Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:22](OCC)=[O:23])[F:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([F:21])=[C:19]([CH3:27])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-2-fluoro-1-methylvinyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 9.99 ppm (s, 1H), 7.84 ppm (d, 1H), 7.37 ppm (d, 1H), 5.26 ppm (m, 1H), 2.18 ppm (d, 3H), 1.38 ppm (d, 3H), 1.36 ppm (d, 3H),
Reaction SMILES: COC1C=CC(C[N:8]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:19][CH2:18][O:17][C:16]=3[CH:32]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:34]1[CH:35]=[CH:36][N:37]=[C:33]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:19][CH2:18][O:17][C:16]=2[CH:32]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)COc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.2 %

Procedure:
To a solution of 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 0.53 mmol) in DCM (30 mL) was added TFA (0.5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 5 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC purification to obtain 2-(2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (55 mg, 13.7%) as an off white solid.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[NH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[O:37])=[CH:28][C:27]=1[O:26][CH3:25]
Reactant: COc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1N

Procedure:
(4-Amino-3-methoxy-phenyl)-(4-methyl-piperazin-1-yl)-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (3-Methoxy-4-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24]C)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:30]B(Br)Br>>[Br:30][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[OH:24])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: BrB(Br)Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Product: O=c1[nH]c2ccc(O)c(-c3ccc(S(=O)(=O)NCCBr)cc3)c2c2ccsc12
Yield: 90.9 %

Procedure:
Following General Procedure F, N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (1.7 g, 3.9 mmol) was reacted with tribromoborane (3.7 mL, 24 mmol) to afford the desired product (1.7 g, 91%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.43 (s, 1H), 8.16 (t, J=5.9 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.75 (d, J=5.4 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.9 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.83 (d, J=5.4 Hz, 1H), 3.51 (t, J=6.4 Hz, 2H), 3.28 (q, J=6.2 Hz, 2H); ESI MS m/z 478 [C19H15BrN2O4S2+H]+; HPLC 98.5% (AUC), tR=15.23 min.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 13 h
Yield: 49.9 %

Procedure:
To a mixture of phthalimide (3.92 g, 26.6 mmol) and potassium carbonate (9.20 g, 66.6 mmol) in acetonitrile (44 ml), was added 4-bromo-1-butene (2.26 ml, 22.2 mmol) at room temperature. The resulting reaction mixture was stirred at 90° C. for 13 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (2.23 g). The compound was used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=C[C:26]([O:29][P:30]([CH3:42])(=[S:41])OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:26][O:29][P:30]([CH3:42])(=[S:41])[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CP(=S)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COP(C)(=S)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
The compound methylphosphonothioic acid O-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester O-methyl ester is prepared according to procedure F using 200 mg of 3-(1H-indol-2-yl)-H-indazole-5-ol (intermediate B) in solution with 284 mg of methylphosphonothioic acid O,O—bis-(4-nitrophenyl)ester in 6 ml of dichloromethane (stabilized with amylene), to which 120 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 1 ml of dichloromethane are added. After stirring at ambient temperature for 4 h 30 min, 325 μl of methanol and 120 μl of DBU in solution in 1 ml of dichloromethane are added. The mixture is left at ambient temperature overnight and the solvent is then evaporated off and the crude is purified by flash chromatography on 35-70 μm silica, eluent: cyclohexane/ethyl acetate 90/10 to 50/50. The fractions obtained are concentrated and purified by preparative LC/MS to obtain 47.7 mg of methylphosphonothioic acid O-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester O-methyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9]2)[N:3]=1.C(B(CC)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)C.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][N:8]([C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: Clc1cccc(-n2ccc(-c3ccccn3)c2)n1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(-c2ccn(-c3cccc(-c4cccnc4)n3)c2)nc1

Procedure:
2-Chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine (256 mg, 1.0 mmol), diethyl-(3-pyridyl)borane (162 mg, 1.1 mmol), bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol), and potassium carbonate (345 mg, 2.5 mmol) were combined in 3 mL of 1:1 DME:H2O and heated via microwave irradiation for 5 min at 160° C. The reaction was diluted with 50 mL EtOAc and partitioned with H2O (50 mL). The EtOAc layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by SiO2 chromatography, eluting with a 20-75% EtOAc in hexanes gradient to afford 6-(3-pyridin-2-yl-1H-pyrrol-1-yl)-2,3′-bipyridine as a tan solid that was dissolved in ether and precipitated as an HCl salt by slow addition of 6 equivalents of 1N HCl in ether. H-NMR (CD3OD, 500 MHz) δ 9.82 (s, 1H), 9.48 (d, 1H), 9.14 (dd, 1H), 8.95 (d, 1H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.44 (d, 1H), 8.28 (dd, 1H), 8.17-8.25 (m, 2H), 8.04 (m, 1H), 7.95 (d, 1H), 7.78 (dd, 1H), 7.15 (m, 1H). MS (ESI) 299.44 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11](=O)[CH3:12]>CO.[Pd]>[CH2:11]([C:3]1[C:2]([OH:1])=[C:7]2[CH2:8][CH2:9][O:10][C:6]2=[CH:5][CH:4]=1)[CH3:12]
Reactant: CC(=O)c1ccc2occc2c1O
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1O)CCO2
Reaction time: 24 h

Procedure:
A mixture of 1-(4-Hydroxy-benzofuran-5-yl)-ethanone (1.37 g, 7.8 mmol) and 10 wt % Pd/C (0.7 g, Degussa type) in MeOH (20 mL) was stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to an oil (0.9 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3H), 2.56 (q, J=7.6 Hz, 2H), 3.14 (t, J=8.6 Hz, 2H), 4.59 (t, J=8.6 Hz, 2H), 4.68 (s, 1H), 6.37 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5](SC)[C:4]=1/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20].C1(=O)C2C(=CC=CC=2)[C:26](=[O:33])C=C1/C=C(\C)/C(O)=O>CCOCC>[CH3:26][O:33][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20]
Reactant: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Reactant: COc1c(/C=C(\C)C(=O)O)c(SC)c(OC)c2ccccc12
Solvent: CCOCC
Product: COC1=C(/C=C(\C)C(=O)O)C(=O)c2ccccc2C1=O

Procedure:
Compound 55 was prepared from 99h (0.180 g, 0.565 mmol) as described above for 30a to give 0.063 g (0.22 mmol, 38%) of the product as a red fluffy solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]([C:12](=O)[CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]([C:12](=[N:16][OH:17])[CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1C=CN(c2ccccc2)N1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)N1C=CN(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 28 g (0.15 mol) of 1-phenyl-3-acetyltriazole (Example 1a), 12 g (0.19 mol) of hydroxylamine hydrochloride and 16 g (0.2 mol) of sodium acetate in 225 ml of ethanol/water 2:1 was stirred overnight at room temperature (=25° C.).
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].P(Br)(Br)[Br:15]>C(Cl)Cl>[C:1]([N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:15])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(=O)N(C)c1ccc(CO)cc1
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-(N-acetyl-N-methylamino)benzyl alcohol (543.0 mg, 3.0 mmol), prepared as in step 2, dissolved in dry CH2Cl2 (11.5 mL) was added dropwise 1M PBr3 in CH2Cl2 (3.6 mL, 3.6 mmol) at 0° C. The reaction was stirred at ambient temperature until TLC indicated complete reaction (~5 hours). The resulting solution was partitioned between ethyl acetate and brine. The combined organic layers were decolorized with charcoal, dried (MgSO4), filtered through celite and concentrated in vacuo. Purification by flash chromatography on silica gel (40% ethyl acetate/hexane) provided 4-(N-acetyl-N-methylamino)benzyl bromide as a colorless solid (595 mg, 81.0%). 1H NMR (300 MHz, CDCl3) δ7.46 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.50 (2H, s), 3.27 (3H, s), 1.88 (3H, br s). MS m/e 242 (M+H)+, 259/261 (M+NH4)+. Analysis calc'd for C10H12NOBr: C, 49.61; H, 5.00; N, 5.79. Found: C, 49.35; H, 4.97; N, 5.65.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[CH:14]1[C:19]([C@@H:20](O)[CH2:21][NH2:22])=[CH:18][C:17]([OH:24])=[C:16]([OH:25])[CH:15]=1.CNC[C@H](O)C1C=CC(O)=C(O)C=1>C(#N)C>[NH2:22][CH2:21][CH2:20][C:19]1[CH:14]=[CH:15][C:16]([OH:25])=[C:17]([OH:24])[CH:18]=1
Reactant: NC[C@H](O)c1ccc(O)c(O)c1
Agent: CNC[C@H](O)c1ccc(O)c(O)c1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: CC#N
Product: NCCc1ccc(O)c(O)c1
Yield: 96.9 %

Procedure:
The results shown in FIGS. 6 and 7 were obtained using a solvent of 95% 0.05 m citrate buffer with a pH of 5.2 and 5% acetonitrile with a flow rate of 0.8 ml/min. In FIGS. 6 and 7, peak 1 represents the solvent front, peak 2 represents 4.9 ng norepinephrine and peak 3 represents 4.88 ng epinephrine. Peak 4 was produced by dopamine (4.30 ng).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.ClC1N=C(C(O)=O)C=CC=1OCC1CC1.[CH3:35][C:36]1([CH3:41])[CH2:40][O:39][CH2:38][NH:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:37]3[C:36]([CH3:41])([CH3:35])[CH2:40][O:39][CH2:38]3)=[O:14])[CH:9]=[CH:8][C:7]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1
Reactant: CC1(C)COCN1
Agent: O=C(O)c1ccc(OCC2CC2)c(Cl)n1
Product: CC1(C)COCN1C(=O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using the mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (24 mg, 37%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 361.1370 [MH+].
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([O:18]C)=[O:17])[NH:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([OH:18])=[O:17])[NH:4]1)[CH3:2]
Reactant: CC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl (1RS,3RS)-cis-1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (5.0 g) is dissolved in methanol (30 ml) and thereto is added 1N NaOH (30 ml). The mixture is stirred at room temperature for 1.5 hour, and the solvent is distilled off. The residue is dissolved in water and is acidified with 5% HCl. The precipitated crystals are collected by filtration, washed with water and dried to give the title compound (3.40 g, 72%) as colorless needles, m.p. 236°-237° C. (recrystallized from aqueous ethanol).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1
Reactant: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2c1ncn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-[N-[1-[(tert-butyl)oxycarbonyl]-benzimidazol-4-yl]carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (400 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (4 ml). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (chloroform:methanol=100:3) to give 4-[N-(1H-benzimidazol-4-yl)carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (290 mg).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([O-:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:19]=[CH:20][S:21][C:5]1=2>C(O)C.O>[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([OH:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:19]=[CH:20][S:21][C:5]1=2
Reactant: O=C([O-])c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Yield: 88.2 %

Procedure:
13.9 ml (0.0556 mol) of 4N sodium hydroxide solution were added dropwise to a suspension of 13.5 g (0.0445 mol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylate in 10 ml of ethanol and 16 ml of water and the mixture was heated at reflux for 1/2 hr. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with dichloromethane and adjusted to pH=3 with 4N hydrochloric acid. The resulting precipitate was filtered off, washed with water, ethanol and subsequently with diethyl ether. There were obtained 10.8 g (88%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepine-1-carboxylic acid as a colorless powder; m.p. 260° (dec.).
Reaction SMILES: [OH:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cnc4ncccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
3-Hydroxy-[1,8]naphthyridine-2-carboxylic acid (15 mg), 4-chloro-6,7-dimethoxyquinoline (47 mg), and 4-dimethylaminopyridine (26 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (6 mg, yield 26%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]1([CH:25]=[CH:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:29])[CH2:27][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CC2CC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C=CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
The mixture 2-[2-(-2-cyclopropyl-vinyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (137) (220 mg, 0.56 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (138) as white solid (209 mg, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])=[C:13]3[CH3:29])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>CO>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:6]1[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=1)[C:13]([CH3:29])=[C:14]2[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CCOC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(C)n(-c2ccnc3ccccc23)c2ccc(OC)cc12

Procedure:
5-Methoxy-2-methyl-1-quinol-4-ylindol-3-ylacetic acid (2g.) in methanol (30ml.) containing concentrated sulphuric acid (1 ml.) was refluxed for 2 hours. The resulting red solution was treated with saturated methanolic sodium acetate solution (30ml.) and the methanol then evaporated in vacuo. The residue was diluted with water (50ml.) and extracted with diethyl ether (2 × 30ml.). The ether extracts were dried (MgSO4) and evaporated, to yield methyl 5-methoxy-2-methyl-1-quinol-4-ylindol-3-ylacetate, m.p. 103°-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24](=[O:26])[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCc1ccccc1)Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-phenethyl-amine (0.055 g, 0.15 mmol), acetyl chloride (0.05 mL, 0.75 mmol), and triethylamine (0.13 mL, 0.95 mmol) were combined and stirred at room temperature for 30 minutes. The mixture was loaded directly onto silica gel and purified by silica gel chromatography (30-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Na+]>CO>[CH3:15][N:13]([CH3:14])[C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:16])=[O:2])[CH2:12][CH2:11]1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](N(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@H]1CC[C@@H](C(C)(C)C(=O)O)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.500 g of cis-(4-dimethylamino-cyclohexyl)-methyl-propionic acid methyl ester are taken up in 5 ml of methanol and the mixture is admixed with 5 ml of 3M NaOH. The mixture is then stirred at 60° C. for 16 hours. The methanol is removed in vacuo and the aqueous residue acidified with 2M HCl to pH 7. The mixture is concentrated under reduced pressure. The residue is taken up in 10 ml of ethanol and the insoluble salts removed by filtration. Concentration of the filtrate under reduced pressure provides the title compound which can be used without further purification.