Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12]CC)=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.O.[OH-].[Li+]>>[O:1]=[C:2]1[C:6]2[NH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)C(=O)CC2

Procedure:
The title compound was synthesized from ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (90 mg, 0.47 mmol) and lithium hydroxide monohydrate (78 mg, 1.86 mmol) according to General Procedure 7 (56 mg, 77%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.84-2.91 (4H), 6.73 (s, 1H); LCMS-MS (ESI+) 165.8 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:31])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:14][O:15][C:16]=2[CH:17]([OH:26])C(O)C2C=CC=CC=2)[CH:9]=1)=[O:4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:31])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:14][O:15][C:16]=2[CH:17]=[O:26])[CH:9]=1)=[O:4]
Reactant: CCCCc1noc(C(O)C(O)c2ccccc2)c1COc1cc(C(=O)OC)n(C)n1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CCCCc1noc(C=O)c1COc1cc(C(=O)OC)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-[3-butyl-5-(1,2-dihydroxy-2-phenyl-ethyl)-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (440 mg, 1.03 mmol) in benzene (2 mL) was added lead tetraacetate (545 mg, 1.23 mmol) with benzene (2 mL) and the reaction was stirred at room temperature for 1 h and then lead tetraacetate (136 mg, 0.3 mmol) and benzene (1.5 mL) added. After 30 min, the suspension was filtered over Celite® and the filtrate was concentrated to give crude 5-(3-butyl-5-formyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a yellow oil (330 mg). The oil was taken up in methanol (12 mL) and sodium borohydride (97 mg, 2.57 mmol) was added in portions over 3 min. Upon addition, the reaction became a clear light yellow solution containing a black precipitate. After stirring at room temperature for 15 min, the mixture was filtered over Celite® and the filter cake was washed with methanol. The filtrate was concentrated and the residue was portioned between 0.5M aqueous hydrochloric acid and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford a yellow oil. The crude material was purified by chromatography (silica, heptane:ethyl acetate 1:0 to 1:1) to afford the title compound (256 mg, 77%) as a colorless oil. MS: m/e=322.2 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[S:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[OH:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.C(O)C>[Cl:25][C:20]1[C:19]([OH:26])=[C:18]([S:15]([N:14]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]([OH:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)(=[O:17])=[O:16])[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(C(O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of N-(4-benzoylbenzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (15 mg, 0.028 mmol) in THF (0.15 mL) and ethanol (0.15 mL) at 0° C. was added sodium borohydride (4 mg, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h. The solvents were removed in vacuo and resulting residue was purified by preparative HPLC to give the title compound (14 mg) as a white solid. MS (ESI): 527.9 (M−H2O)+.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[N+:16]([O-])=O.C.NN>C(O)C>[NH2:16][C:11]1[C:12]2[C:7](=[C:6]([O:5][CH3:4])[CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2c([N+](=O)[O-])cccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cccc2c(N)cccc12
Temperature: 50 °C

Procedure:
Hydrazine hydrate (150 ml) is added slowly to a stirred mixture of 5-methoxy-1-nitro-naphthalene (320 g), and palladized charcoal (0.1 g) in 95% ethanol (2 liters) previously warmed to 50° C. When the hydrazine addition is complete, additional palladized charcoal (0.1 g) is added and the mixture heated to reflux for about one hour. The reaction mixture is filtered through Celite and the filtrate evaporated in vacuo resulting in a white solid which is recrystallized from H2O and ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(O)cc23)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OS(C)(=O)=O)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step E (426 mg, 1.19 mmol) in 5 mL of DMF at 0° C. was added triethylamine (0.532 mL, 3.82 mmol), followed by methanesulfonyl chloride (0.212 mL, 2.73 mmol). The reaction was stirred at room temperature overnight, then partitioned between EtOAc and 50% NaHCO3 solution. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The product was isolated as a yellow gum which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[F:25])[N:9]=1)[CH2:3][C:4]([F:7])([F:6])[F:5].Br[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:35]1[C:27]([NH:1][C@H:2]([C:8]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:25])[N:9]=2)[CH2:3][C:4]([F:6])([F:5])[F:7])=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: N[C@@H](CC(F)(F)F)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2c(F)cccc2nc([C@H](CC(F)(F)F)Nc2ncnc3[nH]cnc23)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 21.3 %

Procedure:
Under nitrogen, to (S)-2-(1-amino-3,3,3-trifluoropropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (5) (35 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. was added 6-bromo-9H-purine (6) (30 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 3 days at 80° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 10 mg of compound 2A as a colorless solid (21%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].O=C1[C@@H](N2C(=O)CCN(C3C=CC=C(C(F)(F)F)C=3)CC2)CCO1>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=[O:7]
Reactant: COC(=O)[C@H](CCO)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: O=C1OCC[C@@H]1N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Product: COC(=O)[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 97 %

Procedure:
In analogy to the procedure described in example 1I, (S)-4-hydroxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester gave a mixture of 4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (ca 5-10%) and the title compound in 97% yield as orange oil. MS: 373.1 (MH+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][N:7]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:5].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([N:29]=[N+:30]=[N-:31])[CH2:8][N:7]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester) (28) (2.6 g, 6.3 mmol) in dry DMF (15 ml) was added NaN3 (0.41 g, 6.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic layer was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness The resulting residue was purified by column chromatography using pet ether: CH2Cl2: MeOH (10:1) to give 1.8 g of desired product.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:44][CH:43]7[CH:38]([CH2:39][CH2:40][CH2:41][CH2:42]7)[N:37]6C(OC(C)(C)C)=O)[NH:34][CH:35]=5)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[N:18]=2)[CH:12]2[CH2:52][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.O>CO>[CH:9]12[CH2:52][CH:12]([CH2:11][CH2:10]1)[C@@H:13]([C:14]1[NH:15][CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:44][CH:43]7[CH:38]([CH2:39][CH2:40][CH2:41][CH2:42]7)[NH:37]6)[NH:34][CH:35]=5)=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[N:18]=1)[NH:8]2
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6CCCCC6N5C(=O)OC(C)(C)C)n4)cc3)cc2)c[nH]1
Solvent: O
Solvent: CO
Product: c1cc(-c2c[nH]c([C@@H]3CC4CCCCC4N3)n2)ccc1-c1ccc(-c2c[nH]c([C@H]3NC4CCC3C4)n2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Compound 8 were taken in 9 ml methanol; 1 ml Conc. HCL and 0.2 ml water was added. Resulting reaction was stirred for 5 h at 50° C. (oil bath temp) completed, after completion of the reaction monitor by HPLC. The resulting slurry was cooled to RT and held with agitation for about 1H. Filtration of the slurry afforded a solid; washed with 15 ml acetone dried directly used in the next reaction.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][OH:11])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([CH:10]=[O:11])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: OCc1cnc2cccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of imidazo[1,2-b]pyridazin-3-ylmethanol (45 mg, 0.3 mmol) and Dess-Martin periodinane (130 mg, 0.3 mmol) in anhydrous DCM (5 mL) were stirred at RT overnight. The reaction mixture was quenched with water (5 mL). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford imidazo[1,2-b]pyridazine-3-carbaldehyde (40 mg, 90.7% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C:28]1([CH3:37])[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:31][CH2:32][O:33][C:28]([CH3:27])([CH3:37])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC1(C)OCCN[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOC(C)(C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (S)-2,2-dimethylmorpholine-3-carboxylic acid (2.44 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (5.8 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [ClH:1].C(OC([CH2:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46]1)=[O:37])=[O:14]
Reactant: CC(C)(C)OC(=O)CNCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
242 μl of 4N HCl in dioxane are added to 300 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 3-(tert-butoxycarbonylmethylamino)propionate in 5 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 2 ml of dichloromethane.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)#[N:2].Cl.Cl.[CH2:14]([NH:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[CH2:14]([N:21]1[C:1]([NH2:2])=[CH:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNCc1ccccc1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(-c2ccccc2)nn1Cc1ccccc1
Yield: 82.3 %

Procedure:
2.9 g of α-cyanoacetophenone and 3.9 g of benzyl hydrazine dihydrochloride were suspended in 50 mL of ethanol. The reaction solution was added with 6.0 ml of triethylamine at room temperature, and heated under reflux for 4 hours. The solvent was evaporated, and the residue was added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:4), to afford 4.1 g of the title compound as a yellow needle powder.
Reaction SMILES: [CH:1]([C:5]1[C:10]([O:11][CH2:12][C:13](O)=[O:14])=[C:9]([Cl:16])[CH:8]=[C:7]([Cl:17])[CH:6]=1)([CH2:3][CH3:4])[CH3:2].S(Cl)([Cl:20])=O>>[CH:1]([C:5]1[C:10]([O:11][CH2:12][C:13]([Cl:20])=[O:14])=[C:9]([Cl:16])[CH:8]=[C:7]([Cl:17])[CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)Cl

Procedure:
A mixture of 5.8 g of the product of Step C and 40 ml of thionyl chloride was refluxed for 2 hours and was evaporated to dryness under reduced pressure. The oil residue was washed with benzene and evaporated to dryness under reduced pressure to obtain 6.2 g of the desired product which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:36])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]=2[O:28]CC2C=CC=CC=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:36])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]=2[OH:28])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(Cc3ccccc3)c2OCc2ccccc2)cc1
Agent: [Pd]
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(Cc3ccccc3)c2O)cc1
Yield: 93.7 %

Procedure:
Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (9.72 g, 0.019 mol) with palladium on carbon (0.97 g, 10 wt. %) generally according to the procedure described for Intermediate 4 provided 7.34 g (92%) of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C23H24O5S: C, 66.97; H, 5.86. Found: C, 66.11; H, 5.95.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][N:16]=[N+]=[N-])[CH:12]=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1S(=O)(=O)NC(C)(C)C
Yield: 74.6 %

Procedure:
16.3 g (50 mmol) of N-tert-butyl-5-azidomethyl-2-methoxycarbonylbenzenesulfonamide are dissolved in 300 ml of methanol and hydrogenated over Pd/C (5%). The mixture is filtered and evaporated to dryness. The crude product obtained is purified by elution through a silica gel column using ethyl acetate/methanol 4:1. 11.2 g (74%) of N-tert-butyl-5-aminomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.   1 ⁢ H ⁢   ⁢ NMR ⁢   ⁢ ( 100 ⁢   ⁢ MHz , CDCl 3 ) ⁢ : ⁢   ⁢ δ =   ⁢ 1.25 ⁢   ⁢ ( s , 9 ⁢ H , C ⁡ ( CH 3 ) 3 ) ,   ⁢ 1.80 ⁢   ⁢ ( bs , 2 ⁢ H , NH 2 ) ,   ⁢ 3.95 ⁢   ⁢ ( s , 3 ⁢ H , OCH 3 ) ,   ⁢ 4.00 ⁢   ⁢ ( s , 2 ⁢ H , Ar ⁢ — ⁢ CH 2 ) ,   ⁢ 6.20 ⁢   ⁢ ( bs , 1 ⁢ H , SO 2 ⁢ NH ) ,   ⁢ 7.58 ⁢   ⁢ ( dd , 1 ⁢ H ; Ar—H ) ,   ⁢ 7.80 ⁢   ⁢ ( d , 1 ⁢ H , Ar—H ) ,   ⁢ 8.10 ⁢   ⁢ ( dd , 1 ⁢ H , Ar ⁢ — ⁢ H ) .
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:19]N1C(=O)CCC1=O>CC(O)C>[Br:19][I:16]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:3]([C:4]([F:7])([F:6])[F:5])([C:2]([F:1])([F:17])[F:18])[O:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1ccc2c(c1)C(C(F)(F)F)(C(F)(F)F)OI2Br
Temperature: 50 °C
Yield: 100 %

Procedure:
Compound 2 (100 mg, 0.26 mmol) was dissolved in 5 mL propan-2-ol and N-bromosuccinimide (48.7 mg, 0.273 mmol) is added. The reaction mixture was heated 30 min at 50° C. After removal of the solvent under vacuum, the residue was purified over silica gel column using dichloromethane as eluant to give 111 mg (0.26 mmol, 92% yield) of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH2:31]([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1)[CH3:32]
Reactant: CCOc1ccccc1CN1CCN(CCCCl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCOc1ccccc1CN1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 64.3 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-ethoxybenzyl)-piperazine; yield 64.3% of theory; m.p. of the dihydrochloride (recrystallized from ethanol) 223°C;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:29][CH2:28][C:23]4([O:24][CH2:25][CH2:26][O:27]4)[CH2:22][CH2:21]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (7.35 g, 42.1 mmol) in ethanol (76.6 mL), triethylamine (5.87 mL, 42.1 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one (Reference Example 15) (11.5 g, 38.3 mmol) in ethanol (76.6 mL) was added dropwise, and the obtained solution was stirred at room temperature for 15 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (14.7 g, 35.0 mmol, 91%) as an amorphous product.