Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.O1CCO[CH2:26][CH2:25]1>CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:21])([CH3:22])[CH2:17][C:18]([O:20][CH2:25][CH3:26])=[O:19])=[CH:13][CH:14]=1
Reactant: C1COCCO1
Reactant: CC(C)(CC(=O)O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(C)(C)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
The acid from STEP 3 (0.5 g) was suspended in absolute EtOH (3.0 mL), added 4N HCl/dioxane (2.0 mL) and stirred overnight at room temperature, and heated to reflux for 1 h. The solution was concentrated to dryness and the residue was dissolved in EtOAC (15 mL), washed with water, dried and concentrated to dryness. The resulting syrup (0.4 g) was dissolved in EtOH (10 mL), added acetic acid (0.1 mL), Pd/C (10%, 0.25 g), and stirred in an atmosphere of hydrogen gas at 50 psi at room temperature. After 16 h, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting colorless syrup was dried in vacuo to give the title compound (0.34 g, 80%): Rf=0.44 (50% EtOAc/Hexane); 1H -NMR (CDCl3) δ7.02 (d, 2H); 6.73 (d, 2H); 4.12 (q, 2H); 2.58 (s, 2H); 2.15 (d, 2H); 1.24 (t, 3H); 0.98 (s, 6H); ES-MS m/z 235(M-H); HRMS calcd C14H21O3 (MH+) 237.1485, found 237.1511.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[N:23]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:22]=2)[CH2:17][CH2:16]1.N>ClCCl.O>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[CH:22]=[C:21]2[CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]([NH2:3])=[O:1])[CH2:16][CH2:17]1
Reactant: NCCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Reactant: N#C[O-]
Agent: N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium cyanate (4.9 g) was suspended in dichloromethane (50 ml) followed by dropwise addition of trifluoroacetic acid (4.4 ml) at 0° C. A solution of 3-[1-(2-aminoethyl)piperidin-4-yl]-5-chloro-1-(4-fluorophenyl)-1H-indol (10.8 g) (Pat. Appl. No. WO 9215302, Chem. Abstr. 117 (1992) 247029) in dichloromethane (100 ml) was added dropwise followed by stirring for 6 h at room temperature. Water (100 ml) was added and the reaction mixture made alkaline with conc. ammonia. The phases were separated followed by extraction with dichloromethane. The combined organic phases were dried over magnesium sulfate. Removal of solvent in vacuo gave a heavy oil which was purified by flash chromatography (silica gel, eluent: triethylamine/methanol/ethyl acetate 5:20:75). The title compound was isolated as a crystalline material, mp. 161°-63° C. Yield: 7.9 g.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:19])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1.BrBr>C(Cl)(Cl)Cl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]([NH:2][CH3:1])[S:19][C:10]=2[CH:9]=1
Reactant: CNC(=S)Nc1ccc(CCc2ccccn2)cc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CNc1nc2ccc(CCc3ccccn3)cc2s1
Yield: 14.2 %

Procedure:
To a solution of 2-[2-{4-(3-methylthioureido)phenyl}ethyl]pyridine (7.1 g) in chloroform (100 ml) was dropwise added a bromine (4.6 g) at ambient temperature under stirring and the mixture was stirred at the same temperature for one hour. Further, the resultant mixture was refluxed under stirring for hours. The reaction mixture was evaporated in vacuo and the residue was heated with 10% hydrochloric acid (100 ml) for one hour at 70° to 80° C. The resultant mixture was washed with ethyl acetate. The separated aqueous layer was adjusted to pH 7.5 with aqueous 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fraction eluted with a mixture of ethyl acetate and diisopropyl ether (6:4 V/V) was collected and solvent was evaporated in vacuo to give a crystalline residue of 6-[2-(2-pyridyl)ethyl]-2-methylaminobenzothiazole (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(#N)C>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone was added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:40]C(=O)C(F)(F)F)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].Br[CH2:48][C:49]([NH:51][CH:52]([CH3:54])[CH3:53])=[O:50].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[F:1][C:2]1[C:3]([NH:40][CH2:48][C:49](=[O:50])[NH:51][CH:52]([CH3:54])[CH3:53])=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CC(C)NC(=O)CBr
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)C(F)(F)F)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NCC(=O)NC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a scintillation vial was combined 40 mg (0.06 mmol) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(2,2,2-trifluoro-acetylamino)-benzamide, 165 mg (0.092 mmol) of 2-bromo-N-isopropyl-acetamide, 17 mg (0.12 mmol) of potassium carbonate, and 0.5 mL N,N-dimethylformamide. The vial was heated in a heating block at 60° C. for 19 hours. 5.5 mg (0.03 mmol) 2-bromo-N-isopropyl-acetamide and 8.5 mg (0.06 mmol) potassium carbonate were added. Additionally, 9.0 mg (0.06 mmol) of sodium iodide was added and the reaction was heated to 60° C. for another 72 hours. The reaction was allowed to cool to room temperature and salts were filtered off. The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added. The reaction was stirred 1 hour at room temperature. The solution was neutralized by adding acetic acid dropwise and then the reaction was concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated and then lyophilized overnight to afford 13.3 mg (0.003 mmol, 43% yield) of 3-fluoro-2-[(isopropylcarbamoyl-methyl)-amino]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a pale yellow powder. 1H NMR (500 MHz, CD3OD) δ 8.42 (s, br., 1H), 8.18 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.45 (dd, 1H), 7.31 (t, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 4.02 (m, 1H), 3.85 (s, 3H), 3.84 (s, 2H), 3.15 (s, br., 3H), 3.04 (s, br., 3H), 1.16 (d, 6H); MS: m/z 504.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]([F:23])([F:22])[C:11]([F:21])([F:20])[C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[F:18][C:12]([F:19])([C:11]([F:20])([F:21])[C:10]([F:9])([F:22])[F:23])[C:13](=[O:14])[CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1cccs1
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1cccs1

Procedure:
The compound was synthesized according to example 1 using 2-acetyl-thiophene and ethyl heptafluorobutyrate as starting materials. 1H NMR (CDCl3): 6.49 (s, 1 H); 7.21 (dd, 1 H, J=3.8 & 5.1); 7.77 (dd, 1 H, J=1.2 & 5.1 Hz); 7.85 (dd, 1 H, J=1.2 & 3.8 Hz). IR (film): 1589 (C═O); 1230 (C—F).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:21]=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O)(=O)C>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:14]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([OH:21])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
Diisopropylamine (1.44 g, 14.3 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under the atmosphere of argon, and a 1.54 M n-butyl lithium-hexane solution (8.8 mL, 13.6 mmol) was added with stirring under ice cooling. The mixture was stirred at 0° C. for 10 min, and then at −78° C. for 5 min. To the mixture, a solution of ethyl 3-phenylpropionate (2.14 g, 12.0 mmol) in anhydrous tetrahydrofuran (2 mL) was added at the same temperature over 6 min, and the reaction mixture was further stirred for 20 min. The cold solution of the enolate thus prepared above was added dropwise via a cannula into a solution of ethyl 2-oxo-4-phenylbutyrate (2.05 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid, and the temperature was raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases. The organic layer having been washed with brine was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1) to give diethyl 3-benzyl-2-phenethyl-2-hydroxysuccinate as oil in amounts of 806 mg (low polar diastereomer, yield: 21%) and 412 mg (high polar diastereomer, yield: 13%), respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=1)=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]([O:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=3)=[O:33])[CH:7]=2)[CH:18]=[CH:17][N:16]=1)=[O:20]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(NC(=O)c4cccc(Cl)c4)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(5-aminonaphthalen-2-yloxy)-N-methylpicolinamide (40 mg, 0.14 mmol) and NaHCO3 (33 mg, 0.44 mmol)in CH2Cl2, 3-chlorobenzoyl chloride (17 □L, 0.14 mmol) was added. The reaction was stirred at RT for 12 h then taken up into CHCl3 and washed with water and brine, dried over Na2SO4, and filtered. The title compound was isolated after purification by column chromatography. MS (ESI pos. ion) m/z: 432.4 (M+H). Calc'd for C24H18ClN3O3-431.87.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]([C:17]3[N:25](S(C4C=CC=CC=4)(=O)=O)[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]([C:17]3[NH:25][C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2[nH]1
Temperature: 85 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A solution of 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.4 g, 7.2 mmol) in ethanol (50 mL) and tetrahydrofuran (100 mL) was treated with an aqueous sodium hydroxide solution (10%, 20 mL). The reaction was stirred at 85° C. for 16 h. At this time, the reaction mixture was cooled to 25° C., concentrated in vacuo, diluted with water (100 mL) and then extracted with ethyl acetate (3×150 mL). The organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with ethanol (15 mL), and dried to afford 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.64 g, 68.9%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 11.64 (s, 1H), 8.52 (d, 1H, J=2.1 Hz), 8.19 (dd, 1H, J1=4.5 Hz, J2=1.8 Hz), 7.95 (dd, 2H, J1=7.8 Hz, J2=1.2 Hz), 7.75-7.69 (m, 3H), 7.42 (t, 1H, J=8.1 Hz), 7.13-7.05 (m, 2H), 6.52 (t, 1H, J=2.1 Hz), 6.44 (d, 1H, J=1.8 Hz), 6.27 (d, 1H, J=9.9 Hz), 2.70-2.57 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[N:10]([CH3:17])[C:11]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:18](=[O:24])[C:19]([OH:21])=[O:20])[N:10]([CH3:17])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(=O)c1cc(COc2cccc(Cl)c2)c(C(=O)OCC)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)C(=O)O)cc(COc2cccc(Cl)c2)c1C(=O)O
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Ethyl 4-(m-chlorophenoxy)methyl-5-ethoxycarbonyl-1-methyl-α-oxopyrrole-2-acetate (7.96 g, 21 mmol) is placed in a 100 ml recovery flask and 25 ml 2.5 N aqueous sodium hydroxide (62.5 mmol) are added. The flask is heated with stirring under nitrogen to 74°. Ethanol (4 ml) is added and the solid begins to dissolve. After 15 minutes the reaction is homogeneous. After heating for one hour, the flask is cooled and 2.5 N aqueous HCl (30 ml, 75 mmol) is added slowly to precipitate the diacid. The resulting solid is filtered, washed with H2O, and then dried in vacuo to give 7.0 g of crude 4-(m-chlorophenoxy)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:14][C:13]=2[N+:26]([O-:28])=[O:27])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>COC(O)C>[CH3:25][CH:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[C:13]([N+:26]([O-:28])=[O:27])[CH:14]=2)=[N:23][NH:22][C:21](=[O:24])[CH2:20]1
Reactant: CCOC(=O)C1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(=O)NN=C1c1ccc(N2CCC(C(=O)O)CC2)c([N+](=O)[O-])c1

Procedure:
1.2 g (3.1 mmol) of 1-[2-nitro-4-(5-methyl-3-oxo-2,3,4,5-tetrahydro-6-pyridazinyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester are heated under reflux in a solution of 0.4 g (9.3 mmol) of sodium hydroxide in 40 ml of methoxyethanol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC=C)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCN(c3cccc4cccnc34)CC2)cc1
Agent: C=COC(=O)Cl
Solvent: ClCCl
Product: c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 8-(4-benzyl-piperazin-1-yl)quinoline (2.63 g, 8.7 mmol) in methylene chloride (30 ml) was added vinyl chloroformate (1.1 ml, 13 mmol) at room temperature slowly. The reaction mixture was refluxed for 2 hours, and then concentrated under vacuum. The residue was dissolved in 12 N hydrochloric acid (20 ml) and stirred at room temperature for 1 hour. The mixture was concentrated, the residue was taken up with 40 ml ethanol and heated up to 50° C. for 2 hours. The solvent was removed under vacuum, the residue was dissolved in 1 N sodium hydroxide-ethyl acetate and extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum. Chromatography (10-30% methanol-methylene chloride plus ammonium hydroxide) afforded 1.86 g (90%) yellow oil; MS EI m/e 213 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[C:71]([C:74]1[CH:79]=[CH:78]C(S(Cl)(=O)=O)=[CH:76][CH:75]=1)(=[O:73])[CH3:72]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:78]=[CH:79][C:74]([C:71](=[O:73])[CH3:72])=[CH:75][CH:76]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)=[NH:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cnc3n(c2=O)[C@H](C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CC3)cc1
Yield: 42 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-acetylbenzene sulfonyl chloride (30.6 mg, 0.14 mmol) yielded 30.0 mg (42.0%) of 35a. MS (ESI) 609.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][N:14]([CH3:29])[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24])(=[O:17])=[O:16]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([S:15](=[O:17])(=[O:16])[N:14]([CH3:29])[CH3:13])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[CH2:7]1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-dimethylsulfamoyl-2-methoxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:19][C@:20]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@:20]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Reactant: CC(C)[C@@](C)(N)CO
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(4-fluorobenzyl)-pyridine-2-carboxylic acid and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1) as starting materials and isolated (29 mg, 25%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 365.1428 (MH+).
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:8]2[CH:18]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:20][C:7]=2[S:6]1(=[O:26])=[O:25].Br>O>[OH:2][CH2:3][CH2:4][N:5]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:8]2[CH:18]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:20][C:7]=2[S:6]1(=[O:25])=[O:26]
Reactant: COCCN1C(CN2CCOCC2)=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Br
Solvent: O
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CCO)C(CN1CCOCC1)=C2
Yield: 56.4 %

Procedure:
A mixture of the product from Step A (1.56 g), 48% HBr(16 mL) and water (4 mL) was heated at reflux temperature for 18 h, evaporated to dryness, mixed with a saturated solution of sodium bicarbonate (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 5% methanol/methylene chloride) to give a firm foam (0.85 g, 56%): mp 104°-108° C. Analysis. Calculated for C13H19N3O6S3 - 0.3H2O: C, 37.63; H, 4.76; N, 10.13. Found: C, 37.61; H, 4.60; N, 10.00.
Reaction SMILES: [Cl:1]C([O-])=O.[N:5]([CH2:12][CH2:13][OH:14])([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]>>[CH2:6]([N:5]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])[CH2:7][OH:8].[ClH:1]
Reactant: O=C([O-])Cl
Solvent: OCCN(CCO)CCO
Product: Cl

Procedure:
100 g of butanediol diglycidyl ether diacrylate were reacted with 5.75 g of chloroformate of the formula III and 3.3 g of triethanolamine at 50° C. for 2 hours. The triethanolammonium chloride formed was then separated off via a pressure filter. (Viscosity: 880 mPas).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1.[CH3:27]O>>[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1
Reactant: CO
Reactant: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(-c3cnccn3)cc2C)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Thionyl chloride (0.076 ml, 1.043 mmol) was added to methanol (7 ml) at 0° C. After 15 minutes, 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylic acid (D85, 0.216 g, 0.745 mmol) was added and the mixture was heated to reflux. After 5 h, the reaction mixture was allowed to cool and was left at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (25 ml) and 10% sodium carbonate solution (20 ml). The aqueous layer was then extracted with dichloromethane (1×10 ml), and the combined organic layers were then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow/brown solid (0.146 g, 65%).