Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([F:27])[CH:14]=1.[OH-:28].[K+].Cl>O1CCOCC1.O.C(OCC)(=O)C.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].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:27][C:15]1[CH:14]=[C:13]([N:6]2[C:7]3[C:3](=[C:2]([OH:28])[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=3)[CH:4]=[CH:5]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 85 °C
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indole-6-carbonitrile (D13) (400 mg, 0.95 mmol) in dioxane (6 mL) and water (6 mL) was added potassium hydroxide (216 mg, 3.9 mmol). The reaction mixture was degassed with argon and then treated with 2-di-tert-butylphosphino-2′,4′,6′-trisisopropylbiphenyl (22 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol). After heating at 85° C. for 1 hour, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 1M hydrochloric acid. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 2-60% ethyl acetate in hexane to yield the title compound (D14), (323 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:39])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29][C:28]=2[CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:39][C:25]2[C:24]([O:23][CH3:22])=[CH:38][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(C)S(C)(=O)=O)n3)c(OC)cc2CC1

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (95 mg, 0.27 mmol), 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (67 mg, 0.27 mmol), and 10-Camphorsulfonic acid (96 mg, 0.41 mmol) in Isopropyl alcohol (4 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.35 g, 0.941 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-methyl-methanesulfonamide as a off white foam (99 mg, 65%). LCMS: 567 (M+H); 1H-NMR, CDCl3: 8.17 (s, 1H), 7.91 (s, 1H), 7.35 (s, 1H), 6.64 (s, 1H), 5.56 (s, 1H), 4.10 (m, 1H), 3.87 (s, 3H), 3.7 (m, 3H), 3.35 (s, 3H), 2.9 (m, 6H), 2.83 (s, 3H), 2.74 (s, 3H), 2.4 (m, 1H), 1.9 (m, 4H), 1.65 (m, 3H), 1.35 (m, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][N:4]=1.[F-].[K+]>CO>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)#[CH:10]
Reactant: CSc1nccc(C#C[Si](C)(C)C)n1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
4-Iodo-2-(methylsulfanyl)pyrimidine (2.0 g, 8.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). To this solution was added triethylamine (1.4 mL, 10.1 mmol), copper (I) iodide (80 mg, 0.4 mmol) and dichlorobis(triphenylphosphine) palladium (II) (140 mg, 0.24 mmol). (Trimethylsilyl)acetylene (1.4 mL, 10.1 mmol) was added dropwise to the resulting solution. After the addition of (trimethylsilyl)acetylene was complete the reaction was stirred at room temperature for 2 hours. Hexane was added to the reaction mixture and the mixture was filtered to remove precipitates. The solution was concentrated to give a syrup, that was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 1.76 g (99%) of 2-(methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine. 2-(Methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine (1.76 g, 8.0 mmol) was dissolved in methanol (60 mL). To this solution was added potassium fluoride (467 mg, 8.0 mmol) and the resulting mixture stirred at room temperature for 5 minutes. The solution was concentrated and ethyl acetate and water were added. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated to give 1.0 g (83%) of 4-ethynyl-2-(methylsulfanyl)pyrimidine as a white solid. 1H NMR (CDCl3): δ 8.51 (d, 1H), 7.06 (d, 1H), 3.34 (s, 1H), 2.56 (s, 3H); MS m/z 151 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>O.CN(C)C(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]=2[CH:3]=1
Reactant: Nc1nc2cc(Br)ccc2[nH]1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2ccc(Br)cc2n1-c1ccccn1
Temperature: 150 °C
Yield: 26 %

Procedure:
To two 10-20 mL microwave vials was added 5-bromo-1H-benzo[d]imidazol-2-amine (3.00 g, 14.1 mmol, Carbocore, The Woodlands, Tex.), N,N-dimethylacetamide (20 mL), 2-fluoropyridine (1.46 mL, 17.0 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (7.84 g, 24.1 mmol). (One-half of the material in each vial, ie 1.5 g of the bromide in each vial.) The mixture was heated at 150° C. for 140 min in the microwave. After cooling to rt, the combined reaction mixtures were poured into water (400 mL) and then extracted with EtOAc/hexane (80:20) (3×150 mL). The combined extracts were washed with water (3×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 3.8% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound (1.06 g, 26%). MS (ESI, positive ion) m/z: 289 (M(79Br)+1).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C1(C)C(C)=CC=CC=1.O>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:28])([CH3:27])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[C:8]1[N:1]=[C:2]([N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]2[CH2:16][C:17]([CH3:27])([CH3:28])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:22])([CH3:21])[CH2:20]2)[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCNC1CC(C)(C)N(OCCC)C(C)(C)C1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OCCC)C(C)(C)C2)n1)C1CC(C)(C)N(OCCC)C(C)(C)C1
Reaction time: 1.5 h

Procedure:
A four-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, dropping funnel and condenser is charged with 27.3 g (0.148 mol) of cyanuric chloride and 200 mL of xylene at 0-5° C. 40 g (0.148 mol) of compound I-102 in 25 mL of xylene are slowly added over 20 minutes to this solution. After 90 minutes, further 40 g (0.148 mol) of compound I-102 in 25 mL of xylene and 25 mL of water are slowly added over 20 minutes to the system allowing the temperature to reach 45° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([OH:28])[CH3:27])=[CH:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([O:28][S:35]([CH3:34])(=[O:37])=[O:36])[CH3:27])=[CH:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1)C(C(C)OS(C)(=O)=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 300 mg of 4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (see Example 5) and 10 mL of methylene chloride was cooled to 0° C. To this mixture, 0.060 mL of methanesulfonyl chloride and 0.204 mL of triethylamine were added. The reaction mixture was allowed to stir at the same temperature for 30 minutes. The reaction was worked up by adding water, and the product was extracted with EtOAc three times. The organic layers were combined, washed sequentially with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, water, and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 344 mg of 4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid, which was used for the next coupling reaction without further purification.
Reaction SMILES: [N:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH2:3][C:4]([OH:6])=O)[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)=[O:53])[CH2:48][CH2:49][CH3:50].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:4](=[O:6])[CH2:3][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH3:2])[CH2:56][CH2:55]1)=[O:53])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)CN(C)C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 500 mg Z-Sar-OH in 15 ml DMF were added 1.1 ml N-ethylmorpholine, 735 mg TOTU and 417 mg 1-butoxycarbonylpiperazine. After stirring for 12 h, aqueous NaHCO3 was added and the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 746 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N+:7]([O-:26])=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In an atmosphere of argon, ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (13.50 g, 57.9 mmol) was dissolved in methylene chloride (300.0 ml) to which was subsequently added metachloroperbenzoic acid (87.9%, 14.79 g, 75.3 mmol) in small portions at 0° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 10 hours. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution at 0° C. and extracted with methylene chloride, and the thus obtained organic layer was washed with saturated sodium bicarbonate aqueous solution, water and saturated brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=5:1—ethyl acetate) to obtain the title compound (10.80 g, 74.9%) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:20].[Na+].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.P([O-])([O-])([O-])=O.O.ON1C(C)(C)CCCC1(C)C>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:9]([OH:20])=[O:10])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Reactant: [O-][Cl+][O-]
Agent: CC1(C)CCCC(C)(C)N1O
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCO1)C(=O)O
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
[(S)-2-Hydroxy-1-(tetrahydro-pyran-2-ylmethyl)-ethyl]-carbamic acid t-butyl ester (843 mg, 3.64 mmol) was dissolved in acetonitrile (18 mL) and phosphate buffer (pH=7, 14 mL). Then 1-oxyl-2,2,6,6-tetramethylpiperidine (40 mg) was added. The mixture was warmed to 35° C. To this clear solution was added a solution of sodium chlorite (832 mg) in water (4 mL) and catalytic amount of bleach (1 mL of 5.25% sodium hypochlorite solution was diluted with water to 20 mL, 1.80 mL of the diluted solution was used). The mixture was stirred at 35° C. for 1.5 hr. Then a second portion of sodium chlorite (832 mg) in water (4 mL) and catalytic amount of diluted bleach was added over 2 h. The mixture was stirred for 1 h and then diluted with water (25 mL) and treated with sodium sulfite solution. The mixture was extracted with methyl t-butyl ether. The aqueous layer was acidified with 1N aqueous hydrochloric acid and extracted with methyl t-butyl ether. The organic layer was washed with saturated sodium chloride solution and solvents were evaporated to afford (S)-2-t-butoxycarbonylamino-3-(tetrahydro-pyran-2-yl)-propionic acid (707 mg, 71%) as an oil: [α]D=+23.8 (chloroform); LR-ES-MS m/z calculated for C13H23NO5 [M]+ 273, observed [M+H]+ 274; 1H NMR (300 MHz, CDCl3) δ ppm 1.30-1.70 (m, 5H), 1.46 (s, 9H), 1.76-2.13 (m, 3H), 3.31-3.69 (m, 2H), 3.99, 4.07 (2×d, J=11.2 Hz, 1H), 4.35 (br. s., 1H), 5.52, 5.88 (2×br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1.ClCCl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5 g (27.64 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 25 ml of dry pyridine and the solution is cooled to 0° C. A solution of 4.82 g (27.4 mmol) of chlorosulfonyl acetic acid methyl ester in 20 ml of dichloromethane is instilled in the cooled solution in the course of about 10 minutes with the temperature being maintained. Then it is stirred for 6 hours at room temperature. The reaction solution is then diluted with 100 ml of dichloromethane, the pyridine is shaken out with 2N hydrochloric acid, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether/hexane yield is obtained as a crystallizate. Melting point 84°-86° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]3[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C[Si]([Cl:26])(C)C.N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:26][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]([N:16]3[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1nc(-c2ccnc(N)n2)ccc1N1CC[C@H](F)C1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: N#Cc1nc(-c2ccnc(Cl)n2)ccc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 26 %

Procedure:
Compound 78 (970 mg, 3.42 mmol) was dissolved in DCM (50 mL) and trimethyl silyl chloride (1.08 mL, 8.54 mmol) and tert-butyl nitrite (1.02 mL, 8.54 mmol) were added. The reaction mixture was stirred at rt for 60 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was suspended in toluene (50 mL), diethyl isopropylamine (1.49 mL) and phosphorus oxychloride (5 mL) were added. The resulting mixture was heated under reflux for 3 hours and then poured into ice water with vigorous stirring. The resulting solution was neutralized with sodium hydrogen carbonate and extracted with ethanol (3×100 mL). The combined organic phases were concentrated in vacuo and the residue purified by column chromatography (Biotage SP1, 100% DCM→10% MeOH-DCM) and trituration with EtOAc to afford the title compound (270 mg, 26%) as a pale brown solid. LCMS, Rt=3.03 min (MeOH-FA), m/z 304.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:21][C:20]([CH3:22])=[CH2:19])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1ccc(Cl)cc1C(C)=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5′-chloro-2′-hydroxyacetophenone (0.86 g, 5.0 mmol), potassium carbonate (1.4 g, 10 mmol) and 3-bromo-2-methylpropene (0.56 mL, 5.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at 60° C. for 4 hours. After cooling, the reaction mixture was diluted with water (100 mL), and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title reference compound (1.1 g) as orange oil (Yield 96%).
Reaction SMILES: C1(N=C=N)CCCCC1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([OH:20])=O.[NH2:21][C:22]1[S:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][N:26]=1>C(Cl)Cl>[CH:27]([C:24]1[S:23][C:22]([NH:21][C:18](=[O:20])[CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Br:10])=[N:26][CH:25]=1)([CH3:29])[CH3:28]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CC(C)c1cnc(N)s1
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)c1cnc(NC(=O)Cc2ccccc2Br)s1
Reaction time: 0.17 h

Procedure:
To a suspension of resin N-Cyclohexylcarbodiimide N′-methylpolystyrene (0.251 g, 2.39 mmol g, 0.6 mmol), previously washed with DCM (3×5 ml), in DCM (4 ml) at room temperature, 2-bromophenylacetic acid (0.086 g, 0.4 mmol) was added. After 10 min., a solution of 2-amino-5-isopropyl-1,3-thiazole (0.0284 g, 0.2 mmol) in DCM (4 ml) was added. The mixture was shaked for 24 hours at room temperature, the resin filtered and washed with DCM (3×10 ml). The filtrated were combined, washed with water, 5% HCl, water, saturated sodium bicarbonate and water, dried over sodium sulfate and evaporated.
Reaction SMILES: S(O[C@@H:6]1[C@@:25]2([CH3:26])[C@@H:18]([CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[C@H:17]2[C@@H:8]([C@:9]3([CH3:28])[C:14]([CH2:15][CH2:16]2)=[CH:13][C:12](=[O:27])[CH:11]=[CH:10]3)[CH2:7]1)(C)(=O)=O.C([O-])(=O)C.[K+].Cl>CN(C)P(N(C)C)(N(C)C)=O>[CH3:23][C:22](=[O:24])[C@@H:21]1[C@:25]2([CH3:26])[C@H:18]([C@H:17]3[C@H:8]([CH:7]=[CH:6]2)[C@:9]2([CH3:28])[C:14](=[CH:13][C:12](=[O:27])[CH:11]=[CH:10]2)[CH2:15][CH2:16]3)[CH2:19][CH2:20]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](OS(C)(=O)=O)[C@]12C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C=C[C@]12C
Temperature: 120 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
12α-Mesyloxypregna-1,4-diene-3,20-dione (3.0 g) was dissolved in 60 ml of hexamethylphosphoramide. To the solution was added 7.2 g of potassium acetate, and the mixture was stirred at 120° C. for 5 hours. To the reaction mixture was added 300 ml of diluted hydrochloric acid, and the whole mixture was extracted with three 200 ml portions of benzene. The extracts were combinedly washed in sequence with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Low-boiling fractions were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: acetone-n-hexane, 4:6 by volume) to give 1.6 g of pregna-1,4,11(12)-triene-3,20-dione as crystals. The physical properties for the obtained crystal were as follows:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]CC3C=CC=CC=3)=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1[Cl:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1[Cl:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1Cl

Procedure:
To 1.0 g of this 4-n-dodecyloxy-3-chlorobenzoic acid was added 10 g of thionyl chloride, and the mixture was refluxed for 3 hours and unreacted thionyl chloride was removed under a reduced pressure. Thus, 4-n-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. A solution of the so-obtained compound in toluene was added dropwise to a solution of 0.59 g of p-benzyloxyphenol and 0.3 g of triethylamine in toluene, and the mixture was stirred overnight. The thus-obtained solution was diluted with ethyl acetate, and the dilution was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous sodium sulfate and concentrated under a reduced pressure to obtain p-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained ester was dissolved in ethyl acetate and 1 g of 5%-Pd/C was added to the solution, and the mixture was stirred at room temperature under a pressure of 3 atmospheres in a hydrogen atmosphere for three days and three nights. The Pd/C was removed by filtration and the filtrate was recrystallized from n-hexane to obtain 500 mg of 4-hydroxyphenyl 4-dodecyloxy-3-chlorobenzoate.