Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCc3ccccc3)cc2C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)c2cc(OCc3ccccc3)ccc2C1
Temperature: 25 °C

Procedure:
To 500 mg (1.41 mmol) 6-benzyloxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XL) in 8 mL DCM are added 618 mg (1.41 mmol) Dess-Martin periodinane and stirred at r.t. over night. After that time, the reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC (ACN/H2O/HCOOH).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Agent: N
Solvent: O
Solvent: CO
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Temperature: 45 °C
Yield: 47.2 %

Procedure:
A solution of 1.17 g (4.88 mmol) of (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:15][CH:14]=2)=[O:12])=[CH:21][CH:22]=1
Reactant: NCCCO
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc(CNCCCO)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a solution of 3-amino-l-propanol (3.00 g) in ethanol (40 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was refluxed for 4.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developed with chloroform: methanol=9:1) to provide the title compound as white powder (1.36 g; yield 45%). 1H-NMR (CDCl3) δ: 1.76(2H,q,J=5.6Hz), 2.29(2H,m), 2.93(2H,t,J=5.6Hz), 3.83(2H,t,J=5.6Hz), 3.90(2H,s), 7.41-7.50(4H,m), 7.71-7.78(4H,m).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:19]([O-:22])(=O)[CH3:20].[Na+]>C(O)(=O)C>[C:5]1(=[O:6])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:19](=[O:22])[C@H:20]2[CH2:11][CH2:10][CH2:9][CH2:3][C@@H:4]12
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A stirred mixture of 1,2,5,6-hexahydrophthalic anhydride (0.77 grams, 5.0 mmol), methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.0 mmol), and sodium acetate (0.40 grams, 4.9 mmol) in 20 mL of acetic acid under N2 was heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo and the residue diluted with 25 mL of methylene chloride and then 25 mL of sat. sodium bicarbonate was added in portions and the resulting mixture stirred for 30 minutes. The organic phase was separated, dried (sodium sulfate), and concentrated to afford the crude product as an oil. The crude product was purified by flash chromatography (silica gel, 1/9 EtOAc/hexanes) to afford 0.72 grams (38%) of methyl 3-(cis-hexahydrophthalimido)-3-(3,4-dimethoxyphenyl)propionate as an off-white solid (wax): mp 92.5°-95° C.; 1H NMR (CDCl3 /TMS) δ 7.02 (m, 2H, Ar), 6.65 (m, 1H, Ar), 5.56 (dd, J=5.5, 10.5 Hz, 1H CHN), 3.86 (2 s, 6H, 2 OCH3), 3.74 (dd, J=16.5, 10.5 Hz, 1H), 3.66 (s, 3H, OCH3), 3.08 (dd, J=5.5, 16.5 Hz, 1H, CHCO), 2.77 (m, 2H, bridgehead Hs), 1.87-1.55 (m, 4H), 1.5-1.2 (m, 4H); 13C NMR (CDCl3 /TMS) δ 179.5, 179.4, 171.1, 148.9, 148.8, 130.9, 120.1, 111.0, 110.9, 55.9, 55.8, 51.8, 51.0, 39.6, 35.2, 23.6, 23.5, 21.6; TLC (1/9 EtOAc/hexanes, UV) Rf =0.36. Anal. Calcd for C20H25NO6. Theory C, 63.99; H, 6.71; N, 3.73. Found C, 63.89; H, 6.81; N, 3.61.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:33])[CH3:32]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(C)=O)cc2)cc1

Procedure:
A solution of 0.219 g (0.507 mmol) of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate in 2.5 mL of acetic anhydride and 0.25 mL of pyridine was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.213 g of methyl (2R)-{4-[2-(acetylamino)ethoxy]phenyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-ethanoate as a white foam. Electrospray Mass Spec 475.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1cc(Br)ccc1Cl
Product: COc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1Cl
Yield: 24.1 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1-chloro-2-methoxybenzene (332 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 100 mg (yield 24%). Melting point was 168 to 171° C. (ethyl acetate-hexane).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)OCC1.C1COCC1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:13][CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][CH2:7]1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25° C. for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR(CDCl3): 3.75 (m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).
Reaction SMILES: [CH:1]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1>>[CH:1]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:25]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[O:26])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1nc2cccc(NC3CCCCCC3)n2n1
Reactant: O=C(Cl)C1CCOCC1
Product: O=C(Nc1nc2cccc(NC3CCCCCC3)n2n1)C1CCOCC1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A10), 50 mg; 0.20 mmol; 1.0 eq.) and tetrahydro-2H-pyran-4-carbonyl chloride (45 mg; 0.30 mmol; 1.5 eq.) as a white solid (33 mg, 46%). HPLC, Rt: 3.02 min. (purity 96.9%). LC/MS, M+(ESI): 358.0, M−(ESI): 356.0.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[NH:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([N:4]([CH2:5][C:6]([OH:8])=[O:7])[C:3]1[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CC(=O)O)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36 g (0.2 mole) of 2,6-dimethylanilinoacetic acid, 400 ml of methylene chloride and 200 ml of 1N NaOH (0.2 mole) are placed into a flask with stirrer, and 17.5 ml (0.22 mole) of chloroacetic acid chloride is slowly added dropwise with stirring, the temperature being maintained at 20°-25° by cooling with ice-water. During the dropwise addition, there is formed a white precipitate. Stirring is continued for 30 minutes and the precipitate is then filtered off with suction; the precipitate is washed with cold water, well pressed out and subsequently dried over P2O5 in a desiccator. For the purpose of obtaining further amounts of final product, the methylene chloride phase is separated in a separating funnel, dried over Na2SO4 and concentrated in vacuo, and the crystalline residue is recrystallised from ethyl acetate. There is obtained a total amount of 44 g (86% of theory) of N-chloroacetyl-2,6-dimethylanilinoacetic acid, m.p. 160° (decomposition).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1.[NH3:14].CO>>[NH2:14][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: N
Agent: Cl
Solvent: CO
Product: COc1c(C)cnc(CN)c1C
Yield: 76 %

Procedure:
A solution of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine HCl (Aldrich 3.7 g, 16.6 mmole) in 7N NH3/MeOH (Aldrich, 200 mLs) was refluxed in a steel bomb for 15 hours. Removed the solvent under reduced pressure, the residue was taken into 5% MeOH/CH2Cl2 and filtering it through a thin layer of silica gel afforded the product at 76% yield. HPLC RT was 2.850 min. 1HNMR (CDCl3) δ 8.18 (s, 1H), 4.32 (s, 2H), 3.76 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:29]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)On2nnc3ccccc32)c(C)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In dichloromethane (70 ml) are added 1-hydroxy-1,2,3-benzotriazole (3.4 g) and further triethylamine (3.7 ml). To the solution is added dropwise a solution of 2,4,6-trimethylbenzenesulfonyl chloride (4.5 g) is dichloromethane (20 ml) at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting residue is washed with ethyl acetate-n-hexane (1:1; 50 ml) and dried to give colorless crystals of 1-(2,4,6-trimethylbenzenesulfonyloxy)-1,2,3-benzotriazole (5.5 g), melting point: 128°-130° C. The product is recrystallized from dichloromethane-n-hexane to give colorless prisms, melting point: 130°-131° C.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:12]([CH:13]2[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10][C:9](=[O:19])[C:8]=3[CH3:20])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH:12]([CH:13]2[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10][C:9](=[O:19])[C:8]=3[CH3:20])=[CH:5][CH:4]=1
Reactant: CCCC1c2cc(OC)ccc2C2=C(C)C(=O)CCC21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCC1c2cc(O)ccc2C2=C(C)C(=O)CCC21
Temperature: 25 °C
Reaction time: 2.6 h

Procedure:
A solution of (9SR,9aSR)-7-methoxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (38.3 mg, 0.142 mmol) in anhydrous CH2Cl2 (1.1 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while 1M BBr3 in CH2Cl2 (0.354 mL, 0.345 mmol) was added by syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2.6 hours, then diluted with 0.2N HCl (5 mL) and EtOAc (10 mL) and shaken. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to a solid (35.2 mg). The crude product was purified by flash chromatography on EM silica gel 60 (230-400 mesh, 1×18 cm column) using 3:1 hexanes-EtOAc as eluting solvent, collecting 3 mL fractions. Fractions 12-26 were combined and concentrated under vacuum to approximately 1 mL of a suspension. The suspension was filtered and the solid portion washed with EtOAc and dried under vacuum to afford (9SR,9aSR)-7-hydroxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:4][CH:3]=1.[NH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([NH2:35])=[O:25])=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(c2ccc(C(=O)O)cn2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(c2ccc(C(N)=O)cn2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 500 and aqueous ammonia, and by the reaction and purification in the same manner as in Example 510, the title compound was obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.35 mmol) was added to a stirred solution of {6-chloro-4-[4-(4-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.043 g, 0.086 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(4-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.039 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s., 1 H) 8.15 (d, J=7.82 Hz, 2 H) 8.10 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.77 (d, J=7.82 Hz, 2 H) 7.54 (d, J=7.82 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.01 (s, 3 H) MS calcd. for C25H17Cl2O4S [(M−H)−] 483, obsd. 482.8.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:23][N:24]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:27][CH2:26][CH:25]([N:24]([CH3:23])[CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Product: CN(CCc1ccccc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-phenethyl-piperidin-4-yl-amine, hydrochloride, praeparative HPLC (Method C) (37%, colourless oil). HPLC-MS m/z=500.1 (M+1), Rt: 3.26 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=O)=[CH:21][C:16]=2[NH:15][CH:14]=1>>[N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[NH:1][C:2]4[C:3]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)=[CH:21][C:16]=2[NH:15][CH:14]=1
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Product: O=C(O)c1cccc2nc(-c3ccc4nc[nH]c4c3)[nH]c12
Temperature: 200 °C
Yield: 80.9 %

Procedure:
2 g (12 mmol) of methyl 2,3-diaminobenzoate and 2 g (12 mmol) of benzimidazole-5-carboxylic acid were successively introduced into 70 ml of polyphosphoric acid preheated to 90° C. The mixture was then heated at 200° C. for 1 hour. The reaction mixture was subsequently cooled to 50 to 60° C. and poured cautiously into ice-water. The resulting precipitate was filtered off with suction and dried. 2.7 g of the product were obtained.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[CH:15]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].NN>C(O)C>[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[CH:15]([CH2:21][NH2:22])[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)C(CN1C(=O)c3ccccc3C1=O)NC2
Agent: Cl
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)C(CN)NC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of the above 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride (42 mg, 0.072 mmol) in ethanol (0.5 ml) was added hydrazine (68 μl, 0.22 mmol). The solution was stirred at 80° C. for 5 h. and at room temperature for 16 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with dichloromethane (5×1 ml). The combined dichloromethane washes were evaporated in vacuo affording 20 mg (67%) of 5-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(OC)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(OC)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.90 min; [M+H]+=263.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([NH:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1)=[O:21])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@@H](COCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 83 %

Procedure:
By using N-tert-butyloxycarbonyl-O-benzyl-D-serine (600 mg, 2.03 mmol) and 3α-aminocholestane (866 mg, 2.23 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (1.13 g, yield; 83%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[Cl:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]1=[O:32].C(=O)([O-])O.[Na+].Cl>CN(C)C=O.C(O)C>[ClH:18].[O:32]=[C:22]1[N:21]([CH2:20][CH2:19][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[NH:9][CH:8]=3)[CH2:2]2)[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ccc2[nH]cc(CC3CCN(CCn4c(=O)[nH]c5ccccc5c4=O)C3)c2c1
Reaction time: 6 h

Procedure:
Under an inert atmosphere and at ambient temperature, 47.3 mmol (10 g) of 3-[3-pyrrolidinylmethyl]-1H-indole-5-carbonitrile, 47.3 mmol (9.97 g) of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione and 47.3 mmol (3.73 g) of sodium hydrogen carbonate are dissolved in 100 ml of dimethylformamide, and stirring is carried out at 100° C. for 6 hours. The reaction mixture is concentrated and the residue is taken up in dichloromethane. The organic phase is washed with water and then with saturated sodium chloride solution, and is dried over magnesium sulphate. Purification is carried out by chromatography on silica using a mixture of dichloromethane/methanol/ammonia 95/5/0.5 as eluant. The compound obtained is converted into the salt by one equivalent of hydrochloric acid in ethanol.