Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:33])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:5]([NH:8][C:9](=[N:21]O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:33])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:5]2[N:6]([N:21]=[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:8]=2)[CH:7]=1
Reactant: Cc1c(Br)cnc(NC(Cc2ccc(S(C)(=O)=O)cc2)=NO)c1-c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(Br)cn2nc(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 102.9 %

Procedure:
A suspension of N-[5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-N′-hydroxy-2-(4-methanesulfonyl-phenyl)-acetamidine (Int. 12, 165 mg, 0.304 mmol) in toluene (6 mL) and pyridine (98 μL, 1.218 mmol) was cooled to 0° C. and p-toluenesulfonyl chloride (232 mg, 1.218 mmol) was added. The reaction mixture was stirred at 0° C. for 25 mins then at RT for 6 days. Sodium hydrogen carbonate (saturated solution, 30 mL) was added and the mixture was extracted with DCM (2×30 mL). The organic phase was concentrated and the resultant residue purified by flash chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as a yellow solid (164 mg).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Na].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:17]
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Reactant: CCO
Agent: [Na]
Product: CCOc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 7-chloro-8-nitroquinoline (3.00 g, 14.4 mmol), sodium (2.65 g) and absolute ethanol (100 mL) was refluxed for 4.5 hr and cooled. The tan precipitate was filtered off, slurried with water and dried to give title compound as tan solid (2.72 g, 87%); mp 161°-164°. Anal. Calcd for C11H10N2O3 : C, 60.55; H, 4.62; N, 12.84. Found: C, 60.34; H, 4.68; N, 12.78.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[CH:33][CH:34]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc(-n2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-n2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde (50 mg) in methanol (2 mL) was added sodium borohydride (2 mg) under ice-cooling, and the mixture was stirred for 30 min. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (tetrahydrofuran/ethyl acetate=1/1) to give the title compound (20 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH-].[K+].[OH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCN1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(OCCN2CCCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromopyridine ( 15.0 g, 63.3 mmol), powdered KOH (6.39 g, 114 mmol), 1-(2-hydroxyethyl)pyrrolidine (14.58 g, 126.6 mmol), and 18-crown-6 (300 mg, 1.14 mmol) in dry toluene (100 mL) was heated to 70° C. for 1 h. The solution was cooled to room temperature and water and EtOAc were added. The organic layer was washed with water and brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo. Short path distillation (153° C. @0.1 mmHg) provided the title compound as a colorless oil which solidified upon cooling (14.9 g, 87%). 1H NMR (250 MHz, CDCl3): δ 8.15 (d, J=2.4 Hz, 1H), 7.65 (dd, J=2.4, 8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.38 (t, J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.62 (m, 4H), 1.82 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[N+:9]([O-])([OH:11])=[O:10]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1F
Reactant: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])ccc1F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
30 g of 2-fluoro-toluene were added at -15° C. over two hours to 33 ml of nitric acid and the mixture was stirred at -15° C. for one hour and was then allowed to rise to 20° C. The reaction mixture was poured into ice and was extracted with ether. The organic phase was washed with water, dried and evaporated to dryness. The residue was rectified to obtain 34.4 g of 2-fluoro-5-nitro-toluene with a boiling point of 100°-101° C. at 10 to 11 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=O)[CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:11]=2[CH:10]=1)([CH3:5])[CH3:4].S(Cl)(Cl)=O>C(Cl)Cl>[O:18]=[C:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[CH2:14][O:13][C:12]2[CH:23]=[CH:24][C:9]([CH2:8][C:7]3[O:1][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]=3)=[CH:10][C:11]1=2
Reactant: CC(C)(CO)NC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(Cc2ccc3c(c2)C(=O)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A stirred, ice water cooled mixture of 10.25 g (0.0302 mol) of 6,11-dihydro-N-(1-hydroxy-2-methyl-2-propyl)-11-oxodibenz[b,e]oxepin-2-yl acetamide of Example 2, and 100 ml of sieve dried CH2Cl2 was treated dropwise over a few minutes with 3.95 g (0.0332 mol) of thionyl chloride. The solution was then stirred 15 minutes with cooling and overnight (about 16 hours) at ambient temperature. The solution was washed with 10% sodium hydroxide solution, dried (Na2SO4) and concentrated to an oil which was dried by azeotropic distillation of toluene. On standing overnight at 5° C. the oil crystallized. Recrystallization from 12 ml of isopropanol afforded 6.10 g (62.9%) of crystals of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)methyl-4,4-dimethyloxazoline, m.p. 101°-103.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]1([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]([C:27]([CH3:34])=[CH:28][C:29](OCC)=[O:30])=[CH:20]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].Cl>O1CCCC1.C(OCC)C>[C:11]1([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]([C:27]([CH3:34])=[CH:28][CH2:29][OH:30])=[CH:20]3)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=C(C)C1=Cc2cc(-c3ccccc3)ccc2OC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=CCO)C1=Cc2cc(-c3ccccc3)ccc2OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3.47 g (98 mmol) of lithium aluminium hydride are added to a solution, which is kept at 0° C. and under argon, of 4.95 g (37 mmol) of sublimed anhydrous aluminium chloride and 50 ml of diethyl ether. The resulting complex is stirred at 0° C. for 20 minutes, and then a solution of 11.9 g (37.1 mmol) of the ester obtained in Step D in 130 ml of a mixture of diethyl ether and tetrahydrofuran (10:3) is added rapidly. The whole is kept at 0° C. for 45 minutes. The excess hydride is decomposed by the addition, in succession, of 10 ml of 0.4N hydrochloric acid, 10 ml of 1N hydrochloric acid and 20 ml of 4N hydrochloric acid. After dilution with 100 ml of water, the reaction mixture is extracted with diethyl ether (from 500 to 2000 ml). The ethereal phases are treated in the customary manner, yielding a pale yellow liquid which is used directly in the following step without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 5-fluoro-3-methyl-2-nitrobenzoic acid (8.0 g, 40 mmol) from Step A above in DMF (100 mL) was added cesium carbonate (20.0 g, 60 mmol) followed by iodomethane (3.0 ml, 48 mmol). The reaction solution was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford methyl 5-fluoro-3-methyl-2-nitrobenzoate (8.4 g, 98%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.71-7.67 (m, 2H), 3.85 (s, 3H), 2.32 (s, 3H); MS (ESI+) m/z 214 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:8][N:9]=[C:10]2[CH2:15]1)=[O:27]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: c1cc(-c2nnc3n2CCNC3)ccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-(4-Pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.745 mmol, e.g. prepared as described below) was treated with N,N-dimethylformamide (DMF) (3 mL) and cooled to 0° C. Triethylamine (0.109 mL, 0.783 mmol) and N,N-dimethyl-4-pyridinamine (DMAP) (0.009 g, 0.075 mmol) were added at 0° C. under argon and the mixture was stirred for 5 minutes; then 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.199 g, 0.820 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added. The reaction mixture was kept at 0° C. for ½ hour. The reaction was quenched with water, extracted with ethyl acetate (two extractions), and the combined organic phases were washed with a saturated sodium bicarbonate solution, followed by water (four washes). The organic phase was dried, and evaporated to give a yellow oil. The residue was purified by silica gel chromatography using 0-20% of methanol in Dichloromethane as the eluent and then triturated with diethyl ether to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine as a white solid. The solid was dried at 50° C. on the high vacuum for 1 day.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:21][CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC1CC1
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: O=C(NC1CC1)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 25 %

Procedure:
The tile compound was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (372 mg, 1.37 mmol) and cyclopropylamine using General Procedure G and was isolated in 25% yield as a white solid. HPLC Rt=10.6 min; 1H NMR (400 mHz, CDCl3) 7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.43 Hz, 1H), 7.23-7.21 (m, 1H), 5.49 (bs, 1H), 2.62-2.59 (m, 1H), 2.25-2.20 (m, 2H), 1.84-1.78 (m, 2H), 1.59-1.55 (m, 5H), 1.38-1.33 (m, 1H), 0.73-0.68 (m, 2H), 0.37-0.33 (m, 2H); 13C NMR (100 mHz, CDCl3) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6, 126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC-MS (SCOUT) 13.5 min, M+ 311.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Yield: 72.3 %

Procedure:
To a suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (50 mg; 0.21 mmol) in methylene chloride (2 mL) was added a catalytic (0.005 mL) amount of DMF followed by oxalyl chloride (0.23 mmol; 2M solution in methylene chloride). The mixture was stirred in a sealed vial until effervescence ceased (approximately 30 minutes), with occasional venting to release gas. 1-Benzyl-1H-indazol-4-amine (Example 155, Steps A-B; 47 mg; 0.21 mmol) was added as a solution in methylene chloride (1 mL) followed by diisopropylethylamine (33 mg; 0.25 mmol). The mixture was stirred for 16 hours at ambient temperature, during which time a suspension formed. The mixture was partitioned between water and methylene chloride and the suspension was extracted multiple times with methylene chloride. The combined organic phases (which contained suspended solids) were concentrated under reduced pressure. The resulting solid material was triturated with ether and collected by filtration. The solids were washed with ether, water and then ether again. The material was dried under vacuum to give an off white solid (67 mg). MS (APCI), m/z=442.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[N:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:20](Cl)=[O:21])[C@@H:8]([CH3:23])[CH2:7]1)[CH3:2].[F:32][C:33]([F:37])([F:36])[CH2:34][OH:35].[H-].[Na+]>O1CCOCC1>[F:32][C:33]([F:37])([F:36])[CH2:34][O:35][C:20]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:6]([N:5]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:31])[CH2:7][C@@H:8]1[CH3:23])=[O:21]
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)Cl)c2cc(OC)c(OC)cc21
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCC(F)(F)F)c2cc(OC)c(OC)cc21
Yield: 156 %

Procedure:
A solution of benzyl-(1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 107A) (24 mg, 0.054 mmol), 2,2,2-trifluoroethanol (0.10 mL, 1.4 mmol), and sodium hydride (56 mg, 60% dispersion in mineral oil, 1.4 mmol) in anhydrous dioxane (1 mL) was stirred at room temperature overnight. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with 10 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 43 mg of an oil. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the desired final product (15 mg, 58%): MS m/z 510 (M+), 528 (M+ +18); 1H NMR (CDCl3) δ 6.99 (C8, s, 1H), 6.44 (C5, s, 1H).
Reaction SMILES: [CH2:1]=O.[CH:3]1([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]3[C@H:13]4[C@H:23]([CH2:24][CH2:25][C@:8]23[CH3:9])[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]2)=[CH:15][CH2:14]4)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)=O>[CH3:1][N:6]([CH:3]1[CH2:4][CH2:5]1)[C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CC1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a mixture of 10 ml of formic acid and 5 ml of formaldehyde was added 1.4 g of 17β-(cyclopropylamino)androst-5-en-3β-ol. The mixture was heated at reflux for 5 hours, the volume was then reduced to 7.5 ml in vacuo, and 10 ml of 50% (w/w) aqueous sodium hydroxide was added. The aqueous layer was separated and extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate The solvent was then removed in vacuo and the product was purified by flash chromatography to give 17β-[N-methyl(cyclopropylamino)]androst-5-en-3β-ol.
Reaction SMILES: O=[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:3]([O:5]CC1C=CC=CC=1)=[O:4].S1CCCSC1C(OCC1C=CC=CC=1)=O.C1(=O)N(CCCCCBr)C(=O)C2=CC=CC=C12.BrN1C(=O)CCC1=O.[NH2:70][C@H:71]([C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])[CH3:72].[BH3-]C#N.[Na+].C(OC(C(N[C@H](C(N1CCC[C@H]1C(O)=O)=O)C)CCCCCN1C(=O)C2=CC=CC=C2C1=O)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:3]([CH:2]([NH:70][C@H:71]([C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])[CH3:72])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])([OH:5])=[O:4]
Reactant: O=C(CCCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: C[C@H](NC(CCCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(OCc1ccccc1)C1SCCCS1
Solvent: CCO
Product: C[C@H](NC(CCCCCN1C(=O)c2ccccc2C1=O)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Benzyl 2-oxo-7-phthalimidoheptanoate (prepared by alkylation of benzyl 1,3-dithiane-2-carboxylate with 5-phthalimidopentyl bromide and subsequent oxidative conversion to the ketone with N-bromosuccinimide) is condensed with L-alanyl-L-proline in the presence of excess NaBH3CN. The condensation product, N-(1-benzyloxycarbonyl-6-phthalimidohexyl)-L-alanyl-L-proline, (390 mg.) in 25 ml of 50% aqueous ethanol is hydrogenated at 40 psi over 10% palladium on charcoal. Removal of solvent and catalyst yields N-(1-carboxy-6-phthalimidohexyl)-L-alanyl-L-proline (320 mg) having the expected spectral and chromatographic properties. A portion of the above intermediate (152 mg) in 2 ml of ethanol is refluxed with hydrazine (32 mg) for 1.5 hours. The phthalhydrazide is removed by filtration; the ethanol is removed under vacuum and the residue is absorbed on strong acid ion-exchange resin. Elution with 2% aqueous pyridine and freeze-drying gives the desired N-(1-carboxy-6-aminohexyl)-L-alanyl-L-proline (58 mg.). The spectral data are consistent with structure. The mass spectrum shows a peak at 311 for the molecular ion minus water (329-18).
Reaction SMILES: C(O[C@H](C)[C@H](NC(C1(CC2C=CC=CC=2)CCCN1)=O)C(OC)=O)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([O:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([OH:50])=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=S(Cl)[Cl:53]>C(Cl)Cl.O>[Cl:53][C:48]([C@@H:44]1[CH2:45][CH2:46][CH2:47][N:43]1[C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])=[O:50]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1)[C@@H](C)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a stirred solution of compound 6 (1 g, 2.76 mmol) and Na2CO3 (732 mg, 6.90 mmol) in CH2Cl2:H2O (20 mL, 1:1) was added a solution of acid chloride [To a solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (825 mg, 3.31 mmol) in CH2Cl2 (20 mL) was added SOCl2 (0.60 mL) drop wise at 0° C. and was refluxed for 2 h. The volatiles were removed under reduced pressure to yield (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate] in CH2Cl2 and the reaction mixture was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure. The residue was diluted with CH2Cl2 (100 mL), filtered and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography using 60% EtOAc/Hexane as eluent to afford compound 7 (750 mg, 45%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[C:40]([O-])(=[O:42])[CH3:41].[Na+].O>CN(C=O)C>[C:40]([O:11][CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])(=[O:42])[CH3:41]
Reactant: CC(=O)[O-]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) in 1 mL of DMF, was added sodium acetate (36 mg, 0.44 mmol). The solution was warmed to 80° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.19 (s, 1H), 7.11 (s, 4H), 5.12 (d, J=13.0 Hz, 1H), 5.08 (d, J=13.0 Hz, 1H), 4.32 (dd, J=11.6, 2.0 Hz, 1H), 4.17-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.77-3.68 (m, 2H), 3.43 (dd, J=9.8, 8.6 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.99 (s, 3H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 485 (M+Na)+, calc. 462.
Reaction SMILES: [Cl:1][C:2]([Cl:16])(Cl)[C:3]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[Sb](F)(F)(F)(F)[F:24].Cl>ClCCl>[F:24][C:2]([Cl:16])([Cl:1])[C:3]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: F[Sb](F)(F)(F)F
Reactant: Cc1cccc2c(Cl)cc(C(Cl)(Cl)Cl)nc12
Agent: Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc2c(Cl)cc(C(F)(Cl)Cl)nc12
Reaction time: 4 h

Procedure:
3.0 g of 2-trichloromethyl-8-methyl-4-chloro-quinoline are dissolved in 45 ml of dry dichloromethane and under intense stirring 1.5 ml of antimony-penta-chloride and 1.0 ml of antimony-penta-fluoride are added by dropping at a temperature of -5° to 0° C. The mixture is stirred at this temperature for 4 hours and allowed to stand at room temperature for 48 hours. 6 ml of icy concentrated hydrochloric acid are added, the precipitate is filtered, washed with some dichloromethane, the filtrate is separated, dried, filtered and evaporated. 2.1 g solid product are obtained which is recrystallized from heptane: 1.9 g of a yellowish crystalline substance, 68.2%, m.p.: 90°-94° C.