Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M22) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (162 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:61][C@@H:62]1[CH2:67][CH2:66][CH2:65][N:64]([CH2:68][C:69]2[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=2[C:71]#[N:72])[CH2:63]1>CN(C=O)C>[C:71]([C:70]1[CH:73]=[CH:74][CH:75]=[CH:76][C:69]=1[CH2:68][N:64]1[CH2:65][CH2:66][CH2:67][C@@H:62]([NH:61][C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:8]=[C:7]3[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:17])[CH2:63]1)#[N:72]
Reactant: N#Cc1ccccc1CN1CCC[C@@H](N)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1CN1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 40 °C
Reaction time: 23 h

Procedure:
To a microwave vial equipped with a stir bar was added 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (50 mg, 0.104 mmol), HOBT (23.85 mg, 0.156 mmol), EDC (29.9 mg, 0.156 mmol), DIPEA (54.4 μl, 0.311 mmol), 2-{[(3R)-3-aminopiperidin-1-yl]methyl}benzonitrile (22.35 mg, 0.104 mmol), and DMF (1038 μl). The vial was sealed and heated to 40° C. The LCMS taken after 23 hours indicates formation of the desired product. The crude reaction mixture was filtered through a column pre-packed with celite. The material was dry loaded onto 2×10 g columns. The desired product eluted and fractions were collected and concentrated in vacuo.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)(=[O:4])=[O:3].P(Br)(Br)[Br:18].O.[OH-].[Na+]>CCOCC>[Br:18][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CS(=O)(=O)c1ccc(CO)c(C(F)(F)F)c1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a suspension of (4-methanesulfonyl-2-trifluoromethyl-phenyl)-methanol (50.3 g, 0.20 mol) in dry Et2O (400 ml), cooled to 0° C., is added PBr3 (6.5 ml, 0.07 mol) dropwise over 10 min. A sticky, thick yellow suspension forms which upon agitation and warming to room temperature changes to a fine white suspension. The reaction mixture is cooled again to 0° C. and water (200 ml) is added slowly. The suspension is neutralised at 10° C. with 4N NaOH aq (30 ml). The product is collected by filtration to give a white solid which is dried at 50° C. under high vacuum.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.C(Cl)Cl.Cl>CC(O)C>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(N[C@H](CO)c1ccc(Cl)c(Cl)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Reaction time: 2 h

Procedure:
To a solution of 69a (0.175 g, 0.301 mmol) and DCM (3 mL) was added 6M HCl (0.0110 g, 0.301 mmol) in IPA and the reaction was stirred for 2 h and then poured into satd. aq. Na2CO3 and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:30 to 500:45) to afford 0.030 g (21.3%) of I-43: MS m/z (APCI-pos) M+1=466.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12](O)=[O:13])([O-:3])=[O:2].C([N:25](CC)CC)C.ClC(OCC)=O.N>C(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]([NH2:25])=[O:13])([O-:3])=[O:2]
Reactant: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(N)=O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
In 100 ml of methylene chloride were dissolved 6.15 g of 2-[3-(2-nitrophenoxy)phenoxy]propionic acid and 4.2 g of triethylamine, followed by dropwise addition of 2.5 g of ethyl chloroformate at a temperature not exceeding 0° C., and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was poured into previously ice-cooled methylene chloride (120 ml) saturated with ammonia gas and the mixture was then stirred at room temperature for 30 minutes. The methylene chloride layer was washed with water (twice), dried and concentrated and the residue was crystallized from methanol and isopropyl ether to give 3.3 g of the title compound.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:23]=3)[N:20]=1)=[CH:8]2.Cl.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO.C(OCC)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:23]=3)[N:20]=1)=[CH:8]2
Reactant: COCOc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(O)cc2cc1-c1nnn(Cc2cccc(OCc3ccc4ccccc4n3)c2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6-methoxymethoxy-3-{2-[3-(2-quinolylmethoxy)-benzyl]tetrazolyl}quinolin-2-one (444 mg, 0.85 mmol) was dissolved in a mixture (100 ml) of chloroform-methanol (10:1). A solution (5 ml) of hydrochloric acid (4N) in ethyl acetate was added to the resultant mixture, and the mixture was stirred at room temperature for 17 hours. Water (400 ml) was added thereto, and a saturated aqueous solution of sodium hydrogencarbonate was added dropwise so as to neutralize the aqueous phase, followed by extraction with a mixture of chloroform-methanol (10:1). The organic phase was dried over magnesium sulfate anhydrate, and the solvent was removed under reduced pressure. The residue was recrystallized from a chloroform-methanol-diethylether mixture, to thereby obtain the title compound as yellow leaf crystals (353 mg, 0.74 mmol, 87.2%).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].NCC(O)=O.N[C@H](C(O)=O)CCSC.[NH2:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27]>O>[NH2:1][C@H:2]([C:7]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCC(N)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: NCC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1A and B above by replacing DL-methionine and glycine respectively with L-methionine and L-valine (Aldrich Chemical Co., Beil 4,427). The title compound had a melting point of 227° to 229° C (d). The title compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.44 mole percent valine and 50.56 mole percent methionine.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[Li]C(CC)C.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][C:3]=1[B:27]([OH:32])[OH:28]
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3O2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(C2CCc3cc(B(O)O)c(F)c(F)c3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7,8-difluoro-2-(4-propylcyclohexyl)chroman (3.82 g) obtained in Example 2 was dissolved in THF (38 mL). To the solution was added dropwise sec-BuLi (0.99 M solution, 15.5 mL) at −70 to −75° C. and stirred after the end of dropping at the same temperature for additional 1 hour. To the solution was added dropwise a THF solution (5 mL) of triisopropyl borate (2.15 g) at −70 to −75° C. After the end of dropping, it was stirred at the same temperature for additional 3 hours. Then temperature thereof was gradually raised to room temperature. The solution was left stirring overnight. While cooling on ice, to the reaction mixture was added 2 M hydrochloric acid and stirred at room temperature for additional 2 hours. The reaction mixture was poured to water, which was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was further washed with heptane to obtain crude 7,8-difluoro-6-dihydroxyboryl-2-(4-propylcyclohexyl)chroman. The product was used in a second step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2cccnc2)nc(N2CCOCC2)n1
Yield: 59.3 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 3-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated under gentle reflux for 5 min. After cooling, the mixture was diluted with water to give an oily solid, which was recrystallized from MeOH to give 0.13 g (59% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 160-161° C.; 1H NMR (CDCl3) (rotamers) δ 8.61 (d, J=4.4 Hz, 1H), 8.42 and 8.32 (2d, J=7.6 and 8.4 Hz, 1H), 7.89-7.87 (m, 1H), 7.70 (dt, J=7.7, 1.65 Hz, 1H), 7.65 and 7.59 (2t, JHF=53.7 and 53.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (br t, J=8.7 Hz, 1H), 7.24 (br t, J=6.2 Hz, 1H), 6.55 and 6.41 (2 m, exchangeable with D2O, 1H), 4.82 and 4.78 (2 d, J=5.3 and 5.1 Hz, 2H), 3.88 (m, 4H), 3.78 (m, 4H); Anal. Calcd. for C21H20F2N8O: C, 57.5; H, 4.6; N, 25.6. Found: C, 57.7; H, 4.5; N, 25.7%.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:7][C:8](=[O:14])[C:9](OCC)=[O:10])[CH3:6]>C(Cl)Cl>[OH:2][CH2:1][CH2:3][NH:4][C:9](=[O:10])[C:8]([O:7][CH2:5][CH3:6])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCO
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCCO
Temperature: -70 °C
Reaction time: 16 h

Procedure:
To a mixture of 500 parts ethanolamine in methylene chloride (900 ml), cooled to -70° C., was added dropwise 2405 parts diethyloxalate. After stirring at room temperature for 16 hours, the mixture was filtered, concentrated and purified by chromatography to yield pure ethyl 2-hydroxyethyloxamate. A mixture of the oxamate (77 parts), sodium carbonate (50.2 parts) and an inhibitor in chloroform were cooled to 0° C. and acryloylchloride (43.3 parts) was added dropwise. After stirring at 0° for 2 hours and room temperature for 3 hours the mixture was filtered to yield 1011 parts crude ethyl N-2-ethyloxamatoacrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](Cl)=[O:31].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31]
Reactant: Cc1ccccc1C=CC(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: Cc1ccccc1C=CC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 41.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-methylcinnamic acid chloride (0.114 mmol), the title compound (18 mg, yield 41%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: C1C=CC=CC=1.[O:7]1[C@@H:31]2[C@:8]31[C@H:17]([C@H:18]1[C@:29]([CH3:32])([CH2:30]2)[C@@:21]([OH:33])([C:22](=[O:28])[CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]1)[CH2:16][CH2:15][C:14]1[C@:9]3([CH3:35])[CH:10]=[CH:11][C:12](=[O:34])[CH:13]=1.C([CH2:39][C:40]([O-])=[O:41])(C)=C>>[C:40]([O:34][C:12]1[CH:11]=[CH:10][C@@:9]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@:8]42[O:7][C@H:31]4[CH2:30][C@@:29]2([CH3:32])[C@H:18]3[CH2:19][CH2:20][C@:21]2([OH:33])[C:22](=[O:28])[CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH:13]=1)(=[O:41])[CH3:39]
Reactant: C=C(C)CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Solvent: c1ccccc1
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(OC(C)=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C

Procedure:
10 g of sulfonic acid resin (Amberlite I R120, marketed by Rohm and Haas Co.) was dehydrated by azeotropic destillation with benzene. The dry resin was suspended in 50 ml isopropenylacetate and 10 g 9β,11β-epoxy-21-acetoxy-17-hydroxy-pregna-1,4-diene-3,20-dione were added. The mixture was heated under reflux for 5 hours, cooled and filtered an the filtrate was evaporated to dryness. The residue which crystallized from methanol (0,5% pyridine) gave in high yield (9,5 grams) 3,21-diacetoxy-17-hydroxy-9β,11β-epoxy-pregna-1,3,5-triene-20-one. Melting point: 194° C., λmax 310 nm (ε5500)⟦alpha⟧sub.D in chloroform -199° C. (c=1% chloroform), νmax (cm-1) (K Br) 3450; 1765; 1740; 1725; 1655; 1625; 1590.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])C1C=CC=CC=1.O1CCCCC1N1C(CCOC2CCCCO2)CC1=O>>[CH3:1][C@H:8]1[C@@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15]
Reactant: O=C1N[C@@H](CCO)[C@@H]1Cc1ccccc1
Agent: O=C1CC(CCOC2CCCCO2)N1C1CCCCO1
Product: C[C@@H]1C(=O)N[C@@H]1CCO

Procedure:
Following the procedure described for the preparation of trans-3-benzyl-4-(2-hydroxyethyl)-2-azetidinone from 8-oxo-2,2-dimethyl-7α-benzyl-3-oxa-1-azabicyclo[4.2.0]octane and using 8-oxo-2,2-dimethyl-7β-methyl-3-oxa-1-azabicyclo[4.2.0]octane one obtains cis-3-methyl-4-(2'-hydroxyethyl)-2-azetidinone.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:17][F:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C:5]([CH2:6][OH:7])([CH2:17][F:18])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC1(C)OCC(CF)(Cn2ccnc2[N+](=O)[O-])CO1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1nccn1CC(CO)(CO)CF
Temperature: 80 °C
Yield: 98.5 %

Procedure:
56.3 mg (0.206 mmol equivalents) of 2,2-dimethyl-5-fluoromethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 2 mL of methanol, 2 mL of 1 mol/L hydrochloric acid was added thereto, and the mixture was heated at 80° C. for 2 hours. After completion of the reaction, the reaction liquid was cooled to room temperature (25° C.), the solvent was then removed by distillation, and the obtained crude product was washed with ethyl acetate to give 47.3 mg (0.203 mmol equivalents) of 1-(2,2-dihydroxymethyl-3-fluoropropyl)-2-nitroimidazole (FIG. 2, Step 2).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([O-:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Na+].[CH2:26](Cl)[CH2:27][CH2:28][CH3:29]>C1COCC1>[CH2:26]([O:24][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCCl
Reactant: CCCCCCCCCCCC([O-])CCCCCCCCCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CCCCCCCCCCC)OCCCC
Temperature: -6.666666666666667 °C

Procedure:
40.3 g (0.118 mole) 12-tricosanol (Example 2) was heated with 3.0 g (0.13 mole, 10% molar excess) sodium metal to 130° C. for a period of 15 hrs during which most of the sodium dissolved with hydrogen evolution to form the corresponding alkoxide, sodium 12-tricosanolate, which is liquid at 130° C. The thus prepared sodium 12-tricosanolate was subsequently treated with 20 ml (0.19 mole, 60% molar excess) n-butyl chloride in the presence of 20 ml THF at 90° C. for 7 days. The resulting reaction mixture was quenched with aqueous sodium hydroxide and extracted with heptane. The heptane solution was cooled to 20° F. during which 8.9 g of solid precipitate (unconverted 12-tricosanol and 12-tricosanone) formed and was removed. The heptane was evaporated at 80° C., 10 torr to yield the 12-tricosanyl n-butyl ether (33.2 g) as a colorless oil having the following properties: VI=147, VIS100=2.768 cSt, VIS40=9.395, cloud point: −3° C., pour point: −4° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
1-Bromo-4-propylbenzene (60 g), 3-methyl-1-butyne-3-ol (38 g), triphenylphosphine (1.3 g) and bis(triphenylphosphine)palladium(II) chloride (0.7 g) were dissolved in triethylamine (260 ml) under nitrogen atmosphere, and then copper(I) iodide (0.2 g) was added thereto. The mixture was stirred at room temperature for 1 hour, and then further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off, followed by extraction with chloroform. The resultant was washed twice with 10% hydrochloric acid, and further with water twice, followed by distilling off chloroform therefrom. The residue was purified by the use of silica gel-chloroform column chromatography to give 3-methyl-1-(4'-propylphenyl)-1-butyne-3-ol (37 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5][N:4]=1.O[Li].O>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NC1(c2ccccc2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylate (crude from step 2) in THF (4 mL) was added LiOH.H2O (150 mg, 3.57 mmol) in H2O (2 mL). The mixture was stirred at room temperature overnight. THF was removed under vacuum and the residue was acidified with 1N HCl, white solids precipitated out, which were collected by filtration, dried on vacuum to give 2-(methylthio)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxylic acid (646 mg). MS 302.3 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:32][CH2:33][C:34]1[CH:54]=[CH:53][C:37]([C:38]([NH:40][C:41]2[CH:42]=[C:43]3[C:48](=[CH:49][CH:50]=2)[N:47]=[C:46]([CH3:51])[CH:45]=[C:44]3[NH2:52])=[O:39])=[CH:36][CH:35]=1.C(N1CCOCC1)C>CN(C=O)C>[NH2:52][C:44]1[C:43]2[C:48](=[CH:49][CH:50]=[C:41]([NH:40][C:38]([C:37]3[CH:53]=[CH:54][C:34]([CH2:33][NH:32][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:9])=[CH:35][CH:36]=3)=[O:39])[CH:42]=2)[N:47]=[C:46]([CH3:51])[CH:45]=1
Reactant: Cc1cc(N)c2cc(NC(=O)c3ccc(CN)cc3)ccc2n1
Reactant: O=C(O)c1cnccn1
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
Product: Cc1cc(N)c2cc(NC(=O)c3ccc(CNC(=O)c4cnccn4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.2 %

Procedure:
To a solution of 10.5 mg (0.08 mmol) of 2-pyrazinecarboxylic acid in 1 ml of DMF were added 27.9 mg (0.085 mmol) TOTU. After 15 min at room temperature 55 mg (0.085 mmol) of 4-Aminomethyl-N-(4-amino-2-methyl-quinolin-6-yl)-benzamide and 39 mg (0.34 mmol) of N-ethylmorpholine were added. After 24 h stirring at room temperature the solution was evaporated and the residue was treated with acetonitrile and water containing 0.005% trifluoroacetic acid. The precipitate was filtered to give 36.7 mg (71%) of the title compound. MS 413.42 (M+1)+, 1H-NMR (DMSO-d6) δ 2.58 (s, 3H), 4.60 (d, 2H), 6.58 (s, NH), 7.55 (d, 2H), 7.81 (d, 1H), 8.00 (m, 3H), 8.65 (br.s., NH2), 8.78 (m, 2H), 8.90 (m, 1H), 9.20 (s, 1H), 9.62 (m, 1H), 10.80 (s, NH), 13.38 (br.s., NH).