Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[C:6](=O)[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:12]=[N:11][C:5]2=[C:6]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:7]=[N:8][CH:9]=[C:4]2[CH:3]=1
Reactant: C1COCCN1
Reactant: O=c1[nH]ncc2cc(Br)cnc12
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1cnc2c(N3CCOCC3)nncc2c1
Temperature: 95 °C

Procedure:
A mixture of 3-bromopyrido[2,3-d]pyridazin-8(7H)-one (0.206 g, 0.91 mmol) and phosphorus oxychloride (5.00 ml, 55 mmol) was heated at 95° C. After 2 h the reaction was cooled to 25° C. and diluted with 30 mL of CHCl3. The solution was cooled to 0° C. and the solid was filtered and washed with CHCl3. The filtrate was concentrated to dryness and azeotroped with toluene (2×). The residue was dissolved in CH3CN and heated with morpholine (0.079 ml, 0.91 mmol) at 190° C. for 15 min in the microwave. The crude material was purified by flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:24) to give the title compound as an orange amorphous solid. MS m/z: 295.0 [M+1].
Reaction SMILES: [N:1]([CH:4]([O:6][CH2:7][CH2:8][OH:9])[CH3:5])=[N+:2]=[N-:3].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][O:9][CH2:8][CH2:7][O:6][CH:4]([N:1]=[N+:2]=[N-:3])[CH3:5])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CC(N=[N+]=[N-])OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOC(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1-azido-ethoxy)-ethanol (0.15 g, 1.14 mmol) in dry tetrahydrofuran (THF) (5 ml) was added NaH (60% dispersion, 0.08 g, 2 mmol) at 0° C. After 15 minutes, ethyl-2-bromoacetate (0.222 ml, 2 mmol) was added. The reaction was maintained at this temperature for 15 minutes and then warmed up to room temperature. The reaction was quenched by addition of saturated aqueous NaHCO3 (5 ml) after 1 hr. After a further period of 5 min, the mixture was partitioned between DCM (50 ml) and saturated aqueous NaHCO3 (50 ml). The aqueous layer was further extracted with DCM (50 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The title compound was obtained as an oil (0.162 g, 65.5%).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[C:21](Cl)(Cl)(Cl)[Cl:22].CCCCCC>>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:21][Cl:22])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2ccccc21
Reactant: ClC(Cl)(Cl)Cl
Agent: C=O
Agent: Cl
Solvent: CCCCCC
Product: O=C(c1ccccc1)N1CCc2cc(CCl)ccc21
Yield: 60 %

Procedure:
1-Benzoyl-2,3-dihydro-1H-indole (Beilstein, 20, 257) (5.58 g, 25 mmole) is dissolved in 50 ml of glacial acetix acid, then 56 ml (ca 70 mmoles) of 40% formaldehyde are added, and dry hydrogen chloride passed into the solution which is maintained at 70° for 3 hours. The solution is evaporated, and the residue dissolved in benzene, and again evaporated to dryness to give 6.53 g of crude product. This residue is treated with carbon tetrachloride-hexane to give 4.05 g (60%) of 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole, m.p. 107.5°-110.0°.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]1[C:23](=[O:24])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:26]=1[OH:27]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1ccccc1Cl)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1ccccc1Cl

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-chlorophenyl)thio]propanedioic acid (1.53 g, 5.07 mmol). m.p. 275-280° C.; 1H NMR (400 MHz, DMSO-d6) δ6.78 (s, 1H), 6.89 (dd, 1H), 7.08 (tt, 1H), 7.19 (tt, 1H), 7.42 (dd, 1H), 7.56 (m, 3H), 8.06 (m, 2H).
Reaction SMILES: [OH:1][C:2]1([CH2:21][C:22](=[O:32])[CH2:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=O)[CH2:7][CH2:6][N:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=2)[CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>ClCCl>[CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:5]2[CH2:6][CH2:7][C:2]3([O:1][C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:23][C:22](=[O:32])[CH2:21]3)[CH2:3][CH2:4]2)=[O:20])=[CH:10][C:11]=1[CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(C(=O)N2CCC(O)(CC(=O)CC(=O)c3cccnc3)CC2)ccc1OC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cccnc2)O3)ccc1OC(C)C
Temperature: 120 °C

Procedure:
To a solution of 4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (1 mmol) in dichloromethane (5 mL) was added PPTS (251 mg, 1.00 mmol). The mixture was heated in microwave at 120° C. for 45 min. Water was added. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography (40-50% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one.
Reaction SMILES: [C:1]1([C:7]2NN=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]([Cl:34])([Cl:33])[C:14]1[N:19]=[C:18]([C:20]([Cl:23])([Cl:22])[Cl:21])[N:17]=[C:16]([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[N:15]=1>N1C=CC=CC=1>[Cl:23][C:20]([Cl:21])([Cl:22])[C:18]1[N:19]=[C:14]([C:13]([Cl:34])([Cl:12])[Cl:33])[N:15]=[C:16]([C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][N:9]=3)=[CH:31][CH:32]=2)[N:17]=1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Product: ClC(Cl)(Cl)c1nc(-c2ccc(-c3nnc(-c4ccccc4)o3)cc2)nc(C(Cl)(Cl)Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Phenyltetrazole (5 pbw) and 4-(4,6-bis-trichloromethyl-s-triazin-2-yl)benzoyl chloride (15.5 pbw) are dissolved in 125 pbv of pyridine and slowly heated to reflux. At about 80° C. nitrogen evolution commences, which comes to an end after about 1 hour. After cooling, the mixture is poured into 500 pbv of ice water, the precipitate that deposits is removed by filtration and is, after drying, recrystallized from 2-methoxy-ethanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50](O)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=5)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OCCc2cc3cc(CC(=O)OC)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a solution of the methyl 2-(2-hydroxyethyl)indole-5-acetate (37.6 mg; 0.16 mmol), Ph3P (47 mg; 1.1 eq), 3-phenyl-6-hydroxy-7-propylbenzofuran (45 mg; 1.1 eq) and THF (5 mL) was added diisopropyl azodicarboxylate (35 μL; 1.1 eq), and the mixture was stirred at room temperature overnight. The mixture was concentrated and chromatographed (silica gel, hexane:ethyl acetate::9:1 to 4:1) affording 18.6 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1c(F)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a mixture of 2-fluoro-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (3.60 g, 15.0 mmol) and pyridine (5.93 g, 75.0 mmol) in dichloromethane (50 mL) was added dropwise Tf2O (6.35 g, 22.5 mmol) at −15° C. After stirring at room temperature for 3 h, the reaction was quenched by addition of iced-brine (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid (3.77 g, Yield: 67.5%). 1H NMR (400 MHz, DMSO-d) δ 10.12 (s, 1H), 7.26-7.30 (m, 1H), 7.04 (s, 1H), 5.78 (s, 1H), 3.62-3.71 (m, 2H), 1.80-1.87 (m, 3H), 1.56-1.64 (m, 3H). MS (ESI) m/z=373 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1.[C:35](Cl)([CH3:37])=[O:36].C(N(CC)CC)C>C1COCC1>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:21][CH:22]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1)(=[O:36])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCc1nc2c(C)cc(NCCN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(NCCNC(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
To 5-(2-aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (20 mg) in THF (1 mL) at °C. was added AcCl (3.4 μL) and triethylamine (18 μL). After 1 h, the solvent was evaporated and the residue was purified (SiO2, 80:20:1CHCl3, MeOH, NH4OH) to give 17 mg of the title compound. 1H NMR (300 MHz, CD3OD) δ 7.63-7.45 (m, 4H), 7.18-7.04 (AB q, 4H), 6.33 (s, 1H), 5.43 (s, 2H), 3.47 (t, 2H J=5 Hz), 3.38 (t, 2H J=5 Hz), 2.86 (q, 2H, J=7.8 Hz), 2.47 (s, 3H), 1.90 (s, 3H), 1.22 (t, 3H, J=7.8 Hz).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([OH:12])=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2[CH:18]=1.CCN=C=NCCCN(C)C.NC1C=CC=CC=1>C1COCC1>[C:1]([NH:5][S:6]([CH2:9][C:10]([NH:19][C:17]1[CH:18]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:12])(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC(C)(C)NS(=O)(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of compound 2-(N-tert-butylsulfamoyl)acetic acid (5 g, 25.6 mmol.) in dry THF (20 mL) was added HOBt (13.8 g, 102.4 mmol.) and EDCI (18.3 g, 102.4 mmol.). Then aniline (3.6 g, 38.4 mmol.) was added successively. The reaction mixture was stirred overnight at room temperature. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by column chromatography (PE:EtOAc=2:1) to afford 2-(N-tert-butylsulfamoyl)-N-phenylacetamide (3.5 g, 51%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[C:25]([C:24]([O:30][CH2:31][N:15]1[C:14]([C:13]2[C:8]([NH:7][CH2:6][C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:9][C:10]([Cl:23])=[C:11]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:12]=2)=[N:18][N:17]=[N:16]1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
In a similar manner to Example 12, azosemide can be reacted with chloromethyl pivalate, triethylamine and sodium iodide in DMF to yield 5-[1-(t-Butylcarbonyloxymethyl)-1H-tetrazol-5-yl]-2-chloro-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(C)([O-])C.[K+].[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]([CH2:37][O:36][CH2:34][CH3:35])[C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CCOCCl
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(S(=O)(=O)c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(p-chlorophenyl)sulfonyl]-2-(trifluoromethyl)pyrrole (0.92 g, 1.84 mmol) and potassium tert-butoxide (0.26 g, 2.21 mmol) in tetrahydrofuran is stirred at room temperature for 5 minutes, treated with a solution of chloromethyl ethyl ether (0.21 g, 2.21 mmol) in tetrahydrofuran, stirred at room temperature overnight, diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid (0.98 g, mp 107°-112° C.).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To 2.0 mL of a methanol solution containing 0.25 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2.0 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added and stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to afford 0.18 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:13][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:12])([CH3:13])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Solvent: C1CCOC1
Product: CC1(O)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-bromoisatin (255 mg, 1.13 mmol) in THF (3.0 mL) was added methylmagnesium bromide (1.12 mL, 3.39 mmol, 3M in ether). The solution was stirred at room temperature for 2 hours. The solution was cooled to 0° C. and was quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted with EtOAc (3×), washed with brine, dried over MgSO4, filtered and concentrated to afford 6-bromo-3-hydroxy-3-methylindolin-2-one 7.45. The solid was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.15 (dd, J=7.9, 1.8 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 5.94 (s, 1H), 1.34 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)=O)(C)(C)C>>[N:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH2:24][C:23](=[O:39])[NH:16][C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:28][C:29]=1[C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2ccncc2)c1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (90 mg, 0.35 mmol) and 3-[2,4′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K58) (104 mg, 0.35 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (120 mg).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)([OH:3])=[O:2]>CN(C)C=O.CO.[Pd]>[C:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)([OH:3])=[O:2]
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1ccccc1CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 27.3 %

Procedure:
A suspension of 8 g of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in 350 ml of dimethylformamide and 50 ml of methanol is hydrogenated in the presence of 1 g of 10% palladium-on-charcoal for 20 hours at 10 bar and at a temperature in the region of 20° C. The reaction mixture is filtered on clarcel and the filtrate is evaporated under reduced pressure. The beige-coloured residue obtained is triturated with 200 ml of boiling methanol, filtered and dried at 100° C. under vacuum (1 mmHg; 0.13 kPa); 2.2 g of 10-(2-carboxy-benzyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained in the form of an off-white solid melting above 260° C. (Analysis, % calculated C: 70.58, H: 4.23, N: 11.76, O: 13.43, % found C: 70.6, H: 4.3, N: 12.1).
Reaction SMILES: [NH3:1].[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]1[O:5][CH2:4]1>>[Si:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:2][CH:3]([OH:5])[CH2:4][NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)CCCOCC1CO1
Reactant: N
Product: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanolic ammonia (7 mol of ammonia in methanol, 100 mL, 0.7 mol,) was charged to a 500 mL, one-neck, round-bottom flask placed in an ice bath. To the above solution 3-t-butyldimethylsilylpropyl glycidyl ether (23.04 g, 0.1 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for three days. The reaction solution was then warmed up to 40–50° C. to remove excess ammonia. Methanol was stripped off under reduced pressure. Crude 3-(t-butyldimethylsilylpropyloxy)-2-hydroxypropylamine was obtained as a clear and colorless oil (24 g, 98% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.O[C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=2)=[CH:29][CH:28]=1)(=[O:26])[C:24]1[CH:33]=[CH:34][CH:21]=[CH:22][CH:23]=1
Reactant: CO[C@@H](Cc1ccc(C#CCCCO)cc1)C(=O)O
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid (Example 21, Step A) and 4-hydroxybenzophenone via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.82–7.70 (m, 3H), 7.54–7.43 (m, 4H), 7.31–7.23 (m, 2H), 7.14 (d, 2H, J=8.1), 6.95 (d, 2H, J=8.8), 4.19 (d, 2H, J=5.9), 3.96 (dd, 1H, J=7.7, 4.4), 3.34 (s, 3H), 3.09 (dd, 1H, J=14.3, 4.4), 2.95 (dd, 1H, J=14.3, 7.7), 2.61 (t, 2H, J=7.0), 2.08 (qn, 2H, J=0.6).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:35])[CH:26]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:22]([C:19]1[N:18]=[C:17]2[N:13]([C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([OH:37])=[O:3])[C:14](=[O:36])[N:15]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][C:32]=4[CH3:34])[N:27]([CH3:35])[CH:26]=3)[C:16]2=[CH:21][CH:20]=1)#[N:23]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C#N)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](CC(=O)O)c3ccccc3)c3nc(C#N)ccc31)cn2C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
To a stirred solution of (R)-3-[5-cyano-1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl]-3-phenyl-propionic acid ethyl ester (70 mg, 0.14 mmol) in dioxane (4 ml) and water (2 ml) was added lithium hydroxide monohydrate (12 mg, 0.28 mmol) at room temperature. After stirring for 6 hours the reaction appeared to be complete. The reaction was concentrated to a low volume and diluted with water. The reaction mixture was acidified using acetic acid and the resulting precipitate was collected via filtration. The solid was purified once by silica gel flash column chromatography (12 g silica gel, 0-10% MeOH/Dichloromethane) and then again by preparative TLC (2×0.5 mm silica gel, 5% MeOH/Dichloromethane) to afford 25 mg (31%) of the title compound. LCMS, M++1, m/z: 466.43.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH2:14]=O>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[CH2:14][NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: C=O
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2cc(F)ccc2CN1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 3-fluoro-DL-phenylalanine (100 g) in conc. HCl (1.0 L) was added aq. formaldehyde solution (37% wt.; 400 mL). The reaction mixture was heated to 90° C. and stirred for 3.5 h, then cooled to RT and stirred overnight and filtered. The filtrate was concentrated and the residue was combined with the precipitate to give 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, which was used without further purification. LRMS (M+H+) m/z 196.1.