Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21](CC)[CH2:22][CH3:23])[CH3:20].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:20]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCc1nnnn1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
5-(1-Phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (2.5 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at room temperature, and the mixture is stirred for 2 hours. After distilling off dimethylformamide under reduced pressure, acetone is added to the resulting residue, and the insoluble materials are filtered off. The mother liquor is concentrated and then purified by column chromatography (Kieselgel 60, made by Merck & Co.). By eluting with chloroform, there is obtained N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (1.2 g), colorless liquid, nD25 =1.5303.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH3:17].S(=O)(=O)(O)O>C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)CCCCOCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCOCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 61.1 g of 5-benzyloxypentanoic acid, 566 ml of ethanol and 10 ml of concentrated sulfuric acid is refluxed for 15 h. The mixture is cooled to room temperature, 10 ml of triethylamine are added and evaporated. The residue is diluted with 250 ml of ether and the solution is washed in water and brine dried (MgSO4) and evaporated. The residual oil is distilled to give ethyl 5-benzyloxypentanoate, b.p. 110°-113° C. (0.7 mm/Hg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:17]([NH:20][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a stirred solution of 1.06 g (5.0 mmol, 1 eq.) of 4-phenylaminobenzoic acid, prepared by the method of Portnaya, et al., Zhur. Obshchei. Khim., 30: 2693 (1960), n-propylamine (0.82 mL, 10.0 mmol, 2 eq.) and 0.061 g (0.5 mmol, 0.1 eq.) of DMAP in THF at 0° C. was added 1.05 g (5.5 mmol, 1.1 eq.) of EDCl. The mixture was stirred overnight while the bath melted. The mixture was poured into 150 mL of ethyl acetate and extracted with 50 mL each of water, 1N aqueous HCl, water, and saturated aqueous NaHCO3 solution. The ethyl acetate layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on SiO2 eluting with 1:1 ethyl acetate-hexanes to give 0.51 g (40%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 10.57 (bs, 2H), 7.21-7.41 (m, 9H), 3.96 (s, 2H), 2.75 (m, 2H), 1.64 (hextet, 2H), 0.92 (t, 3H). MS (DCl) m/e 255 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,4-difluorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 37.3 mg (74.8%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.52 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.08 (t, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.92 (m, 1H), 8.12 (d, J=5 Hz, 1H), 9.60 (s, 1H); MS (ESI/APCI+) m/e 333 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1
Yield: 111.3 %

Procedure:
N-benzyloxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (10 g) and 3,4-dihydoxyphenethylamine hydrochloride (4.2 g) were added to a mixture of n-butyl alcohol (100 ml) and water (14 ml) and then the mixture was refluxed for 4 hours. The above-mentioned acetal (1 g) was added to the mixture and the resultant mixture was refluxed for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ethyl acetate and collected by filtration. The crystals were recrystallized from a mixture of methanol and ether to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.0 g), mp 210° to 212° C. (dec).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25]C)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O1CCCC1.[OH-].[Na+].Cl>O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([OH:25])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate (1.0 g, 2.66 mmol) was added to tetrahydrofuran (20 mL). Aqueous sodium hydroxide (2.5 N, 2.7 mL) and water (2.5 mL) were added, and the suspension was heated to reflux and held for 16 hours. The solids all dissolved during this time. The reaction was cooled to room temperature, and hydrochloric acid solution (1 N, 11 mL) was added. The aqueous suspension was extracted with methylene chloride (2×20 mL). The combined organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 30 mL of dichloromethane yielded, upon filtration and drying, 0.90 g (94%) of 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid as a white solid: mp 126–128° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]=[C:10](Cl)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[CH2:20][CH:19]([C:18]([O:22][CH3:23])=[O:21])[O:8][N:9]=2)[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
) A solution of N,N-diethylethanamine (0.544 mol) in ethanol (600 ml) was added dropwise to a stirred suspension of N-hydroxy-3-pyridinecarboximidoyl chloride (0.259 mol) and methyl 2-propenoate (1.295 mol) in ethanol (1500 ml) over a period of 1 hour. The reaction mixture was stirred for 1 hour at RT. The reaction mixture was evaporated. The residue was mixed with diethyl ether and filtered. The organic layer was separated, washed three times with water, separated again, dried (MgSO4), filtered and left overnight. Partial crystallization occurred on overnight standing. The crystals were filtered and dried and the filtrate was evaporated, yielding 52.6 g (98%) of (±)-methyl 4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxylate (interm. 1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1([O:33][C:34]([NH:36][OH:37])=O)C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:33]
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 33.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (150.0 mg, 0.428 mmol) in THF (5 mL) was added hydroxylamine carboxylic acid phenyl ester (75 mg, 0.449 mmol) and stirred for 17.5 h at reflux. The mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (89:10:1) followed by purification by radial chromatography using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 369 (59 mg, 34%) as white solid. 1H NMR (CDCl3) δ1.54-1.72 (m, 3H), 1.81-2.05 (m, 5H), 2.23 (s, 3H), 2.37 (s, 3H), 2.53-2.79 (m, 5H), 3.85-4.07 (m, 5H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.25 (d, 1H, J=4.2 Hz), 8.10 (s, 1H), 8.40 (d, 1H, J=3.7 Hz); 13C NMR (CDCl3) δ 17.90, 18.58, 21.71, 29.04, 29.37, 30.08, 31.25, 43.84, 53.30, 57.64, 60.19, 121.29, 131.51, 133.03, 134.11, 136.25, 138.92, 145.97, 146.88, 158.41, 160.63; ES-MS m/z 410 (M+H). Anal Calcd. For C23H31N5O200.1(H2O)90.3CH2Cl2): C, 64.07; H, 7.34; N, 16.03. Found: C, 64.13; H, 7.44; N, 15.69.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([F:38])=[CH:33][N:32]=1>CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@@:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[C:34]([F:38])=[CH:33][N:32]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84 mL, 62.25 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[NH:19][C:11]2[NH:12][C:13]([S:17][CH3:18])=[N:14][C:15](=O)[C:10]=2[CH:9]=1)[CH3:7].CN(C)C1C=CC=CC=1>>[CH3:18][S:17][C:13]1[NH:12][C:11]2=[N:19][C:8]([CH2:6][CH3:7])=[CH:9][C:10]2=[C:15]([Cl:3])[N:14]=1
Reactant: CCc1cc2c(=O)nc(SC)[nH]c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Phosphorous oxychloride (21 mL) was carefully added to a mixture of 5.66 g (27.0 mmol) of 1,7-dihydro-6-ethyl-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-4-one and 1.70 mL of N,N-dimethylaniline. The reaction was heated to 95° C. for 12 hours. At this time the reaction was cooled and concentrated under vacuum. The residue was combined with 60 g of ice and stirred for 1 hour. The solids were collected by filtration, washed with 30 mL of water and suspended in 100 mL of water. The solids were again collected, washed with 30 mL of water, and dried in vacuo (40° C., 10 torr) to provide 5.50 g (89.6%) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as a yellow solid. nmr (500 MHz, dmso-d6) δ1.24 (t, J=7.5 Hz, 3H), 2.52 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 6.21 (s, 1H), 12.27 (s, 1H)
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][C@@:13]12[C@@:21]([OH:26])([C:22]([CH2:24][OH:25])=[O:23])[C@H:20]([OH:27])[CH2:19][C@H:18]1[C@@H:17]1[CH2:28][CH2:29][C:30]3[C@@:36]([CH3:37])([C@H:16]1[C@@H:15]([OH:38])[CH2:14]2)[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3.C(=O)CCC>C(#N)C>[CH3:6][CH2:1][CH2:2][CH:3]1[O:26][C@:21]2([C:22]([CH2:24][OH:25])=[O:23])[C@@H:20]([CH2:19][C@@H:18]3[C@:13]2([CH3:12])[CH2:14][C@H:15]([OH:38])[C@H:16]2[C@H:17]3[CH2:28][CH2:29][C:30]3[C@:36]2([CH3:37])[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3)[O:27]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Solvent: CCCC=O
Solvent: CC#N
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
The reaction is carried out in a nitrogen atmosphere. 15,4 g p-toluenesulphonic acid is dissolved into 200 ml acetonitrile. To the solution 50,0 g 16α-hydroxyprednisolone and 17.6 ml butanal are added. The temperature rises to 25° C. After 30 min most of the material is dissolved. Shortly thereafter the product starts to crystallize. After 3 hours the reaction is stopped by the addition of 75 ml aqueous saturated sodium hydrogen carbonate solution, whereupon the product crystallizes. The dried product is dissolved in methylene chloride and methanol and is crystallized by the addition of ligroine (b.p. 40-65) giving crude budesonide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH-].[Na+].[Na+].[Cl-].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:19][CH2:18]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 105 °C

Procedure:
To a 4-dram vial was added 5-Chloro-2-nitroaniline (0.5 g, 2.90 mmol, 1 equiv.), NaOH (0.229 g, 5.71 mmol, 1.98 equiv.), 4′M NaCl (0.82 mL, aq.), and 1-methylpiperazine (0.643 g, 0.71 mL, 5.79 mmol, 2 equiv.). The mixture was heated on a hot plate to 105° C. for 22 h. De-ionized H2O (6 mL) was added to the mixture, which was cooled to room temperature, and the precipitate collected on a Buchner funnel. The precipitate was then washed with de-ionized H2O (5 mL) and heptane (5 mL). After drying in a vacuum oven (80° C., 30 in. Hg) overnight, the product (0.624 g, 91.1%) was collected. According to HPLC analysis, the sample had a purity of 99.6%.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH3:13])=[CH:7][C:6]=1[CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH:12]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:13])=[CH:7][C:6]=1[CH3:15]
Reactant: CC(=O)c1cc(C)c(OCC(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(C)c1OCC(F)F
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (0.89 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3,5-dimethylphenyl)ethanone (0.68 g, 2.98 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>CO>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][CH2:2][N:13]1[CH2:14][CH2:15][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12]1)[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)CCCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
3-Chloro-N,N-diethylpropan-1-amine (1.6 g) is added to a mixture of tert-butyl piperazine-1-carboxylate (2.0 g) and NEt3 (1.5 ml) in methanol (30 ml). The mixture is stirred for 6 hours at 70° C. and cooled to room temperature. The solvent is removed under reduced pressure. Satd. aqueous NaHCO3 is added to the crude product and the aqueous layer is extracted with EtOAc (3×). The combined organic layers are dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give tert-butyl 4-(3-(diethylamino)propyl)piperazine-1-carboxylate (2.48 g). m/z(+) 300 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]2[N:9]=[C:10]3[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:29][CH2:28]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (crude from previous reaction) in dichloroethane (6 mL) was added 2,3-dichlorophenylpiperazine hydrochloride (321 mg, 1.20 mmol) followed by Et3N (0.34 mL, 2.40 mmol, 2 equiv). The resulting suspension was stirred for 5 min and NaBH(OAc)3 (356 mg, 1.68 mmol, 1.4 equiv) was added as a powder. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and H2O and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4–5% MeOH/CH2Cl2) gave the title compound as a white foam (378 mg, 0.845 mmol, 70% over 2 steps). The foam was dissolved in Et2O/CH2Cl2 and 1 N HCl in Et2O (0.82 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (355 mg). MS: APCI: M+1: 447.1 (Exact Mass: 446.13).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]=1[N+:21]([O-:23])=[O:22].S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[CH3:28][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([CH3:3])=[C:5]([N+:21]([O-:23])=[O:22])[CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.14 g (3.50 mmol)) in DMF (3.0 ml), 4′-methyl-3′-nitro-p-toluenesulfonanilide (1.00 g (3.26 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.34 ml (3.56 mmol)) was added dropwise. After one hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid separated was filtered and washed to give 0.79 g (76%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.CN(C)[CH:16]=[S:17].C(O)C>C1(C)C(C)=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:17][CH:16]=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)C=S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20.26 g of N,N-dimethylthioformamide is heated to 60° C. for 3 hours. The resulting solid is suspended in 25 mL of xylene and the mixture is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and 15 mL of ethanol are added. The resulting suspension is filtered, and the brown solid is washed with a minimum amount of ethanol. The solid is dissolved in 120 mL of ethanol, heated to boiling, and filtered hot to remove trace solids. After reduction of the volume to about 100 mL, the solution is allowed to stand overnight at room temperature. The resulting solid is filtered and washed with ethanol to provide 4.68 g of 5-nitrobenzothiazole as reddish-brown needles.