Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[C:4]([F:14])[CH:3]=1.O[CH2:16][CH:17]([CH2:19]O)O.[N+]([C:24]1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O.S(Cl)(Cl)=O>>[F:14][C:4]1[C:5]([CH:9]([CH3:13])[C:10]([O:12][CH3:24])=[O:11])=[C:6]([F:8])[CH:7]=[C:2]2[C:3]=1[CH:16]=[CH:17][CH:19]=[N:1]2
Reactant: OCC(O)CO
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(C(=O)O)c1c(F)cc(N)cc1F
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Temperature: 170 °C
Yield: 95.2 %

Procedure:
As shown in step 1-iv, a mixture of 2-(4-amino-2,6-difluorophenyl)propanoic acid (19.0 g, 94.45 mmol), glycerol (35.83 g, 28.41 mL, 389.1 mmol), nitrobenzene (7.209 g, 6.028 mL, 58.56 mmol) and concentrated sulfuric acid (30.57 g, 16.61 mL, 311.7 mmol) was heated gently. After cessation of the initial vigorous reaction, the mixture was heated to 170° C. for 16 hours. After cooling, the volatiles were removed under reduced pressure, the residue dissolved in MeOH (150 mL), 150 mL of 6N NaOH were added, and the mixture was heated at 110° C. for 3 hours. After cooling to RT, the mixture was acidified with concentrated HCl to a pH of 3. The resulting dark precipitate was collected by filtration and washed with water. The precipitate was taken up in ethanol and thionyl chloride (11.24 g, 6.891 mL, 94.45 mmol) was carefully added dropwise. After addition was complete, the mixture was heated at 50° C. for 20 hours. After cooling to RT, the volatiles were removed under reduced pressure and the residue was dissolved in a mixture of sat'd NaHCO3 and DCM. The layers were separated and the aqueous layer extracted with DCM. The combined organics were dried over MgSO4, reduced in volume under reduced pressure, and subjected to medium-pressure silica gel chromatography (0% EtOAc/Hexanes to 30% in 36 minutes) to provide methyl 2-(5,7-difluoroquinolin-6-yl)propanoate (14.0 g, 56% yield for two steps). The methyl ester (5.0 g) was saponified by taking it up in methanol (30 mL), treating the resulting solution with NaOH (16.58 mL of 6 M, 99.50 mmol), and stirring at RT for 20 hours. After careful acidification with conc. HCl to a pH of 2, the resulting precipitate was collected by filtration and dried under high vacuum to provide 2-(5,7-difluoroquinolin-6-yl)propanoic acid, which was used as is in subsequent reactions. Compound 1003 can be prepared by the same procedure as used in the preparation of compound 1004 by replacing-diethyl 2-methylmalonate with diethyl malonate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([F:16])[C:11]([CH:12]=O)=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Cl.[NH2:20]O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][CH2:29][OH:30]>O>[C:12]([C:11]1[C:14]([F:16])=[CH:15][C:8]([C:6]2[CH:5]=[C:4]([CH3:18])[N:3]=[C:2]([NH:1][C:29](=[O:30])[CH3:28])[N:7]=2)=[CH:9][C:10]=1[F:17])#[N:20]
Reactant: Cc1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Reactant: CCO
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1nc(C)cc(-c2cc(F)c(C#N)c(F)c2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 4-(2-amino-6-methyl-4-pyrimidinyl)-2,6-difluorobenzaldehyde (4.0 g, 16.1 mmol) in water (150 mL) and EtOH (50 mL) were added hydroxylamine hydrochloride (1.23 g, 17.7 mmol) and sodium carbonate (1.87 g, 17.7 mmol). The mixture was stirred for 3 hours at 100° C. The reaction mixture was filtered and the solid was washed with water. The combined filtrate was extracted with EtOAc, and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was combined with the solid obtained after filtration of the reaction mixture and treated with acetic anhydride (used as solvent) into a sealable tube. The tube was sealed and the reaction mixture was stirred for 5 days at 100° C. LCMS analysis showed a mixture of mono and bis-acetylated desired product together with their respective acetylated oximes. The reaction mixture was heated for 2 more days at 110° C. The mixture was concentrated and the resulting residue was treated with CH3OH. The mixture was filtered and the solid was washed with more CH3OH to provide the title compound (1.3 g) as a tan solid. To the filtrate solution (150 mL) containing mostly bis-acetylated desired product was added K2CO3 (˜1 g) and the reaction mixture was stirred overnight at room temperature. More K2CO3 (˜1 g) was added followed by water (˜50 mL) and the reaction mixture was stirred overnight at room temperature. LCMS analysis showed complete conversion to the mono-acetylated product. The reaction mixture was diluted with water and filtered. The resulting solid was washed with CH3OH to provide the title compound (1.03 g) as a brown solid. LC-MS (ES) m/z=289 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:36][CH3:37])=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:12]=[CH:13][C:14]([CH:16]3[C:21](C)(C)[C:20]([O:24][CH3:25])=[C:19](C(C)(C)C)[C:18]([O:30][CH3:31])=[C:17]3O[SiH3])=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:60]1CCCC1>>[S:1]1[C:5]([C:6]2[C:7]([O:36][CH3:37])=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[C:20]([O:24][CH3:25])[C:19]([OH:60])=[C:18]([O:30][CH3:31])[CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2
Reactant: COC1=C(O[SiH3])C(C(=O)C=Cc2cc(-c3cc4ccccc4s3)c(OC)cc2OC)C(C)(C)C(OC)=C1C(C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethyl-siloxy-3,5-dimethoxyphenyl)-2-propen-1-one, from Ex-59B, (0.135 g, 0.228 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (0.061 g. 0.228 mmol), and the mixture was stirred at room temperature for two hours. Upon quenching with water, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. Silica gel chromatography (hexane/ethyl acetate, 1:1) gave 0.05 g (46%) of the desired 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-phenyl)-2-propen 1-one product as a yellow solid, m.p. 85-105° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][Cl:9])[CH2:3][CH2:4][CH3:5].[N-:10]=[N+:11]=[N-:12].[Na+].[OH-].[Na+]>CN(C=O)C.CCOCC>[ClH:9].[CH2:2]([NH:6][CH2:7][CH2:8][N:10]=[N+:11]=[N-:12])[CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCNCCN=[N+]=[N-]
Yield: 68.8 %

Procedure:
7.0 g of 2-butylamino-ethyl chloride hydrochloride (Org. Synth. IV 1963, 333) are stirred together with 7.9 g of sodium azide in 50 ml of DMF at 500. After cooling, 82 ml of 1N sodium hydroxide solution are added dropwise. The mixture is taken up in 700 ml of ether, washed with water and, after drying the ether phase, treated with 25 ml of hydrochloric acid (5 molar in dioxane). After evaporating the ether phase, the residue is suspended in ether. The crystals are filtered and washed with ether. There are obtained 5 g of 2-butylamino-ethyl azide hydrochloride, Rf=0.14.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[O:21]1[C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:30][CH:29]=2)=O)=[CH:24][N:23]=[CH:22]1>C1COCC1>[O:21]1[C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:32][CH:33]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][N:23]=[CH:22]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 5.2 (21 mmol) in THF (60 mL) was added dropwise and the reaction was maintained at −78° C. for 1.5 hours. The reaction was quenched saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 5.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2 (M+H).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccccc1F
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2-fluorophenol: 1H-NMR (CDCl3) δ 8.02 (1H, d, J=2.4 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.15-6.89 (4H, m), 5.52 (2H, s), 3.92 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1cnccn1)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1cnccn1)c1ccc(Cl)cc1

Procedure:
10 g of 4'-chloro-2-(2-pyrazinyl)-acetophenone, 10 g of hydroxylamine hydrochloride and 12 g of anhydrous sodium carbonate are stirred at 60° in 100 ml of ethanol for 2 hours. The mixture is then treated with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulfate and subsequently concentrated. The residue is crystallized from acetone/n-hexane to yield 4'-chloro-2-(2-pyrazinyl)-acetophenone oxime, m.p. 134°.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[C:24]2[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(CC)CC>CCCCO>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[C:24]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=1)[CH3:3])=[CH:13]2
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cc(C#N)c34)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (208 mg, 0.75 mol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (compound 5505) (160 mg, 0.90 mmol) and Et3N (228 mg, 2.25 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture stirred at 150° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 50% Hex/EA) to afford the desired product, (S)-4-(1-(8-methyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5506, compound 264 in Table 4) (90 mg, 28% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:23]([NH:30][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and rubber septum, there were placed 3.0 g (0.0093 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 30 mL of dry tetrahydrofuran. Stirring was commenced and to the resulting ethereal solution were then added with 2.0 g (0.0186 mole) of benzylamine (available from the Eastman Kodak Company of Rochester, N.Y.), which was added over a five-minute period at room temperature (ca. 20° C.). The well-stirred reaction mixture was then heated to 60° C. and thereafter kept at that temperature for a period of six hours. Upon completion of this step (as revealed by thin layer chromatography (TLC) analysis), the final reaction mixture was filtered to remove precipitated benzylamine hydrochloride and the filtrate was subsequently evaporated to near dryness while under reduced pressure to afford a solid material as the residue. Trituration of the latter material with diethyl ether then gave 880 mg (22%) of essentially pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the free base compound: mass spectrum, m/e 392; NMR (CDCL3) consistent with product. The latter batch of material was next dissolved in dry benzene and thereafter treated with anhydrous hydrogen chloride gas to ultimately yield 320 mg (8%) of pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the hydrochloride salt (in the form of a monohydrate), m.p. 201°- 202° C. after one recrystallization from methanol-diethyl ether. The pure product was further characterized by means of mass spectrum (MS) analysis, in addition to elemental analysis. Mass spectrum, m/e 392.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH2:12]([N:19]1[C:23]2[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]1[Cl:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccnc(Cl)c2n1Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc2c1N(Cc1ccccc1)C(Cl)N2
Yield: 31.5 %

Procedure:
5 ml of phosphorus oxychloride and 0.338 g of phosphorus pentachloride were added to 0.383 g of 3-benzyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one, and the mixture was heated under reflux for 24 hours. The solvent was concentrated under reduced pressure, and the residue was poured into 50 g of ice/water. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.13 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:1).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)c2cc1OC
Temperature: 130 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinazoline (94 mg), and cesium carbonate (137 mg), and the mixture was stirred at 130° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, the mixture was filtered, and the residue was washed with chloroform/methanol. The solvent was removed from the filtrate by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (51 mg, yield 91%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[NH:11][C:12](=O)[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:6]([NH:9][C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(Cl)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Phosphorus oxychloride (6.42 mL, 70.2 mmol) was added dropwise to a solution of 16 (3.40 g, 7.02 mmol), triethylamine (1.96 mL, 14.04 mmol), and chloroform (14 mL) over 30 minutes at room temperature under nitrogen. The reaction mixture was then heated to 70° C. for 30 h. The mixture was cooled to ambient temperature, added dropwise over 2 h to a 0° C. solution of saturated aq. NaHCO3 (500 mL), and stirred for an additional 1 h. The layers were separated, aqueous layer back extracted with methylene chloride (2×100 mL), combined organic layers were dried (MgSO4), filtered and concentrated to a yellow solid. Purification was achieved via flash chromatography (SiO2, 5% Acetone-CHCl3) to afford 81 (3.17 g, 90%) as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 11.08 (s, 1H), 6.09 (d, J=4.0 Hz, 1H), 5.99 (dd, J=6.0, 4.0 Hz, 1H), 5.76 (t, J=6.8 Hz, 1H), 4.41 (dd, J=11.2, 3.2 Hz, 1H), 4.32 (td, J=7.2, 3.2 Hz, 1H), 4.24 (dd, J=11.6, 6.8 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H); [M+H]+ 503.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][C:13]1=[O:21]>>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:21])[CH2:14]2)=[O:19])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CN1CCC(C(=O)O)CC1=O
Reactant: NCc1nccnc1Cl
Agent: Cl
Product: CN1CCC(C(=O)NCc2nccnc2Cl)CC1=O
Yield: 62 %

Procedure:
2-Aminomethyl-3-chloropyrazine hydrochloride (content 77%; 5.36 mmol, 1.0 g) and 1-methyl-2-oxopiperidine-4-carboxylic acid (5.36 mmol, 0.843 g) were applied according to the procedure in example 13 step 13a and purified using column chromatography (silica gel; dichloromethane with 10% methanol) to give N-((3-chloropyrazin-2-yl)methyl)-1-methyl-2-oxopiperidine-4-carboxamide (940 mg).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:35]([CH2:36][CH2:37][C@:19]12[CH3:20])[C@:32]1([CH2:33][OH:34])[C:27](=[CH:28][C@@H:29]([O:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH2:30][CH2:31]1)[CH2:26][CH2:25]3)(=[O:16])[CH3:15].O>CC(C)=O>[C:14]([OH:17])(=[O:16])[CH3:15].[OH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:35]([CH2:36][CH2:37][C@:19]12[CH3:20])[C@:32]1([CH:33]=[O:34])[C:27](=[CH:28][C@@H:29]([O:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH2:30][CH2:31]1)[CH2:26][CH2:25]3
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@@H](O[Si](C)(C)C)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C[C@@H](O[Si](C)(C)C)CC[C@@]43C=O)[C@@H]1CC[C@@H]2O
Reaction time: 0.25 h

Procedure:
One equivalent of Jones Reagent is added to a solution of 3β-trimethylsiloxy-4-androstene-17β,19-diol 17-acetate in acetone at 5° C. After stirring for 15 minutes, the acetone layer is poured into cold water with vigorous stirring. The solid is filtered, washed with water and dried in a vacuum oven. Cr stallization from hexane yields 17β-hydroxy-3β-trimethylsiloxy-4-androsten-19-one acetate.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[NH4+].C(OCC)(=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]2N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC[C@H]2NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
(R)-Methyl 1-amino-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-02) (0.661 mmol, 1 eq) was dissolved in dichloromethane and DIPEA (2.5 eq) under a protecting gas atmosphere, and 2-chlorobenzoic acid chloride (1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was diluted with 10% ammonium chloride solution and ethyl acetate, and the phases were separated. The organic phase was washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1) to yield (R)-methyl 1-(2-chlorobenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-02). Yield: 74%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[N:9][N:8]=2)[CH:2]=1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:10]4[O:11][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[N:8][N:9]=4)=[O:20])[CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1nnc(-c2cccnc2)o1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nnc(-c2cccnc2)o1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 34.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)carbamate (249 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.728 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and crystals were separated by filtration, which was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 110 mg (34.2%) of the desired product as a solid.