s, 3H, CONCH3), 3.51(br d, 2H, HCH2), 3.74(s, 3H, NCH3), 3.89(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.10(s, 2H, ArCH2), 6.81(s, 1H, H2 -indole).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]4[C:28]5[N:29]=[C:30]([NH2:32])[O:31][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]4[C:28]5[N:29]=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[O:31][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4oc(N)nc34)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(N4CCN(C(C)c5ccc(F)cc5)CC4)ncn3)cccc2o1

Procedure:
4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2-amine (0.06 g, 0.14 mmol, Example 63) was reacted with acetic anhydride under the conditions of Example 1(b) to give the desired product. Mp: 199.8° C. MS (ESI, pos. ion) m/z: 477 (M+1).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[K+].[Br-].[CH3:14][C:15]([CH3:17])=O>>[ClH:2].[Cl:1][CH:5]1[C:6](=[C:15]([CH3:17])[CH3:14])[C:7]([Cl:10])=[C:8]([NH2:9])[CH:3]=[C:4]1[OH:11]
Reactant: Nc1c(Cl)ccc(O)c1Cl
Reactant: CC(C)=O
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)=C1C(Cl)=C(N)C=C(O)C1Cl

Procedure:
Corresponding to the procedure and data in Example 1, 2,4-dichloro-3-aminophenol hydrochloride was reacted with acetone. The reaction product obtained according to this example of this invention had the following characteristic data: IR-spectrum (KBr) cm-1 1652, 1598, 1570, 1480, 1438, 1370, 1315, 1260, 1238, 1225, 1218, 1176, 1112, 1085, 1010, 980, 930, 870, 835, 805, 762, 730, 710, 675, 655.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:49])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:48])[CH2:9][CH2:10][C@@:11]3([C:27]([NH:29][CH2:30][CH2:31][CH:32]4[O:37][C:36]([CH3:39])([CH3:38])[O:35][CH:34]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:51])[CH3:50].CC1C=CN=C(N)C=1C.[CH3:61][C:62]1([CH3:69])[CH2:66][C:65](=[O:67])[O:64][C:63]1=[O:68]>N1C=CC=CC=1.C(OCC)(=O)C>[C:44]([O:43][C:41](=[O:42])[CH2:40][CH:34]1[O:35][C:36]([CH3:38])([CH3:39])[O:37][CH:32]([CH2:31][CH2:30][NH:29][C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:48])([CH2:9][CH2:10]3)[C@@:7]3([CH3:49])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:51])([CH3:50])[C@@H:2]([O:1][C:65](=[O:67])[CH2:66][C:62]([CH3:69])([CH3:61])[C:63]([OH:68])=[O:64])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:33]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)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
Agent: Cc1ccnc(N)c1C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)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 tert-butyl 2-(6-(2-((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-carboxamido)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Example 79, 0.5 g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added. Contents were refluxed for about 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, 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: 806 [M+Na].
Reaction SMILES: C(N1C(=O)C(N[C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])(C)C(=O)NC1=O)C.[NH2:26][C:27]1([CH2:42][CH3:43])[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](=[O:40])[NH:29][C:28]1=[O:41]>>[CH2:42]([C:27]1([NH:26][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](=[O:40])[NH:29][C:28]1=[O:41])[CH3:43]
Reactant: CCC1(N)C(=O)NC(=O)N(c2ccccc2)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Product: CCC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(c2ccccc2)C1=O

Procedure:
Compound 20k was prepared by the same method described for 20f using 5-amino-5-ethyl-1-phenylbarbituric acid (0.50 g, 2 mmol). The crude 5-ethyl-1-phenyl-5-(tetrafluorobenz-amido)barbituric acid (20k) was obtained as yellow crystals that were pure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH2:19]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol) and K2CO3 (1.88 g, 13.6 mmol) were suspended in DCM (7 mL). MeNH2 (40% in H2O, 7 mL) was added slowly and the mixture stirred at room temperature for 4 h. The mixture was diluted with H2O and extracted with DCM (3×40 mL). The combined DCM layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the product as a bright orange solid (1.47 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[NH2:21])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl-].C([O:33][C:34](=O)[C:35](O)=[O:36])C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[C:13](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:21][C:34](=[O:33])[C:35]2=[O:36])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)O
Reactant: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2N)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At a bath temperature of +40° C., under argon and with exclusion of moisture, 582 mg (2.3 mmol) of 4-(2-amino-4-nitrophenylamino)benzoic acid ethyl ester is combined with 488 mg (4.8 mmol) of triethylamine in 27 ml of dry tetrahydrofuran. A solution of 659 mg (4.8 mmol) of oxalic acid ethyl ester chloride and 8 ml of dry tetrahydrofuran is added dropwise to this batch and stirred for 2 hours at room temperature. The mixture is then combined with 0.2 ml of triethylamine and 0.1 ml of oxalic acid ethyl ester chloride, and agitated for one hour at room temperature. The batch is filtered, and the filtrate is concentrated and distributed in water/ethyl acetate. The organic phase is concentrated. The residue is refluxed for 2 hours at the bath temperature in 25 ml of 1N hydrochloric acid and 25 ml of ethanol. The thus-precipitated product is suctioned off, washed with water, and dried, yielding 220 mg of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)benzoic acid ethyl ester (further processed without purification).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[N:3]1.Br[C:21]1[CH:22]=[C:23]([CH:30]=[O:31])[C:24]2[O:28][CH:27]=[CH:26][C:25]=2[CH:29]=1>>[CH3:1][N:2]1[C:6]([C:21]2[CH:22]=[C:23]([CH:30]=[O:31])[C:24]3[O:28][CH:27]=[CH:26][C:25]=3[CH:29]=2)=[CH:5][CH:4]=[N:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: O=Cc1cc(Br)cc2ccoc12
Product: Cn1nccc1-c1cc(C=O)c2occc2c1

Procedure:
From 1-Methyl-5-tributylstannanyl-1H-pyrazole (826 mg) and 5-bromo-benzofuran-7-carboxaldehyde (500 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[C:22]=1[OH:35].Cl>O1CCCC1.O>[OH:35][C:22]1[C:21]([C:20](=[O:19])[CH2:2][C:1]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:3])=[CH:26][CH:25]=[CH:24][C:23]=1[O:27][S:28]([C:31]([F:34])([F:32])[F:33])(=[O:30])=[O:29]
Reactant: CC(=O)N1CCOCC1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCOCC1)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
A solution of N-acetylmorpholine (1.72 g, 13.3 mmol, 2 eq) in 30 ml dry tetrahydrofuran under nitrogen was cooled in an acetone/dry ice bath (−78° C.) and treated with LDA (10 ml, 2M solution in THF, 3 eq). The reaction mixture was stirred for 60 minutes then 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoic acid methyl ester [α] (2 g, 6.6 mmol, 1 eq as a solution in 10 ml dry THF) was added. The reaction mixture was allowed to warm from −78° C. to room temperature and stirred over night. The reaction was diluted with water (4 ml) followed by 2M hydrochloric acid (40 ml), then extracted three times with dichloromethane. The extracts were combined, washed with brine, dried with magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography eluting with ethyl acetate to afford trifluoro-methanesulfonic acid 2-hydroxy-3-(3-morpholin-4-yl-3-oxo-propionyl)-phenyl ester [D]. Yield 1.06 g, 40%
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>CN(C)C=O>[CH2:28]([N:31]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(C(F)(F)F)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3cccc2C(F)(F)F)no1
Yield: 95.9 %

Procedure:
1.19 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 1.33 g (96%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 216°-218°.