Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[OH:43][CH:44]([C:46]1[O:47][C:48](=[O:63])[C:49]2[C:54]([C:55]=1[C:56]1[S:60][C:59]([CH:61]=O)=[CH:58][CH:57]=1)=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH3:45].[NH4+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:2][N:3]([CH3:25])[CH2:4][CH:5]=[CH:61][C:59]1[S:60][C:56]([C:55]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48](=[O:63])[O:47][C:46]=2[CH:44]([OH:43])[CH3:45])=[CH:57][CH:58]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)s1
Reaction time: 0.33 h
Yield: 40858.1 %

Procedure:
In a 100 ml 3-necked round bottomed flask (2-(dimethylamino)ethyl)-triphenylphosphonium bromide (1569 mg, 3.79 mmol) was loaded and suspended under Argon in 15 ml of Dioxane. Potassium bis(trimethylsilyl)amide solution 0.5 M in toluene (6.0 ml, 3.03 mmol) was added drop wise and a yellow\orange color appeared. The mixture was further stirred for 20 min then 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate B37, 455 mg, 1.515 mmol) dissolved in 5 ml of dioxane was added The mixture was further stirred at rt for 2 h then poured into 100 ml of NH4Cl sat. sol. and 200 ml of EtOAc. Phases were separated and the organic one was dried over sodium sulfate. Solvents were removed and the crude was purified by chromatography eluting with DCM\20% MeOH in DCM mixtures to leave 4-(5-(3-(dimethylamino)prop-1-en-1-yl)thiophen-2-yl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (220 mg, 0,619 mmol, 40.9% yield) as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][C:25](=O)[CH3:26])=[N:9][CH:8]=1)(C)(C)C.OS(O)(=O)=O.O.[OH-].[Na+]>CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]([C:6]([OH:5])=[O:28])=[CH:8][N:9]3[C:25]([CH3:26])=[CH:24][N:23]=[C:10]3[C:11]=2[Cl:22])=[C:15]([Cl:21])[CH:16]=1
Reactant: CC(=O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12

Procedure:
4-(4-Bromo-2-chlorophenylamino)-5-chloro-6-(2-oxopropylamino)-nicotinic acid tert-butyl ester (0.075 g, 0.15 mmol) was dissolved into concentrated H2SO4 (0.50 mL). After ten minutes, ice and water were and the mixture was stirred for ten minutes. The mixture was diluted with EtOAc, neutralized with 1 M NaOH, washed with brine, dried over Na2SO4 and concentrated to provide the desired product as an off-white solid. MS APCI (+) m/z 416, 418 (M+, Cl, Br pattern) detected.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>CO>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
Add sodium tetrahydroborate (1.01 g, 26.35 mmol) slowly to a solution of 1-(6-chloro-pyridin-3-yl)-ethanone (10 g, 64.27 mmol) in methanol (100 mL). Stir at RT for 15 min. Pour the reaction mixture into a beaker containing saturated NaHCO3 (40 mL) and then extract between water (100 mL) and DCM (400 mL). Wash the organic layers with saturated aqueous sodium chloride, dry over sodium sulfate and concentrate. Purify by normal phase column chromatography (20% ethyl acetate in hexanes→70% ethyl acetate in hexanes) to afford the title compound (7 g, 69%). MS (ES) m/z 158 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][CH2:13][C@H:14]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1)[CH3:15]>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][CH2:13][C@H:14]([N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)[CH3:15])=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 19.16 %

Procedure:
(R)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (0.314 g, 2.025 mmol) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.44 g, 1.688 mmol). The product was purified by Flash-chromatography. Yield 19.16%. 1H-NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.63 (s, 3H), 3.79-3.87 (m, 1H), 3.92-3.99 (m, 1H), 4.60-4.66 (m, 1H), 6.63 (d, 1H), 7.29 (s, 1H), 7.50 (d, 1H), 7.69-7.74 (m, 2H), 7.82 (dd, 1H), 8.05 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21].[I-].[Na+]>C(C(C)=O)C>[C:20]([NH:19][CH2:18][CH2:17][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])(=[O:22])[CH3:21]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CC(=O)NCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)NCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Yield: 21.1 %

Procedure:
2-Amino-6-trifluoromethoxybenzothiazole (9.4 g), N-(2-chloroethyl)acetamide (9.7 g) and sodium iodide (13.5 g) in methyl ethyl ketone (30 cc) are heated for 40 hours to boiling. After cooling to a temperature in the region of 20° C., the reaction medium is added to distilled water (200 cc), treated with 1N sodium hydroxide (40 cc) and then extracted with ethyl acetate (200 cc). After drying over magnesium sulphate and then concentration to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is purified by chromatography on a silica column with a mixture of ethyl acetate and methanol (90:10 by volume) as eluent. 3-(2-Acetamidoethyl)-2-imino-6-trifluoromethoxybenzothiazoline (2.7 g) is obtained, which product is converted to a hydrochloride subliming at about 180° C.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:32]([CH3:43])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].C([O-])=O.[NH4+]>[Pd].CO>[CH3:44][C:2]([CH3:1])([CH3:45])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:32]([CH3:43])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Yield: 89.5 %

Procedure:
A solution of tert-butyl (3R,5E)-3-({[(1s)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-methyl-4-phenoxyphenyl)hex-5-enoate (615 mg, 1.00 mmol), ammonium formate (310 mg, 4.9 mmol) and 10% palladium on charcoal (65 mg) in methanol (8 mL) was stirred at 20° C. for 16 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated under reduced pressure to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-methyl-4-phenoxyphenyl)hexanoate (550 mg, 90%), as a foam, which was taken onto the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)[CH:9]=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[CH:11]=1)[CH2:2][CH2:3][CH3:4].[ClH:46]>>[ClH:46].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:9]=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CNCCCNCCCNC(=O)OC(C)(C)C)cc(CNCCCNCCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Product: CCCCOc1cc(CNCCCNCCCN)cc(CNCCCNCCCN)c1
Reaction time: 2 h
Yield: 48 %

Procedure:
To the crude di-tert-butyl ((((((5-butoxy-1,3-phenylene)bis(methylene))bis(azanediyl))bis(propane-3,1-diyl))bis(azanediyl))-bis(propane-3,1-diyl))dicarbamate from Step 4 was added methanolic HCl (50 mL, 1.0 M). The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The solid was collected by vacuum filtration and washed with Et2O (10 mL) and hot MeOH (10 mL) to afford the desired product (0.27 g, 48%) as a white solid. 1H NMR (500 MHz, D2O) δ ppm 7.20 (s, 3H), 4.30 (s, 4H), 4.15 (t, J=6.5 Hz, 2H), 3.26-3.20 (m, 12H), 3.14 (t, J=7.5 Hz, 4H), 2.22-2.10 (m, 8H), 1.79 (quint, J=6.5 Hz, 2H), 1.48 (sext, J=7.5 Hz, 2H), 0.96 (t, J=7 Hz, 3H). 13C NMR (125 MHz, D2O) 159.2, 132.9, 123.5, 117.3, 68.8, 50.8, 44.7, 44.6, 44.1, 36.5, 30.3, 23.7, 22.6, 18.5, 13.0. LRMS [M+H]+437.4.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)=[CH:20][C:19]=3[Cl:32])=[CH:14][CH:13]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:28]([OH:30])=[O:29])[CH2:25][CH2:26][CH2:27]4)=[CH:20][C:19]=3[Cl:32])=[CH:16][CH:17]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(C4(C(=O)O)CCC4)cc3Cl)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Powdered potassium hydroxide (56.9 mg, 1.01 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylate (Intermediate 7-1; 152 mg, 0.34 mmol)/in tert-butanol (10 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 1 hour LCMS showed the reaction was complete. The reaction mixture was quenched with HCl (2.027 mL, 2.03 mmol) in ethanol (10 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was washed with water (50 mL) and dried in a dessicator to afford 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylic acid (68.0 mg, 46.2%) as a cream solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[CH3:12]I>[Zn].C(O)(=O)C>[CH3:12][O:11][C:5]1[C:4]([NH2:1])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: CI
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1nccc(C)c1N

Procedure:
3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide and reduced with zinc and acetic acid to give 2-methoxy-3-amino-4-methylpyridine. This material was coupled with 2-(4-(1-methylpropyl)phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH3:31][NH2:32].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[C:45]([C:51]3[C:52]([CH3:67])=[CH:53][C:54]([F:66])=[C:55]([NH:57][C:58]([NH:60][CH2:61][CH2:62][CH:63]4[CH2:65][CH2:64]4)=[O:59])[CH:56]=3)[C:46]([CH3:50])=[N:47]2)=[CH:42][N:41]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:63]1([CH2:62][CH2:61][NH:60][C:58]([NH:57][C:55]2[CH:56]=[C:51]([C:45]3[C:46]([CH3:50])=[N:47][C:48]4[C:43]([CH:44]=3)=[CH:42][N:41]=[C:40]([NH:32][CH3:31])[CH:49]=4)[C:52]([CH3:67])=[CH:53][C:54]=2[F:66])=[O:59])[CH2:65][CH2:64]1
Reactant: CN
Reactant: Cc1cc(F)c(NC(=O)NCCC2CC2)cc1-c1cc2cnc(Cl)cc2nc1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC4CC4)c(F)cc3C)cc2cn1
Temperature: 90 °C
Yield: 59.4 %

Procedure:
Add Pd2(dba)3 (0.020 g, 0.022 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl [t-butyl X-Phos] (0.019 g, 0.045 mmol), methylamine (2.0M in THF, 1.114 mL, 2.228 mmol) and Cs2CO3 (0.436 g, 1.337 mmol) to a solution of 1-(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(2-cyclopropylethyl)urea (0.184 g, 0.446 mmol) in dioxane (4 mL) and heat at 90° C. for 3 h. Cool to RT, remove the solids via filtration, rinse with DCM, then THF, concentrate the filtrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 1-(2-cyclopropylethyl)-3-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea (108 mg, 59%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.16 (d, J=12.4 Hz, 1H), 6.78-6.72 (m, 1H), 6.59 (m, 1H), 6.52 (s, 1H), 3.10 (q, J=6.5 Hz, 2H), 2.82 (d, J=5.0 Hz, 3H), 2.26 (s, 3H), 1.95 (s, 3H), 1.37 (m, 2H), 0.70 (m, 1H), 0.35 (m, 2H), 0.04 (m, 2H); MS(ESI) m/z: 408.2 (M+H+). Suspend 1-(2-cyclopropylethyl)-3-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea, (0.108 g, 0.265 mmol) in acetonitrile (4 mL), treat with 0.5 M HCl (0.53 mL, 0.265 mmol), freeze and lyophilize the resulting clear solution to provide the title compound. MS(ESI) m/z: 408.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C([O-])(=O)C.[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5](=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:15]([OH:19])[OH:16])[CH:3]=2)[O:8]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2cc(B(O)O)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (21 g), pinacol diborane (25 g), palladium acetate (0.92 g) and potassium acetate (2.4 g) in N,N-dimethylformamide (250 mL) was stirred at 90° C. for 2 hr under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (80 mL), and 0.5 M hydrochloric acid (40 mL) and sodium periodate (7.0 g) were added at 0° C. The reaction mixture was stirred at room temperature for 2 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (15 g, 84%) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([CH2:7][C:5]1[S:6][C:2]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:3][CH:4]=1)=[CH:9][N:10]2[C@@H:18]1[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]1[OH:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccccc1
Product: Cc1cccc2c1c(Cc1ccc(-c3ccccc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and benzeneboronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a pale yellow powder. APCI-Mass m/Z 466 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.25 (m, 1H), 3.35-3.49 (m, 2H), 3.66-3.73 (m, 2H), 4.38 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.17 (d, J=5.9 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 7.24 (t, J=7.3 Hz, 1H), 7.31-7.38 (m, 5H), 7.56 (d, J=7.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH3:27])[N:5]([C:13](=[O:26])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].[CH3:29][N:30]([CH3:32])[NH2:31]>C(O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH3:27])[N:5]([C:13](=[O:26])[CH2:14][NH:31][N:30]([CH3:32])[CH3:29])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: CN(C)N
Reactant: COC(=O)[C@H](C)N(C(=O)COS(=O)(=O)c1ccc(C)cc1)c1c(C)csc1C
Solvent: CCO
Product: COC(=O)[C@H](C)N(C(=O)CNN(C)C)c1c(C)csc1C

Procedure:
A mixture of 8.5 g (0.02 mol) N-[(4-methylphenyl)-sulphonyloxyacetyl]-N-(2,4-dimethylthien-3-yl)-alanine-methylester (=Ex. 3.9) and 2.4 g (0.04 mol) 1,1-dimethylhydrazine in 150 ml ethanol is refluxed for four hours, then evaporated in vacuo, the residue taken up in dichloromethane, washed subsequently with water, aqueous 1 N HCl and water, dried over MgSO4, and evaporated in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([C:32]([O:34][CH3:35])=[O:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O.Cl>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[C:17]3[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH2:15][C:14]([C:32]([O:34][CH3:35])=[O:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:13][C:5]=2[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(Cc1cc(OC)c(OC)c(OC)c1)(Cc1cc(OC)c(OC)c(OC)c1)C(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(C(=O)OC)Cc2cc(OC)c(OC)c(OC)c2-c2c(cc(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Dissolved in 4 ml of dichloromethane were 200 mg (0.41 mmol) of dimethyl 1,3-bis(3,4,5-trimethoxyphenyl)propane-2,2-dicarboxylate. The solution was added with 0.4 ml of trifluoroacetic acid and 580 mg (1.25 mmol) of ferric perchlorate, followed by stirring at room temperature for 2 hours. After the reaction mixture was added with 2N-HCl and then dissolved in 20 ml of ethyl acetate, the water layer was removed. The organic layer was washed with water and then with saturated NaHCO3, and then was dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel: "MERCK #9385", 10 g, eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 183 mg of the title compound were obtained as a colorless solid (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(F)cc2)cc1
Yield: 58 %

Procedure:
A solution of 4-fluorobenzaldehyde (5 mmol) and 4-sulfamyl-phenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 205–206° C., was obtained in 58% yield.
Reaction SMILES: [NH:1]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:2]([C:12]([NH:14][C@H:15]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:16])=[O:13])[CH2:3][NH:4]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:2]([C:12]([NH:14][C@H:15]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH3:16])=[O:13])[CH2:3][NH2:4]
Reactant: C[C@H](NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@H](CN)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound (247) (0.51 g, 1.02 mmol) from above was dissolved in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the crude residue (248) (0.49 g) was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]4)[C:5]=2[CH2:4][CH2:3]1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][C:11]([C:10]3[C:5]4[CH2:4][CH2:3][CH:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[C:6]=4[CH:7]=[N:8][CH:9]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:22]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC4N)ccc21
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NC1CCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 39 %

Procedure:
In analogy to the procedure described for the preparation of example 4, (rac)-6-(7-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-4) and ethanesulfonyl chloride gave the title compound as an off-white powder in 39% yield. MS: 386.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].N12CCCN=C1CCCC[CH2:28]2.CI>C(#N)C>[CH3:28][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)[CH3:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (208 mg, 0.54 mmol) is suspended in acetonitrile (5 mL). 1,8-Diazabicyclo[5,4,0]undec-7-ene (0.096 mL, 0.64 mmol) is added and followed by the addition of methyl iodide (0.073 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica, eluent: DCM, MeOH) to provide 171 mg of the title compound. Yield: 79%; m/z 403 [M+H].