Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17]3[CH:22]=[C:23]([O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][C:16]=3[S:15]2(=[O:31])=[O:30])=[CH:10][CH:9]=1)=[O:6])(C)C.O.Cl>O1CCOCC1>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17]3[CH:22]=[C:23]([O:26][CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:25][C:16]=3[S:15]2(=[O:31])=[O:30])=[CH:10][CH:9]=1)([OH:6])=[O:4]
Reactant: CC(C)OC(=O)Cc1ccc(N2C(=O)N(C)c3cc(OC(C)C)ccc3S2(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(CC(=O)O)cc1)S2(=O)=O
Yield: 70.9 %

Procedure:
A solution of 2-(4-isopropoxycarbonylmethylphenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (95 mg) in a mixture of 1,4-dioxane (6 ml), water (2 ml) and conc. hydrochloric acid (1 ml) was refluxed for two hours. After the mixture was concentrated in vacuo, the residue was extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4. After the solvent was evaporated under reduced pressure, the crystalline residue was recrystallized from ethanol to yield 2-(4-carboxymethylphenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (61 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+].COCCOC>C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-(4-hydroxynaphthalen-1-yl)prop-2-enoate (242 mg, 1.00 mmol, 1.00 equiv), TsNHNH2 (0.744 g), NaOAc (0.41 g), ethylene glycol dimethyl ether (15 mL), water (3 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting solution was diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 2×10 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (16/84). This resulted in 194 mg (80%) of ethyl 3-(4-hydroxynaphthalen-1-yl)propanoate as colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C@@:8]12[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][C:18]=3[C@H:17]1[CH:16](O)[CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)#[N:7].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:6]([C@@:8]12[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][C:18]=3[C:17]1=[CH:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)#[N:7]
Reactant: COc1ccc2c(c1)CC[C@@]1(C#N)[C@@H]3CC[C@H](OC4CCCCO4)[C@@]3(C)CC(O)[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC[C@]1(C#N)C2=CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of phosphorus oxychloride was added in drops to a solution of 27.6 g of 4 in 275 ml of pyridine at a temperature of 0-5° C., and it was stirred for another 1.5 hours at this temperature. Then, the mixture was moved into a dropping funnel and added in drops to an ice-cooled, saturated sodium bicarbonate solution. Then, it was extracted with dichloromethane, the collected organic phases were washed with brine, dried on magnesium sulfate, and the solvent was removed in a vacuum. In this way, 23.5 g (89%) of almost colorless, foamy 5 was obtained, which was used without further purification in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH:11]2[CH2:15][N:14]([CH2:16][CH3:17])[N:13]([CH2:18][CH3:19])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH:11]2[CH2:12][N:13]([CH2:18][CH3:19])[N:14]([CH2:16][CH3:17])[CH2:15]2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Agent: [Ni]
Solvent: CCO
Product: CCN1CC(NC(=O)c2ccc(N)cc2)CN1CC

Procedure:
A solution of 20 g. (0.069 mole) of 4-nitro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide in ethanol was treated with Raney nickel and shaken in three atmospheres of hydrogen in a Parr apparatus at room temperature for two hours. The mixtures was filtered, the filtrate concentrated and the residue crystallized from isopropyl ether-ethyl acetate. The product (12.0 g.; 66.5%) melted at 119°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 173.7 %

Procedure:
2,4-Difluorobenzoic acid (50 g, 316 mmol) was dissolved in concentrated sulfuric acid (200 ml), and N-iodosuccinimide (68 g, 300 mmol) was added by portions at not more than 5° C. After the completion of the addition, the mixture was stirred at the same temperature for 4.5 hr. The reaction mixture was poured into ice water (ca. 600 ml), then 10% aqueous sodium sulfite solution was added, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give crude crystals (85 g). The crude crystals obtained in the same manner were combined (total amount 205 g), and recrystallized from 50% aqueous ethanol (820 ml) to give 2,4-difluoro-5-iodobenzoic acid (148 g, yield 73%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16](=[O:27])[C:17]([C:20]2[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH3:18])[CH2:12]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C@:17]([OH:19])([CH3:18])[C:16]2=[O:27])[CH2:12]1.[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C@@:17]([OH:19])([CH3:18])[C:16]2=[O:27])[CH2:12]1
Reactant: CC(O)(C(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(O)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc21
Product: C[C@]1(O)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc21
Temperature: 80 °C

Procedure:
A mixture of N-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-2-(2-chloropyridin-3-yl)-2-hydroxypropanamide (0.094 g, 0.233 mmol), chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-tert-butyl ether adduct (Sigma Aldrich, 0.011 g, 0.014 mmol), sodium tert-butoxide (Aldrich, 0.045 g, 0.467 mmol) in Dioxane (0.933 ml) in a microwave vial was heated to 80° C. overnight. The reaction mixture was directly loaded onto a Biotage samplet. Purification by Biotage (25 g column; 0-100% EtOAc/hexane) followed by a second purification by Gilson HPLC (Gemini Gradient 10-70 method, Gemini-NX 10 u C18 column, 100×50 mm, solvets: ACN/0.1% TFA and water/0.1% TFA) to produce mixtures (R)-1-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one and (S)-1-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.0059 g, 0.016 mmol, 7% yield). M+1: 367.0. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55 (s, 3 H) 2.53-2.72 (m, 2 H) 3.48-3.67 (m, 2 H) 4.63-4.77 (m, 1 H) 5.18-5.37 (m, 1 H) 7.03-7.18 (m, 1 H) 7.32-7.45 (m, 1 H) 7.46-7.61 (m, 2 H) 7.71-7.79 (m, 1 H) 7.79-7.88 (m, 1 H) 8.19-8.30 (m, 1 H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8]C(OCC)=O.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C@@H](C(O)=O)C2)=[CH:18][CH:17]=1.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[ClH:8].[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C@@H:6]([NH2:3])[CH2:7]2)=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(c1)C[C@H](C(=O)O)CC2
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C[C@H](N)CC2
Product: Cl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 2 ml (0.0140 mol) of triethylamine in 20 ml of acetone and then 1.6 ml (0.0161 mol) of ethyl chloroformate in 20 ml of acetone are added slowly at a temperature of -10° C. to -5° C. to a solution of 2.5 g (0.0120 mol) of 7-methoxy-1,2,3,4-tetrahydro-(2R)-2-naphthoic acid in 30 ml of acetone. The mixture is stirred at -5° C. for 2 hours and a solution of 1.3 g (0.0193 mol) of NaN3 in 10 ml of water is then added dropwise. After 1 hour at -5° C., the mixture is poured into 200 ml of water and extracted with toluene. The two phases are separated, the organic phase is dried over sodium sulfate and filtered and the solution is heated at 100° C. for 1.5 hours. The solvent is evaporated off under reduced pressure, the residue is taken up with 22 ml of water and 26 ml of 37% hydrochloric acid and the mixture is refluxed for 3.5 hours. After cooling, the pH of the solution is rendered basic by the addition of 3.5 N NaOH, extraction is carried out with ethyl ether, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The hydrochloride of the base obtained in this way is prepared with a saturated solution of hydrochloric acid in ethyl ether. This gives 1.6 g of the title compound, which is crystallized from isopropanol to give 1.2 g of product. M.p. 205° C.-207° C.; [α]D20 =+66.6° (c=0.5%, MeOH).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[OH:13])[CH2:2][CH2:3][CH3:4].[CH3:14]O.[OH-].[K+].CI>O>[CH2:1]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C)cc(C)cc1O
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CCCCc1c(C)cc(C)cc1OC
Reaction time: 3 h

Procedure:
83 g. of 2-butyl-3,5-dimethyl-phenol are dissolved in 225 ml. of methanol. After the addition of 60 g. of potassium hydroxide in 25 ml. of water, the solution is treated at room temperature with 34.2 g. of methyl iodide. The mixture is heated to boiling under reflux conditions for 3 hours, then cooled, diluted with water and extracted with ether. The ether extract is washed with diluted sodium hydroxide solution, dried over sodium sulfate and evaporated. There is obtained 2-butyl-3,5-dimethyl-anisole, which is purified by absorption on silica gel, using hexane/methylene chloride 70:30 parts by volume as the eluent, before processing further.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)O1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: CC1(C)OB(c2ccc3ncsc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2ncsc2c1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.109 g; 0.786 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g; 0.026 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.137 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.024 g (18%) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19]C(N)=O>>[NH2:19]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: NC(N)=O
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 55 %

Procedure:
Prepared as in Example 41 from 2-benzoyl-benzo[b]thiophen-3-ol, but using urea instead of ammonium acetate, with a yield of 55% of theory; m.p. 121°-122° C. (petroleum ether/ethyl acetate 2:1). The product was identical to that of Example 1, based on its TLC, mixed melting point and IR-spectrum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:34][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2CC[C@@H]1O2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2CC[C@@H]1O2
Temperature: 70 °C

Procedure:
(1S,2R,3S,4R)-3-(2,3-diamino-5-chloropyridin-4-ylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide (17) (300 mg, 0.971 mmol), and 4-morpholinobenzaldehyde (167 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with hot ethanol to afford the desired product (466 mg, 23%) as a yellow solid. NMR: δ (1H, 400M Hz, DMSO-d6): 1.50-1.80 (4H, m), 2.96 (1H, d, J=8.4 Hz), 3.23 (4H, s), 3.76 (4H, s), 4.33 (1H, d, J=4.5 Hz), 4.57 (1H, s), 5.49 (1H, t, J=8.8 Hz), 6.99 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.18 (1H, s), 7.62 (1H, s), 7.91 (1H, s), 8.02 (1H, d, J=8.0 Hz), 12.96 (1H, s). LCMS (254 nm): [M+H]+ 469.15 (95.56%) HPLC: 91.64% (220 nm).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:31]([Mg]Br)[CH3:32].[CH2:35]1COCC1>>[OH:28][C:27]1([CH2:26][CH2:25][C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:32][CH2:31]1.[N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH:31]([CH3:32])[CH3:35])=[O:28])[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C1CCOC1
Reactant: COC(=O)CCc1nc(-c2ccc(C)c(NC(=O)c3cnc4ccccn34)c2)no1
Reactant: CC[Mg]Br
Product: Cc1ccc(-c2noc(CCC(=O)OC(C)C)n2)cc1NC(=O)c1cnc2ccccn12
Product: Cc1ccc(-c2noc(CCC3(O)CC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of methyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)propanoate (93) (100 mg, 0.25 mmol) in anhydrous THF at −15° C. under argon was added dropwise a solution of ethylmagnesium bromide (247 L, 0.74 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched with saturated NH4Cl. The crude product was extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. The crude product was purified by preparative HPLC to yield both N-(5-(5-(2-(1-hydroxycyclopropyl)ethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F55a) and isopropyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)propanoate (F55b). 1H NMR for (F55a) (400 MHz, CD2Cl2) δ 9.89 (d, J=6.8 Hz, 1H), 9.81 (s, 1H), 9.56 (s, 1H), 8.21 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.0 (t, J=8.0 Hz, 1H), 7.88 (dd, J=1.6, 7.6 Hz 1H), 7.53 (t, J=7.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 3.23 (t, J=7.2 Hz, 2H), 2.47 (s, 3H), 2.12 (t, J=7.2 Hz, 2H), 0.79 (t, J=6.8 Hz, 2H), 0.53 (t, J=6.8 Hz 2H). MS m/z 404.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].BrC1C(NC(C(C)C)CNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and tert-butyl N-(2-amino-2-methyl-propyl)carbamate using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. LCMS (ESI) 379 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3,5-dichloropyrazine-2-carbonitrile (2.00 g, 11.5 mmol) in 30 mL NMP were added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (2.71 g, 12.6 mmol) and DIEA (4.07 mL, 13.8 mmol). The mixture was stirred at RT for 1.5 h. To it was poured 300 mL water. After stirring vigorously for 2 h, the solid was isolated by filtration, washed with water and dried in vacuum oven for overnight to afford tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (4.55 g, 35.5 mmol) in THF (90 mL) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 24 mL, 46 mmol) was added. After 30 min., Benzaldehyde (4.90 g, 46 mmol) was added. After 15 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 9.46 g (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]3[CH2:16][O:15]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][C:18]=1[N:30]1[CH2:37][C@H:36]2[NH:38][CH2:39][C@@H:31]1[CH2:32][CH:33]=[CH:34][CH2:35]2.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]([OH:15])[CH2:16][N:38]3[CH2:39][CH:31]4[N:30]([C:18]5[CH:19]=[CH:20][C:21]6[C:22]7[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=7)[CH2:28][C:29]=6[CH:17]=5)[CH2:37][CH:36]3[CH2:35][CH:34]=[CH:33][CH2:32]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(OC[C@@H]3CO3)ccnc2c1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2c(c1)Cc1ccccc1-2
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O[C@H](COc1ccnc2cc(Cl)ccc12)CN1CC2CC=CCC1CN2c1ccc2c(c1)Cc1ccccc1-2
Temperature: 95 °C

Procedure:
(S)-7-Chloro-4-oxiranylmethoxy-quinoline (20 mg, 0.084 mmol) and Z-(1S,6S)-7-(9H-fluoren-2-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (22 mg, 0.073 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via reverse phase chromatography (gradient 20% to 90% CH3CN/water for 12 min) to yield the title compound as a residue.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH:14]=[C:15]1[CH3:21])[C@@H:10]([CH3:23])[C:9]3=[CH2:24].[OH-:26].[Na+]>CO>[O:26]1[C:11]23[C@:16]([CH3:17])([C@H:15]([CH3:21])[CH2:14][C:13](=[O:22])[CH:12]12)[C@@H:18]1[C@H:8]([C@H:6]2[C@@:4]([CH2:20][CH2:19]1)([CH3:5])[C:3](=[O:25])[C@H:2]([F:1])[CH2:7]2)[C:9](=[CH2:24])[C@H:10]3[CH3:23]
Reactant: C=C1[C@H](C)C2=CC(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C=C1[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](F)C[C@@H]23)[C@@]2(C)[C@H](C)CC(=O)C3OC32[C@@H]1C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
345 mg of 16α-fluoro-1β,6β-dimethyl-7-dimethylenandrost-4-ene-3,17-dione (its preparation is described in Example 2) is dissolved in methanol (20 ml) and the resulting solution cooled to 0° C. Thereupon ice cold 36% hydrogen peroxide (2 ml) and 2% sodium hydroxide (1 ml) are added. The mixture is stirred for about 24 hrs at 0°-5° C. and then poured into ice water. The product is filtered off, washed with water and then dried to give 4,5-epoxy-16α-fluoro-1β,6β-dimethyl-7-methylenandrostane-3,17-dione.