Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[NH2:8][C:9]1[N:14]=[C:13](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH2:37][C:38]([O:40]C)=[O:39])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])=[C:11]([CH3:42])[N:10]=1.[OH-].[K+]>C(O)CCC>[NH2:8][C:9]1[N:14]=[C:13]([NH:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4])[C:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH2:37][C:38]([OH:40])=[O:39])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])=[C:11]([CH3:42])[N:10]=1
Reactant: CCC[C@H](N)CO
Reactant: COC(=O)Cc1ccc(OC)c(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Temperature: 160 °C

Procedure:
(S)-(+)-2-Amino-1-pentanol (100 mg) was added to a suspension of the product from step (v) (243 mg) in butan-1-ol (2 mL). The reaction was heated in a microwave at 160° C. for 2 h. 5M KOH (0.5 mL) was added and the mixture heated in a microwave at 100° C. for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC to give the subtitle compound as a white solid, 60 mg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:22]([O:24][CH3:25])=[O:23].O>C(Cl)Cl>[C:22](=[O:23])([O:24][CH3:25])[O:13][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(OC(=O)OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 2-tert-butyl-4-ethyl-phenol (10 g, 56.1 mmol) in DCM (50 mL) was added Et3N (17 g, 168.0 mmol) and methyl chloroformate (11 g, 116.4 mmol) at 0° C. The mixture was stirred overnight at room temperature. Water was added to quench the reaction and the mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-tert-butyl-4-ethylphenyl methyl carbonate (12 g, 91%). 1H NMR (300 MHz, CDCl3), 7.06-7.02 (m, 2H), 7.02 (s, 1H), 3.92 (s, 3H), 2.64 (q, J=7.5 Hz, 2H), 1.37 (s, 9H), 1.54 (t, J=7.5 Hz, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc([N+](=O)[O-])cc32)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(N)cc32)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
(R)-2-Methyl-4-[2-(6-nitro-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (390 mg, 0.96 mmol) and 10% Pd/C (0.102 mg, 0.10 mmol) were mixed with MeOH (9.6 mL). The reaction was hydrogenated at ˜1 bar for 30 min at ambient temperature then filtered under vacuum and concentrated, to give the title compound (360 mg, 100%) as an off white glass. 1H NMR (Me-d3-OD): 7.64 (1H, d), 6.97 (1H, d), 6.47 (1H, dd), 4.32-4.17 (3H, m), 3.82 (1H, d), 3.28 (2H, s), 3.24-3.14 (1H, m), 3.07 (2H, t), 2.92 (1H, d), 2.81 (1H, d), 2.32 (1H, dd), 2.24-2.07 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C3C(F)=C(F)C(F)=C(F)C=3F)=O)=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>N1C=CC=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([N:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[CH:45][CH:44]=3)=[O:20])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.029 mmol) was agitated with 4-morpholinoaniline (0.155 mg, 0.87 mmol) in 10% pyridine in dimethylformamide (2 ml) for 24 h. The resin was filtered and washed liberally with dimethylformamide, MeOH, DCM, and dried under vacuum. The dry resin was cleaved in 60% trifluoroacetic acid in dichloromethane (2 ml) for 2 h at room temperature. The supernatant was evaporated under vacuum, and the crude product was purified by preparative TLC (eluent: 10% methanol in dichloromethane to give product as a white solid. Yield 6.6 mg (50%). MS (m/z): 457.2 [M+H]+. 1H NMR.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9]3)[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[ClH:28].C(OCC)C>CO>[ClH:28].[ClH:28].[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10][CH2:9]3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCc2cc(CN3CCC3)ccc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: c1cc2c(cc1CN1CCC1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(Azetidin-1-yl-methyl)-1,2,3,4-tetrahydro-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (5.162 mmol, 1 equiv.) was dissolved in methanol (20 ml); K2CO3 (10.32 mmol, 2 equiv.) was added, and the mixture was stirred for 1 hour at 25° C. Methanol was concentrated in vacuo, and the residue was taken up in dichloromethane (30 ml) and washed with distilled water (5 ml). The aqueous phase was extracted with DCM (20 ml), and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. For purification, the crude product was dissolved in diethyl ether (50 ml), and a hydrochloride was precipitated with 2 M HCl in diethyl ether solution (3 equiv.). The hydrochloride was filtered off, washed with diethyl ether and dried in vacuo to yield the desired product. Yield: 1.03 g (73%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12].C(OCC)(=O)C>O1CCCC1>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:12]
Reactant: COCCOC(=O)Cl
Reactant: Nc1cccc(CO)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOC(=O)Nc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
To a solution of 15.0 g of 3-aminobenzyl alcohol in 120 ml of tetrahydrofuran was added dropwise a solution of 18 ml of 2-methoxyethyl chloroformate in 70 ml of tetrahydrofuran under ice-cooling. After stirred for 30 minutes under ice-cooling and then at room temperature for 30 minutes, additional 2 ml of 2-methoxyethyl chloroformate was added, and the mixture was stirred at room temperature for 1 hour. After ethyl acetate was added, the mixture was washed successively with an aqueous saturated sodium bicarbonate solution and then an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to obtain 30.2 g of 3-[(2-methoxyethoxy)carbonylamino]benzyl alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([Cl:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]([Cl:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Product: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([OH:17])[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1O
Yield: 87.1 %

Procedure:
1.65 g of lithium aluminum hydride were suspended in 100 ml of tetrahydrofuran, and then 5.00 g of 4-chlorosalicylic acid in 50 ml of tetrahydrofuran were added dropwise to the resulting suspension, whilst stirring and ice-cooling. The resulting mixture was then heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled on ice, and sodium sulfate decahydrate was added to decompose the excess hydride. Insoluble substances were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was then purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.00 g (yield 87%) of the title compound as a colorless solid substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]=[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:20][CH:21]=3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: Nc1ccc2ccc(=O)[nH]c2c1
Product: O=C(Nc1ccc2ccc(=O)[nH]c2c1)c1ccc(-c2ccccc2)nc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-1H-quinolin-2-one (D89) (30 mg, 0.19 mmol) and 6-phenylnicotinic acid (D48) (45 mg, 0.22 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 11.80 (br, 1H), 10.73 (br, 1H), 9.21 (d, 1H), 8.42 (dd, 1H), 8.18 (m, 3H), 8.01 (d, 1H), 7.84 (d, 1H), 7.64 (d, 1H), 7.53 (m, 4H), 6.40 (dd, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([O:53][C:54]1[C:63]([CH3:64])=[CH:62][C:57]([C:58]([NH:60][NH2:61])=O)=[CH:56][C:55]=1[CH2:65][CH3:66])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C.CCOC(C)=O.C1COCC1>[CH2:46]([O:53][C:54]1[C:63]([CH3:64])=[CH:62][C:57]([C:58]2[O:13][C:11]([C:9]3[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[N:10]=3)=[N:61][N:60]=2)=[CH:56][C:55]=1[CH2:65][CH3:66])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (200 mg, 1.02 mmol) and DIPEA (0.43 mL) in DMF (100 mL) is added TBTU (395 mg, 1.23 mmol). The reaction mixture is stirred at 0° C. for 15 min before adding 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide. Stirring is continued for 1 h and the reaction mixture is then diluted with EtOAc and washed with sat. aq. NaHCO3. The aq. phase is extracted with EtOAc and the combined org. phases are dried over MgSO4, filtered and evaporated to give a brown oil. The oil is dissolved in THF (5.0 mL) and Burgess reagent (155 mg, 0.65 mmol) is added. The reaction mixture is heated to 110° C. for 15 min under microwave conditions. The reaction mixture is evaporated and purified by prep. TLC (eluting with Heptane/EA 9:1) to afford {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyrimidin-2-yl}-isopropyl-amine as a yellow oil (125 mg, 56%); LC-MS: tR=1.16; [M+H]+=444.08.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:28]3\[C:29](=[O:33])[NH:30][C:31]4[C:27]\3=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:32]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(OC)ccc43)c(C)c2C1=O
Yield: 52.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 6-methoxy-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 15 (31 mg, yield 52.7%) as a red solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[I:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[I:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:24]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(I)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.70 g, 2.71 mmol), 2-iodo-5-methylbenzoic acid (0.64 g, 2.71 mmol), DIPEA (1.41 mL, 8.13 mmol) and HATU (1.24 g, 3.25 mmol) in DMF (4 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 503 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:22]([OH:25])[OH:23])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
First, 5.5 g (20 mmol) of 2-(4-bromophenyl)benzoxazole was put into a 300 mL three-neck flask and the atmosphere in the flask was substituted by nitrogen. 120 mL of THF was added and cooled to −78° C. under a nitrogen stream. After cooling, 13 mL (22 mmol) of 1.6 M n-butyllithium was dripped to this solution, and the mixture was stirred at the same temperature for 2 hours. After a certain time, 4.4 mL (40 mmol) of trimethyl borate was added to this solution, and the temperature of the solution was raised to room temperature, and then, the solution was stirred for 16 hours. After a certain time, 100 mL of 1M hydrochloric acid was added and stirred for 1 hour. An aqueous layer of the obtained mixture was extracted with ethyl acetate. The obtained extract was washed with a saturated saline together with the organic layer and then dried over magnesium sulfate. The obtained mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was recrystallized with ethyl acetate/hexane, so that 3.3 g of target white powder was obtained with a yield of 69%.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(#N)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Reactant: Brc1ncccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ncccn2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per Method K′ above), DIEA (0.75 mL) and 2-bromopyrimidine (204 mg) (Aldrich) in acetonitrile (5 mL) were heated under reflux overnight. The solvent was removed under reduced pressure and the black liquid was subjected to a column chromatography, eluted with 1:1 EtOAc/hexanes, to give pure N-t-butoxycarbonyloxy 2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamine as a pale yellow oil. 1H NMR (CDCl3) δ=8.21 (d, J=5.1 Hz, 2H), 6.36 (t, J=5.1 Hz, 1H), 4.64 (d, J=13.8 Hz, 2H), 3.14–3.07 (m, 2H), 2.76 (dt, J=2.7, 13.2 Hz, 1H), 1.69 (d, J=13.8 Hz, 1H), 1.57–1.30 (m, 11H), 1.20–1.03 (m, 3H);
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:17]([CH2:18][CH2:19][C@:3]23[CH3:4])[C@@H:16]2[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[O:37])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 17β-hydroxyestr-4-en-3-one (5.48 g) and 3-(4-hexyloxyphenyl)propionic acid (5.75 g) in dry pyridine (60 ml) pTSA (0.200 g) and DCC (5.77 g) are added. After 72 h stirring at room temperature acetic acid (2 ml) is added, and the reaction mixture is kept overnight at +4° C. The same work-up procedure as in Example 1 gives 17β-[3-(4-hexyloxyphenyl)-propanoyloxy]estr-4-en-3-one (m. p. 52°-53° C.) in a 87% yield after recrystallization from methanol/water.
Reaction SMILES: OO.[CH3:3][NH:4][C:5]([NH:7][NH:8][C:9](=[S:28])[NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=S>C(O)C>[CH3:3][NH:4][C:5]1[S:28][C:9]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:16]=2)=[N:8][N:7]=1
Reactant: CNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Agent: OO
Solvent: CCO
Product: CNc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
2 ml of 30% Hydrogen peroxide are added to 1.58 g (4 mmol) of N-methyl-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarbothioamide in 30 ml of ethanol and the reaction mixture is briefly heated to boiling. The sulphur which separates is filtered off hot with the aid of active charcoal and the filtrate is concentrated by evaporation and purified by preparative layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=1)=[O:44]
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 53.2 %

Procedure:
To a suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (800 mg, 1.84 mmol) in methylenechloride (30 ml) cooled to 0 C was added DIEA (300 mg, 2.32 mmol) followed by chloroacetyl chloride (300 mg, 2.65 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 500 mg (53%) of 2-chloro-N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetamide an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([O:9][CH2:10][CH3:11])OCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:9][CH2:10][CH3:11])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:12]=1[NH2:13])=[O:14]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(OCC)=C(C#N)C(=O)OC
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)OC
Yield: 26 %

Procedure:
The crude product obtained in Step A (4.76 g, containing approximately 1.9 g, 9.6 mmol of 2-cyano-3,3-diethoxy-acrylic acid methyl ester) was combined with 2,4,6-trichlorophenylhydrazine (2.02 g, 9.6 mmol) in ethanol (15 ml). The resulting mixture was refluxed for 18 hours. The solvent was removed in vacuo, and the residue was extracted with methylene chloride/water (100 ml of each) with the pH adjusted to 10 with sodium carbonate. The separated aqueous extract was washed with two 50 ml portions of methylene chloride. The three combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (5.98 g). The purity of this crude title compound was significantly improved by flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=15:85 in volume), yielding 910 mg of the title compound as an orange oil. TLC Rf (silica gel plates, u.v. detection; ethyl acetate hexane=15.85 in volume): 0.26. The product was used in the next step without further purification.