Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C.C(O)=O>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3cc(C)on3)cc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: Cc1cc(NS(=O)(=O)c2ccc(C#Cc3ccc(O)c(C(=O)O)c3)cc2)no1
Reaction time: 0.08 h

Procedure:
Ethyl 2-hydroxy-5-[[4-[(5-methyl-3-isoxazolyl)aminosulfonyl] phenyl]ethynyl]benzoate (1.5 g) was added to a boiling solution of potassium hydroxide (6 g, 92 mmol) in water (100 ml). After 5 min, ethanol (25 ml) was added and the solution acidified with formic acid. The precipitate was collected by filtration, washed with water and dried. Yield 1.4 g, quantitative.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH2:24])=[O:23])[C:18]([OH:20])=[O:19]>>[C:22]([CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])(=[O:23])[NH2:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(=O)CC(N)C(=O)O
Product: NC(=O)CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-succinamic acid to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:22][CH:23]=[CH2:24])[CH:8]([CH3:21])[CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH:1]1([CH2:6][N:7]([CH2:22][CH:23]=[CH2:24])[CH:8]([CH3:21])[CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: C=CCN(CC1CCCC1)C(C)CCCC(=O)c1ccc(F)cc1
Product: C=CCN(CC1CCCC1)C(C)CCCC(=O)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 26, react 5-[(cyclopentylmethyl)(2-propenyl)amino]-1-(4-fluorophenyl)hexan-1-one with 1H-imidazole to obtain the title compound.
Reaction SMILES: [Zn](C)[CH3:2].Cl[C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:10])[C:6]([F:9])([F:8])[F:7]>C(Cl)Cl.C1(C)C=CC=CC=1.O.Cl[Ti](Cl)(Cl)Cl>[CH3:10][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:2])[C:6]([F:9])([F:8])[F:7]
Reactant: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Reactant: C[Zn]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
To a stirred solution of TiCl4 (57 mg, 0.30 mmol) in dry CH2Cl2 (5 ml) was added a solution (1.05 mol/l) of ZnMe2 (0.87 ml, 0.91 mmol) in toluene via a syringe at −78° C. After 15 min, to this was added a solution of Compound 69 (217 mg, 0.91 mmol) in dry CH2Cl2 (2 ml) at same temperature. The reaction mixture was stirred at −78° C. for 1 h and warmed to room temperature. After 2 h, the mixture was diluted with water and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried(MgSO4) and concentrated in vacuo to give crude product (200 mg) (Compounds 69:70=1:2.4) as a pale yellow oil. This was employed in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[N:4]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:3]1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Reactant: BrCc1ccccn1
Product: CC1(C)CN(Cc2ccccn2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione with 2-bromomethylpyridine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(O)cc1OC
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCC(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
A mixture of 3,4-dimethoxyphenol (10 g), ethyl 4-bromo-butyrate (15.2 g), anhydrous potassium carbonate (11.7 g), potassium iodide (1.5 g) and N,N-dimethylformamide (40 ml) is stirred for 15 hours at 60° to 70° C. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (30 ml), to the solution is added a 2.5N aqueous solution of sodium hydroxide (67 ml), and the mixture is stirred for 40 mintues at 50° to 60° C. The reaction mixture is concentrated under reduced pressure. To the concentrate is added water, and the mixture is acidified (pH 3) with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate - hexane to give 4-(3,4-dimethoxyphenyloxy)butyric acid as colorless prisms (12.5 g). To polyphosphoric acid (60 g) is added 4-(3,4-dimethoxyphenyloxy)butyric acid (6.0 g) obtained above, and the mixture is stirred for 30 minutes at 100° C. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated. The residue is recrystallized from ethyl acetate - hexane to give 7,8-dimethoxy-3,4-dihydro-1benzoxepin-5(2H)-one as colorless prisms, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:30][S:31]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:2]([NH2:1])=[O:29])=[CH:6][CH:7]=2)=[CH:39][CH:40]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Oc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(OS(C)(=O)=O)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 72 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-(methylsulfonyloxy)phenylboronic acid (125 mg) followed by aqueous sodium carbonate (2M, 0.58 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and then purified by chromatography on silica using ethyl acetate 50-100% isohexane as eluent to afford the sub-titled compound as a white solid (234 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH3:16])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH3:16])[C:14]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)OCN(C(=O)OCc3ccccc3)[C@H]2C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.1 %

Procedure:
In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (1.72 g) prepared in Example 10 and then water (5 mL) and conc. hydrochloric acid (2 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene, the aqueous layer was discarded, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under a reduced pressure, the residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (1.40 mg) as white crystals in a yield of 89%.
Reaction SMILES: [CH2:1]([C:8]1[C:9](N(C2CC2)C)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1[C:32](C#N)=[N:33][C:34]2[C:39](N=1)=[CH:38]C=C(Cl)C=2)C1C=CC=CC=1.C1([Mg]Br)CC1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[C:9]([CH2:32][NH:33][CH:34]2[CH2:39][CH2:38]2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1nc2cc(Cl)ccc2nc1Cc1ccccc1)C1CC1
Reactant: N#Cc1nc2cc(Cl)ccc2nc1Cc1ccccc1
Agent: Br[Mg]C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2nc(Cc3ccccc3)c(CNC3CC3)nc2c1
Temperature: -60 °C
Reaction time: 0.67 h

Procedure:
(±)-(3-Benzyl-7-chloroquinoxalin-2-yl)-cyclopropyl-methylamine (16): To a stirred solution of 3-benzyl-7-chloro-2-cyanoquinoxaline (4.0 g, 14.3 mmol) in anhydrous CH2Cl2 (80 mL) at −64° C. under nitrogen was added dropwise cyclopropylmagnesium bromide (0.76 M in THF, 52 mL, 39.5 mmol). The reaction mixture was stirred at −68˜−30° C. for 40 min. It was cooled to −60° C. and TFA (12 mL) was added to the reaction mixture followed by NaBCNH3 (1.25 g, 18.9 mmol). The mixture was slowly warmed to −20° C. over 20 min, and then cooled to −30° C. and quenched with aq. NaHCO3 and extracted with CH2Cl2 (2×100 mL). The organic solution was washed with brine (60 mL), dried over MgSO4 and concentrated. Purification by flash column (SiO2, EtOAc/hexane MeOH/NH4OH 30:70:3:0.3) gave C-(3-Benzyl-7-chloro-quinoxalin-2-yl)-cyclopropyl-methylamine (16) as an oil (1.8 g). This oily product was slightly contaminated by impurities, but it was used directly for the next step without any further purification. 1H NMR (CDCl3) δ 8.02 (m, 1H), 7.96 (m, 1H), 7.67 (m, 1H), 7.19 (m, 5H), 4.52 (m, 1H), 4.41 (m, 2H), 1.37(m, 1H), 0.61 (m, 1H), 0.36 (m, 1H), 0.12 (m, 1H), 0.01 (m, 1H); MS (ESI), (M+H)+323.26, 325.26.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9](N)=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3].N([O-])=O.[Na+]>[Cu]Cl.O.COC(C)(C)C>[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9]([Cl:1])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3]
Reactant: Cl
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of concentrated hydrochloric acid was added 2.0 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution consisting of 0.42 g of sodium nitrite and 3 ml of water was added under ice cooling. After stirring at the same temperature for 1 hour, 40 ml of t-butyl methyl ether was added and 0.85 g of copper(I) chloride was added. After stirring for 30 minutes, water was added, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was subjected to column chromatography (eluent: hexane/ethyl acetate=2/1) to give 0.52 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[NH2:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1>N1C=CC=CC=1>[O:37]1[CH:38]=[CH:39][C:35]([NH:34][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)=[N:36]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O

Procedure:
Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), 3-aminoisoxazole (0.12 ml) and pyridine (5 ml) and the resultant suspension was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate), evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.14 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H), 3.29 (m, 4H), 7.06 (d, 1H), 7.50 (d, 1H), 7.63 (m, 3H), 8.09 (m, 2H), 8.13 (s, 1H), 8.85 (d, 1H), 11.46 (s, 1H); Mass Spectrum: M+H+ 445.
Reaction SMILES: [Cl:1][C:2]([Cl:31])([Cl:30])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:29])[C@@H:14](NC(OC(C)(C)C)=O)[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6].FC(F)(F)C(O)=O.C([N:42](CC)C(C)C)(C)C.[C:48]([O:52][C:53]([NH:55][C@H:56]([C:60]([OH:62])=O)[CH:57]([CH3:59])[CH3:58])=[O:54])([CH3:51])([CH3:50])[CH3:49].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[Cl:31][C:2]([Cl:30])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:29])[C@@H:14]([NH:42][C:60](=[O:62])[C@@H:56]([NH:55][C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH:57]([CH3:59])[CH3:58])[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1cccn1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cn1cccn1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To (S)-1-((S)-2-tert-butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (730 mg, 1.47 mmol) in anhydrous dichloromethane (3 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.1 mL, 14.7 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (7 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (1.3 mL, 7.3 mmol), N-(tert-Butoxycarbonyl)-L-valine (319 mg, 1.5 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (782 mg, 2.1 mmol). Following 16 h at room temperature the reaction was cooled to 0° C., diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:2 then 1:3 to give the title compound (460 mg, 52%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z) 599.1 [M+H], Tr=2.83 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]3[O:22][N:21]=[C:20]([CH:23]4[CH2:25][CH2:24]4)[N:19]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[C:26]1([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[ClH:1].[CH:23]1([C:20]2[N:19]=[C:18]([C:14]3[N:15]=[CH:16][C:17]4[N:5]([CH2:4][CH2:3][CH2:2][N:35]5[CH2:34][CH2:33][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)([OH:38])[CH2:37][CH2:36]5)[C:6]5[C:11]([C:12]=4[CH:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=5)[O:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCCCn1c2ccccc2c2cc(-c3nc(C4CC4)no3)ncc21
Solvent: CN(C)C=O
Product: Cl
Product: OC1(c2ccccc2)CCN(CCCn2c3ccccc3c3cc(-c4nc(C5CC5)no4)ncc32)CC1
Yield: 12 %

Procedure:
The compound was synthesized by mixing (Compound 6) (0.76 g, 2.2 mmol), 4-phenylpiperidin-4-ol (0.48 g, 2.7 mmol), TEA (0.55 g, 5.4 mmol) in DMF, in the same manner as illusterated in example 3. The compound was isolated as the hydrochloride (0.15 g, 12%) as an yellow solid. M.p. 184°-185° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[Si](C(C)C)(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]ccc2c1F
Reaction time: 0.17 h

Procedure:
TBAF (1M solution in THF, 15.8 mL, 15.8 mmol) was added to a solution of compound 22e (2.76 g, 7.9 mmol) in THF at 0° C. After 10 min at room temperature, the reaction was diluted with EtOAc and washed sequentially with brine, saturated NaHCO3, and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to afford compound 22f.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:31])[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[ClH:32]>O.C(O)C>[ClH:32].[ClH:32].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:21]3=[O:31])[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCN(c3ccccc3)C2=O)cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(CC(C(=O)O)c2cn(C3CCN(c4ccccc4)C3=O)cn2)cn1

Procedure:
A solution of 23.1 mg (0.06 mmol) of the compound from example 9a in 0.5 ml of water and 0.5 ml of 37% strength hydrochloric acid was treated in a microwave at 180° C. for 3 min. The reaction solution was taken up in ethanol and concentrated under reduced pressure several times. Freeze-drying of the residue taken up in water afforded 19.0 mg of the desired compound in the form of an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:38](=[NH:43])(OCC)[CH3:39].C(N(CC)CC)C>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[NH:43][C:38]([CH3:39])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nnc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.025 g, 0.048 mmol), ethyl acetimidate hydrochloride (6.6 mg, 0.053 mmol), triethylamine (11 mg, 0.11 mmol), and MeCN (0.15 mL) was heated in a microwave reactor at 200° C. for 1 h. The reaction was partitioned between water and DCM, and the product was extracted with DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatograph, elution with mixtures of EtOAc in hexanes to provide the title compound. LC/MS: m/e 543.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.12 (1H, s), 7.92 (1H, s), 7.57 (1H, d, J=6.8 Hz), 7.20-7.60 (3H, m), 6.87-6.93 (3H, m), 4.40-5.20 (3H, br), 2.53 (3H, s), 1.22 (9H, s).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C:22](=[CH:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O.[FH:38].N>N1C=CC=CC=1>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@:22]([Br:30])([C@@H:23]([F:38])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)C3=CC[C@@]21C
Reactant: F
Agent: N
Solvent: c1ccncc1
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@@]3(Br)[C@@H](F)C[C@@]21C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At -30° C., 1.5 g. of 17-acetoxy-6-chloro-1α,2α -methylene-4,6,9(11)-pregnatriene-3,20 -dione and 1.5 g. of N-bromosuccinimide are added in succession to 7.5 ml. of a 70% solution of hydrogen fluoride in pyridine. After 1.5 hours, the solution is introduced into a mixture of ice water and 25% ammonia solution. The thus-precipitated product is vacuum-filtered, washed with water, dissolved in ethyl acetate, and dried over sodium sulfate. The crude product is recrystallized from acetone/hexane. Yield: 836 mg. of 17-acetoxy-9-bromo-6-chloro-11β-fluoro-1α,2α -methylene-4,6-pregnadiene-3,20 -dione; m.p. 189°-191° C. (under decomposition). UV: ε283 = 13,400.