Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1CC(C)(C)N(O)C(C)(C)C1.OO.N=O.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][N:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][C:24](=[O:29])[CH2:23][C:22]1([CH3:31])[CH3:30]>C(O)(C)(C)C>[OH:29][CH:24]1[CH2:25][C:26]([CH3:27])([CH3:28])[N:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])[C:22]([CH3:31])([CH3:30])[CH2:23]1
Reactant: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Ferrous chloride tetrahydrate (0.99 g, 5.0 mmol) is added to 400 mL of tert-butyl alcohol which is heated to 40° C. The mixture is stirred for 15 minutes and 0.78 g (5.0 mmol) of 2,2'-dipyridyl is added to the tert-butyl alcohol solution. The solution is then stirred for five minutes and 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine is added. A solution of 49 g (0.72 mol) of 50% aqueous hydrogen peroxide mixed with 100 mL of tert-butyl alcohol is added to the reaction mixture over a 10-hour period at 40-45° C. Another 6 g (0.088 mol) of 50% aqueous hydrogen peroxide is then added while the reaction mixture is heated at 45° C. for four hours until the starting nitroxyl compound is reacted. Analysis by gas chromatography shows the reaction mixture contains 6 area % of 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one compared to 22 area % in Example 6. Solids are removed by filtration, and after 1.5 g of sodium borohydride is added, the filtrate is stirred for one hour. The filtrate is diluted with water, and the mixture is thoroughly extracted with ethyl acetate. The extract is concentrated to afford 24.2 g of a light tan crystalline solid which has the same gas chromatography retention time as an authenic sample of the title compound. In a similar experiment, the final product is recrystallized several times from heptane to obtain 16.9 g (69% yield) of the title compound, melting at 127-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([CH3:32])=[CH2:31])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+](=[CH2:36])=[N-]>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([CH3:16])[S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]4([CH3:36])[CH2:32][CH2:31]4)[CH:21]=3)(=[O:18])=[O:19])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C2(C)CC2)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of {(R)-4-[(3-isopropenyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (70.7 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a solution of diazomethane in diethyl ether (1M, 8 mL) slowly at 0° C. under an argon atmosphere, and then a portion of palladium acetate (5 mg) was added. After the mixture was stirred for 10 minutes, a second portion of palladium acetate (5 mg) was added and the mixture was stirred for another 20 minutes, followed by addition of a second portion of a solution of diazomethane in diethyl ether (1M, 5 mL). After being stirred at 0° C. for 2 hours under an argon atmosphere, the reaction mixture was then quenched by the addition of a few drops of acetic acid, and then filtered through a glass funnel and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-10% methanol in dichloromethane) to afford ((R)-4-{methyl-[3-(1-methyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonyl]-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (74.5 mg, 99%) as a colorless semisolid. MS cald. for C23H28F3N3O4S 499, obsd. (ESI+) [(M+H)+] 500.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](O)=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:15])[O:10][C:9]1=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Solvent: CC(=O)Cl
Product: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1

Procedure:
The (S,S)-2,4-dibenzylglutaric anhydride [mp 172°-174°; [alpha]D =-19.1° (c=1 in CHCl3)] is prepared similarly by refluxing (S,S)-2,4-dibenzylglutaric acid in acetyl chloride for 3 hours, concentrating the mixture and recrystallizing from toluene.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:8]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])C>C(O)(=O)C.[Pd]>[CH2:21]([N:7]1[C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[NH:18][C:4](=[O:3])[C:5]1=[O:6])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN(C(=O)C(=O)OCC)c1c([N+](=O)[O-])ccc2c1CCCN2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3
Reaction time: 12 h
Yield: 71 %

Procedure:
A solution of the product from Example 88 (0.63 g) in 75 mL of acetic acid was treated with 56 Pd/C (0.2 g) and shaken on a Parr apparatus under a hydrogen atmosphere (52 psi) for 12 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was washed with ether to give the title compound (0.35 g, 71% yield).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.CN(C=O)C.[Cl:17]N1C(=O)CCC1=O>CCOC(C)=O>[Cl:17][C:7]1[C:8]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cc2sccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1[nH]c2ccsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a 20 mL vial fitted with a magnetic stir bar at 25° C. was added 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.1 g, 0.599 mmol, 1 equiv) and 2 mL of anhydrous DMF. N-chlorosuccinimide (NCS) (0.08 g, 0.599 mmol, 1 equiv) was subsequently added and the reaction vessel contents stirred for 1 h at 25° C. before heating the reaction vial to 55° C. for 12 h. The reaction was then allowed to cool to 25° C. and was diluted with EtOAc (10 mL). The resulting mixture was then washed with water) 3×5 mL). The organic phase was dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The resulting residue was dissolved in a small volume of methanol, filtered through a 0.45 micron syringe filter, and further purified via preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min) afforded the desired 6-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 70 (5.5 mg, 5%). LC/MS m/e 199.9 (M−H). tR of product: 2.3-2.7 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.41 (d, J=5.32 Hz, 1H), 6.97 (d, J=5.27 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33](Cl)=[O:34])[CH:31]=1>ClCCl>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33]([NH:1][C:2]2([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]2)=[O:34])[CH:31]=1
Reactant: Cc1ccc(Br)cc1CC(=O)Cl
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.00 g (11.75 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 1.19 g (11.75 mmol) of triethylamine were dissolved in 40 ml of dichloromethane. 2.65 g (10.69 mmol) of (5-bromo-2-methylphenyl)acetyl chloride (Example 3A), dissolved in 40 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 4.79 g (87% of theory) of the title compound as a beige powder.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].Cl.[CH3:22][O:23][C:24](=[O:30])[CH2:25][C@H:26]([OH:29])[CH2:27][NH2:28]>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:28]([CH2:27][C@@H:26]([OH:29])[CH2:25][C:24]([O:23][CH3:22])=[O:30])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: COC(=O)C[C@H](O)CN
Agent: Cl
Product: COC(=O)C[C@H](O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 59 %

Procedure:
In analogy to the procedure described in Example 12D, (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 12C) and (S)-4-amino-3-hydroxy-butyric acid methyl ester, hydrochloride (intermediate 24) gave the titled compound in 59% yield as light yellow oil. MS: 365.17 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1F
Reaction time: 4 h

Procedure:
4′-Bromo-2′-fluorobiphenyl (5 g) was dissolved in chloroform (80 mL) at room temperature. Chlorosulfonic acid (5 g) was added dropwise and a precipitate appeared soon after addition was complete. Stirring was continued for a further 4 hours, after which the solid was collected by filtration. Further crops of crystals were collected from the filtrate. The solid was washed with cold chloroform and the washings also allowed to crystallise.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21](Cl)[Cl:22]>O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:21][Cl:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (1 g, 4.6 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.55 g, 18.4 mmol), TBAHSO4 (156 mg, 0.46 mmol) and a solution of chloromethyl sulfochloridate (559 μL, 5.5 mmol) in DCM (5 mL). The title compound was obtained as colorless oil (877 mg, 71.8%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:33])([F:32])[CH2:21][O:22][C:23]1[C:24]([C:29](O)=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:24]3[C:23]([O:22][CH2:21][C:20]([F:33])([F:32])[F:19])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncccc1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3OCC(F)(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=463.1 [M+H]+. The 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was prepared as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[C:42]([O:56][CH3:57])=[N:43][CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)(=[O:39])=[O:38])[C:42]([O:56][CH3:57])=[N:43][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cnc2OC)cc1
Yield: 54.5 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 4-methoxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (149 mg, 0.34 mmol), sodium carbonate (2M, 511 μl, 1.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol) according to the method described in Example 3 to give 82 mg (55% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7](C)C(=O)C)=[CH:4][C:3]=1C=O.[CH:16]1(N)[CH2:18][CH2:17]1.[BH4-].[Na+]>C1COCC1>[CH3:17][CH2:16][CH2:18][CH2:12][CH2:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NC1CC1
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-chloro-3-formylbenzyl)-N-methylacetamide from the previous step (1 eq.) in THF (0.08 M) was added cyclopropylamine (2 eq.) and freshly activated 3A molecular sieves. The resulting mixture was stirred at RT for 48 h. The molecular sieves were then filtered off and the filtrate was evaporated in vacuo. The resulting residue was taken up in methanol (0.07 M) and added sodium borohydride (2 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of 1 N aq. HCl. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H2O. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]([CH2:47][CH2:48][O:49][CH3:50])=[C:45]=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:45]([NH:44][CH2:47][CH2:48][O:49][CH3:50])=[O:46])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COCCN=C=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCCNC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol) and triethylamine (0.029 mL, 0.211 mmol) in DCM (0.75 mL) was added 1-isocyanato-2-methoxyethane (11.0 μL, 0.105 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (26.3 mg, 60.5%) as a hygroscopic, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.83-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.82-2.93 (m, 2H), 3.14-3.21 (m, 2H), 3.23 (s, 3H), 3.24-3.31 (m, 2H), 3.31-3.37 (m, 2H), 3.60 (t, J=5.8 Hz, 2H), 4.08-4.17 (m, 1H), 4.29 (s, 2H), 4.49-4.56 (m, 1H), 5.61-5.70 (m, 1H), 6.66-6.73 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 505.0.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1C#N.[C:11]([NH:13][C:14]([NH2:16])=[NH:15])#[N:12].Cl.[OH-].[Na+]>O>[CH3:9][C:5]1[C:6]2[C:11]([NH2:12])=[N:13][C:14]([NH2:16])=[N:15][C:2]=2[S:3][C:4]=1[CH3:10]
Reactant: N#CNC(=N)N
Reactant: Cc1sc(N)c(C#N)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1sc2nc(N)nc(N)c2c1C
Temperature: 25 °C
Yield: 5.2 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiophene-3-carbonitrile (500 mg, 3.29 mmol), cyanoguanidine (276.6 mg, 3.29 mmol) and HCl (2 N, 1.5 mL) in water (10 mL) was refluxed under nitrogen for 2 h. The reaction mixture was cooled to room temperature, and basified with diluted NaOH aqueous solution to PH 7˜8. After evaporation of water, the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (33 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.27 (s, 3H), 5.85 (bs, 2H), 6.29 (bs, 2H). MS 195 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])[O:18][C:14]=2[C:13]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:36])[CH3:35])[CH2:30]2)=[C:12]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:11]=1[CH3:43])#[N:9].S(Cl)(Cl)=O>ClCCl>[C:8]([C:10]1[C:15]2[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[O:18][C:14]=2[C:13]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:35])[CH3:36])[CH2:30]2)=[C:12]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:11]=1[CH3:43])#[N:9]
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a dichloromethane (2 ml) solution of tert-butyl N-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-β-alaninate (I-279) (51 mg, 0.104 mmol), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in dichloromethane (1 ml), and at room temperature, thionyl chloride (10 μl, 0.138 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, the then dissolved in chloroform, and washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous sodium sulfate and concentration, the insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=20:1, v/v), the eluate was purified in slurry with diethyl ether to obtain the entitled compound (8.00 mg, 17%) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.[Br-].[Li+].O.C(=O)(O)[O-].[Na+]>C(#N)C.[Cu]Br.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cu]Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Yield: 53 %

Procedure:
18.96 g of 7α-(5-chloropentyl)-estr-4-ene-3,17-dione is dissolved in 350 ml of anhydrous acetonitrile and mixed under inert gas at 80° C. with a solution of 4.36 g of lithium bromide and 22.5 g of copper(I) bromide in 390 ml of anhydrous acetonitrile. It is stirred for 5 more minutes, the mixture is cooled in an ice bath and mixed with water and ethyl acetate. The organic phase is shaken out with saturated sodium bicarbonate solution, the aqueous phase with ethyl acetate, the combined organic phases with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The raw yield of 19.1 g is chromatographed on silica gel in hexane and ethyl acetate, whereby 10.0 g of oily 7α-(5-chloropentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained, which can be crystallized from hexane/dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH2:26][C:27]#[CH:28])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[C:27]([CH2:26][NH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][N:22]=4)[N:17]=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (7.6 g, 44 mmol) was added to a heated solution (40° C.) of 3-nitro-N-prop-2-ynyl[1,5]naphthyridin-4-amine (5.0 g, 22 mmol) and anhydrous triethylamine (6.7 mL, 48 mmol) in anhydrous dichloromethane (150 mL). The reaction was heated at 40° C. for 1.7 hours and then concentrated under reduced pressure. The residue was triturated with water; the resulting solid was isolated by filtration, washed sequentially with toluene and a small amount of diethyl ether, and then dissolved in dichloromethane. The solution was concentrated under reduced pressure and dried under high vacuum to provide 6.00 g of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine as a brownish-yellow solid.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)(=O)CCCCCCCCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCCCC.[OH-].[Na+:68].[N+]([O-])(O)=O>O>[Na+:68].[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In 945 ml water were dissolved 32.4 g of behenic acid, 9.9 g of arachidic acid and 5.6 g of stearic acid at 90° C. Then, after adding 98 ml of 1.5M aqueous sodium hydroxide solution with stirring and further adding 0.93 ml of concentrated nitric acid, the solution was cooled to a temperature of 55° C. to obtain an aqueous behenic acid sodium salt solution.