Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([OH:30])=[O:29])[CH:18]=[CH:19][CH:20]=1.[C:31]1([C:37]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)O)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([O:30][CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CC2CCCCC2C(=O)O)c1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (501 mg) was added to a stirred solution of 2-[(3-methoxyphenyl)methyl]cyclohexanecarboxylic acid (500 mg), benzoin (427 mg), and 4-dimethylaminopyridine (12.2 mg) in dichloromethane (10 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 1 hour, and then a mixture of ethyl acetate and 1N hydrochloric acid was added thereto. The organic layer was separated, washed successively with 1N hydrochloric acid, sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel using n-hexane--toluene as an eluent to afford 2-oxo-1,2-diphenylethyl 2-[(3-methoxyphenyl)-methyl]cyclohexanecarboxylate (455 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19](=O)[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:19](=[N:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)[CH2:20][CH3:21]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC=Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and triethylamine (8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled in an ice/water bath, was added slowly titanium tetrachloride (11.4 mL of a 1.0M solution in dichloromethane, 11.4 mmol). After 25 min, propionaldehyde (1.8 g, 25.6 mmol) was added slowly as a solution in dichloromethane. After an additional hour of stirring in the ice/water bath, an aqueous potassium carbonate solution was added (˜100 mL of a 1M solution). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title product which was used without further purification. 1H NMR (CDCl3) δ 1.2 (t, 3H), 2.5 (dq, 2H), 7.05 (d, 2H), 7.56 (d, 2H), 7.84 (t, 1H, J=4.4 Hz).
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[CH:15]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16]1.C(O)(=O)C>C1COCC1>[CH2:13]([O:12][C:10]([C:9]1[N:7]=[CH:8][S:20][C:19]=1[NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:11])[CH3:14]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: S=C=NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncsc1NC1CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a vigorously stirred solution of 311 mg of potassium tert-butylate (2.77 mmol) in THF (5 ml) were slowly added 5 ml of a THF-solution of 300 mg of ethyl isocyanoacetate (2.52 mmol) and 250 mg of cyclopropyl isothiocyanate (2.52 mmol) at −20° C. The mixture was stirred for 15 min at −20° C. and was then allowed to warm to 0° C. in 1.5 h before 0.3 ml of acetic acid were added. The reaction mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography (heptane/ethyl acetate 95:5 to 75:25) to give 5-cyclopropylamino-thiazole-4-carboxylic acid ethyl ester (198 mg, 37%) as a yellow oil. MS (ISP) 213.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([Cl:19])[C:10]=1[NH:20][NH2:21].C(O)(=O)C>C(O)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[C:11]([Cl:19])[C:10]=1[N:20]1[C:4]([CH3:5])=[CH:3][C:2]([CH3:1])=[N:21]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Yield: 85.8 %

Procedure:
Pentan-2,4-dione (0.100 g) was added to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (4.5 ml), followed by glacial acetic acid (0.5 ml), at room temperature. The reaction mixture was heated under reflux for 1 hour, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane as eluant, to provide a colourless oil initially which crystallised, after removal of extraneous solvent in vacuo, to furnish the title compound (0.265 g), m.p. 87-89° C. δ(CDCl3): 2.10 (s,3H), 2.32 (s,3H), 6.07 (s,1H), 7.72 (s,2H). MS (thermospray): M/Z [M] 309.0; C12H9Cl2F3N2 requires 309.12.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:24](Cl)=[O:25])=[N:22][CH:23]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:27])([F:16])[F:28])=[CH:23][N:22]=3)[N:7]=2)/[S:13]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cn1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc(C(F)(F)F)cn3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-5-(trifluoromethyl)picolinamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), 5-(trifluoromethyl)picolinoyl chloride (63 mg, 0.301 mmol, 3 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (4 mg, 39.5 mg theoretical, 10%). LC-MS m/z 396.3 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](I)=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](/[CH:39]=[CH:38]/[C:37]([O:41][CH2:42][CH3:43])=[O:40])=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (O) (0.051 g) in toluene (31 mL) was treated with triphenylphosphine (0.058 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]-azepine (0.97 g) followed by ethyl acrylate (4.3 mL, 4.0 g). The mixture was then treated with triethylamine (0.37 mL, 0.27 g). The mixture was heated to 104° C. for 1.5 hours and then it was cooled to room temperature. Another portion of tris(dibenzylideneacetone)dipalladium (O) (0.025 g) and more triphenyl phosphine (0.029 g) was added to the mixture. The mixture was then treated with more ethyl acrylate (2.8 mL) and it was heated to 105° C. for 1 hour and then it was cooled to room temperature and concentrated to a brown glass. It was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a pale yellow solid (0.115 g). The solid was recrystallized from ethyl acetate (10 mL) at room temperature to give an off-white solid (0.0712 g); mp 233.8°-234.5° C.; 1NMR (CDCl3) 7.73 (d, 1, J=16), 6.69 (d, 1, J=16) for trans olefin protons; MS: m/z=336 (M+1). Analysis for C16H14ClNO5 : Calculated: C, 57.24; H, 4.20; N, 4.17; Found C, 57.09; H, 4.16; N, 4.09.
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[NH:5]1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([OH:14])=[O:13])[NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)O)=C(C)C)C2O1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 550 mg of benzyl α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 8 ml of tetrahydrofuran is added 5% palladium carbon, and the mixture catalytically hydrogenated under atmospheric pressure for 2 hours. The insoluble material is removed by filtration, and the filtrate concentrated under reduced pressure. The residue (471 mg) is crystallized from a mixture of ether and petroleum ether to yield 421 mg of α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetic acid in 95% yield.
Reaction SMILES: C(=O)([O-])[O-:2].[Mg+2:5].[S:6](=[O:8])=[O:7]>>[S:6](=[O:2])([OH:8])[O-:7].[Mg+2:5].[S:6](=[O:2])([OH:8])[O-:7]
Reactant: O=S=O
Reactant: O=C([O-])[O-]
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
According to the invention a method of recovering magnesia from magnesium carbonate containing raw material includes the steps of forming a slurry of uncalcined raw material, heating the slurry to a temperature between 40° and 90° C., treating the slurry with sulphur dioxide to form soluble magnesium bisulphite, separating undissolved impurities from the solution of magnesium bisulphite, precipitating magnesium sulphite from the solution, separating the precipitate from the mother liquor and recovering magnesia from the separated precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:31][N:29]([CH3:30])[CH3:28])=[CH:24][CH:25]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1
Reactant: O=c1c(-c2ccccc2Cl)cc(-c2ccccn2)cn1-c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-n2cc(-c3ccccn3)cc(-c3ccccc3Cl)c2=O)cc1
Temperature: 60 °C
Yield: 27.7 %

Procedure:
3-(2-Chlorophenyl)-5-(2-pyridyl)-1-(4-hydroxyphenyl)-1,2-dihydropyridin-2-one (82 mg) and 57 mg of N,N-dimethylaminoethyl chloride were dissolved in 2 ml of dimethylformamide, 55 mg of potassium carbonate were added thereto at 60° C. and the mixture was stirred for one night. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by an NH silica gel column chromatography (hexane-ethyl acetate system) to give 27 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 71.7 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-fluorophenyl isocyanate (0.86 mL, 9.51 mmol) in DMA afforded 1.89 g of the title compound as a solid, mp 208-209° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([CH3:14])[CH2:8][CH2:7]2)[CH3:3].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.[OH-].[Na+]>O>[CH3:3][N:2]([C:4]1[CH:13]=[C:12]2[C:11]3[N:10]([CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17])[CH:9]([CH3:14])[CH2:8][CH2:7][C:6]=3[CH:5]=1)[CH3:1]
Reactant: CC1CCc2cc(N(C)C)ccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(N(C)C)cc3c1=O)CCC2C
Temperature: 120 °C

Procedure:
6-(N,N-Dimethylamino)-2-methyltetrahydroquinoline (25 g., 0.132 mole) is mixed with diethyl ethoxymethylenemalonate (28.4 g., 0.132 mole), and the mixture is heated at 120° C. for 3 hours. Polyphosphoric acid (200 g.) is added, and the solution is heated gradually to 120° C. with occasional stirring. The solution is maintained at 120° to 130° C. for one hour then poured into 500 ml. of water, with stirring. The solution is neutralized with 40 percent sodium hydroxide solution. The yellow product is separated by filtration and recrystallized from ethanol giving ethyl 6,7-dihydro-9-(N,N-dimethylamino)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 219°-222° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[C@H:10]([CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[C@H:10]([CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC=C1c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of (S)-3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Example #199, Step B, isomer 2, SFC (Table 1, Method 42), Rt=6.856 min., 0.55 g, 1.333 mmol) and 10% Pd/C (0.142 g) in MeOH (20 mL) was stirred at rt for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (3S,4S)-3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 100%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (brs, 1H), 6.98-6.91 (d, J=8.0 Hz, 1H), 6.75-6.70 (d, J=8.0 Hz, 1H), 6.70-6.65 (s, 1H), 4.76-4.70 (q, J=6.8 Hz, 1H), 4.64-4.52 (d, J=13.2 Hz, 2H), 4.47-4.18 (m, 1H), 4.10-3.96 (m, 1H), 3.18-2.66 (m, 3H), 2.10-1.90 (m, 2H), 1.62-1.55 (m, 1H), 1.53-1.45 (m, 12H), 0.70 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.864 min.; MS m/z: 415 [M+H]+& 359 [M+H−56]+. SFC (Table 1, Method 45), Rt=4.693 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C@@H:9]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:3]1.[ClH:33]>O.O1CCOCC1>[ClH:33].[ClH:33].[Cl:33][C:31]1[CH:32]=[C:27]([C:4]2[CH:5]=[C:6]([NH:7][C:8](=[O:26])[C@@H:9]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:2]([CH3:1])[N:3]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 ml vial was added 800 mg of 17.8.B, 15 ml of dioxane, 10 drops of water and 4.5 ml of hydrogen chloride (2.0 M solution in diethyl ether). After 16 hours 10 ml of concentrated HCl were added and stirred at room temperature for 16 hours. The solvent was removed with a stream of nitrogen (dried with MeOH) to give 740 mg of 2-((S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetic acid diHCl salt as a light yellow solid (Note: trace methyl ester was observed in final product).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[CH:8]=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].C1OCCOCCOCCOCCOCCOC1.O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[CH:8]=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)cn1C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Yield: 69.3 %

Procedure:
Add together 4-cyano-3-(4-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-11) (600 mg, 2.22 mmol), 1-fluoro-2-nitrobenzene (313 mg, 1.0 Eq.), potassium fluoride/alumina (322 mg, 2.5 Eq.), and 18-crown-6 (60 mg, 0.1 Eq.) in acetonitrile (25 mL) and stir at reflux for 18 hours under a nitrogen atmosphere. Cool mixture and add water and methylene chloride (50 mL each) and stir vigorously. Separate layers and wash the organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 762 mg as a dark solid. Purify the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide 602 mg of the title compound as a yellow solid. Mass spectrum (m/e): 392.2 (M*+1): (Bruker 300) 1NMR δ (CDCl3) 7.93-8.00 (1H, d), 7.50-7.57 (1H, t), 7.35-7.40 (2H, d), 7.19-7.29 (2H, m), 7.03-7.13 (2H, m), 4.05-4.20 (2H, dd), 3.95-4.10 (3H, s), 1.00-1.10 (3H, t).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH2:6]1)(=O)C>CO.[OH-].[K+]>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ccnc4)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3ccnc3)=CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
The method followed that described in Synthesis Example 4, but using 3β-acetoxy-17-(1H-imidazol-1-yl)-androsta-5,16-diene (Compound 10) (2.72 g, 7.16 mmol) in methanol (30 ml), 10% methanolic KOH (17 ml), and the mixture was stirred at room temp under N2 for 2 h. Following the conentional workup gave rise to Compound 11 (2.34 g, 95%), mp 220-223° C. 1H NMR (300 MHz, CDCl3): δ 1.01 (3H, s, 18-Me), 1.06 (3H, s, 19-Me), 3.53 (1H, m, 3α-H), 5.39 (1H, d, J=5 Hz, 6-H), 5.69 (1H, s, 16-H), 7.08 (2H, br. s, 4′ and 5′-H), and 7.64 (1H, s, 2′-H). Analysis calculated for C22H30ON2: C, 78.05; H, 8.94; N, 8.28; Found: C, 78.02; H, 9.00; N, 8.22. HRMS calcd. for C22H30ON2 338.2358, found 338.2361.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: O=C(Cl)c1ccco1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethylacetate to yield 212 mg (43%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.96 (m, 4H), 5.45 (s, 2H), 6.66 (m, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.20 (m, 2H), 7.27 (m, 2H), 7.46 (d, J=9.0 Hz, 1H), 7.69 (dd, J=2.4, 9.0 Hz), 7.89 (s, 1H). EIMS m/z 514 (M+23). Anal. (C26H20ClFN4O3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1
Reactant: COc1cc2nc(C)nc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Solvent: CCO
Product: COc1cc2nc(C)nc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 1257.6 %

Procedure:
A mixture of 6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline (0.081 g, 0.236 mmole), Pt/S (0.008 g, 15 mol %), ammounium fromate (0.098 g, 1.56 mmol) and EtOH (3 mL) was heated with stirring at 70° C. for 3 hours. The reaction mixture was then filtered while hot and washed with hot EtOH. The crude product of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.924 g) was obtained as a yellow solid, which was used in the next reaction without further purification. LC/MS: m/z 312 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH3:21])=[CH:19][C:18](=[O:22])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]2)=[C:7]([CH3:23])[CH:6]=1)(=[O:3])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH:21]=[O:25])=[CH:19][C:18](=[O:22])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]2)=[C:7]([CH3:23])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: COC(=O)c1cn(-c2ccc(OC(C)=O)cc2C)c(C)cc1=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(OC(C)=O)cc2C)c(C=O)cc1=O
Yield: 72 %

Procedure:
In 315 ml of dioxane was dissolved 10.5 g of methyl 1-(4-acetoxy-2-methylphenyl)-6-methyl-4-oxo-1,4-dihydronicotinate under heating, and 4.43 g of selenium dioxide was added thereto. They were reacted at 100° C. for 2 hours. After cooling the reaction mixture, to room temperature, selenium was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (25:1 by volume) mixture) to obtain 7.9 g of methyl 1-(4-acetoxy-2-methylphenyl)-6-formyl-4-oxo-1,4-dihydronicotinate having a melting point of 216°-217° C.