Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH3:60])(O)[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C([SiH3])CCC.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([CH3:60])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: CCCC[SiH3]
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
To a solution of 45 (38 mg, 46 μmol) in dry DCM (1 mL) flushed with argon was added tris(pentafluorophenyl)borane (5 mg, 9.6 μmol). After stirring for 10 min, n-butylsilane (8 μL, ˜2 equiv) was added. Stirring was continued for 3 days. The mixture was directly loaded onto a preparatory TLC plate, developed with 15% EtOAc in petroleum ether to give 46 (21 mg, 56% yield) as a single diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.14-7.31 (m, 19H), 6.81-6.99 (m, 6H), 4.86 (d, J=10.5 Hz, 1H), 4.81 (s, 2H), 4.58 (d, J=12.0 Hz, 2H), 4.45 (d, J=12.0 Hz, 1H), 4.33 (d, J=10.8 Hz, 1H), 4.07-4.16 (m, 2H), 4.04 (d, J=15.0 Hz, 1H), 3.61-3.89 (m, 8H), 2.49 (q, J=7.5 Hz, 2H), 2.15-2.20 (m, 2H), 1.41 (d, J=6.0 Hz), 1.11 (t, J=7.5 Hz, 3H).LCMS m/z 832 (M+Na), 810 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])C)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.C(O)(C)C.Cl.O.[Pd]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: CN(CCC(C(=O)N1CCCCCC1)c1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CNCCC(C(=O)N1CCCCCC1)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
A solution of the product of step (a) (6.93 g, 19.0 mmol) in ethanol (60 ml) was added to a suspension of 10% Pd/C (10.67 g) in isopropanol (50 ml) plus 5 drops of concentrated hydrochloric acid. The reaction mixture was heated to 50° C. and 50 psi (about 3.5×105Nm-2) in a Parr bottle for 4 h. The catalyst was filtered off and the filtrate concentrated under reduced pressure to afford an oil. The oil was dissolved in water (80 ml), cooled (ice/water) and basified with aqueous sodium hydroxide (2M). The basic phase was washed with diethyl ether (3×50 ml) and the combined organic phases washed with brine (50 ml), water (50 ml), dried (MgSO4) and concentrated to afford the title compound as an oil (3.38 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)[CH3:27]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(Cl)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:13][S:12][C:9]1[N:8]=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Oc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(Oc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of 7.0 g (23.0 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester in 50 ml ethanol a solution of 1.37 g (34.50 mmol) sodiumhydroxide in 30 ml water was added and the resulting mixture was stirred 1 h at RT. The pH of the solution was adjusted to 1 with 25% HCl. The mixture was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting solid was triturated twice with 10 ml diisopropylether, filtered off and dried to give 3.00 g (47%) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (ISN): 257.1 (M-H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].ICC.CCN(C(C)C)[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH:22]([CH3:24])[CH3:23])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Product: CC(C)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 146.2 %

Procedure:
To a stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (10.0 g, 43.8 mmol) in DMF (20 mL) was added 2-iodoethane (9.67 g, 56.9 mmol) and DIPEA (7.35 g, 56.9 mmol). The resulting solution was stirred at ambient temperature for 6 h. After this time, the solvent was removed under vacuum and the residue was dissolved in CH2Cl2 (50 mL). The organic layer was washed with water (2×50 mL), 2N sodium hydroxide (50 mL) and brine (50 mL). The organics were dried (Na2SO4) and concentrated under vacuum. Three reactions were run in parallel and then combined for purification via column chromatography (silica gel, EtOAc) to provide the title compound (17.3 g, 49% yield) as a yellow oil: LC (ELS)/MS: 91%, m/z 271.6 [C14H17Cl2N+H]+; 1H NMR (300 MHz, CDCl3): δ 0.75 (dd, 1H, J=4.2 Hz, J==8.1 Hz), 1.05 (dd, 6H, J=4.7 Hz, J=6.3 Hz), 1.44 (t, 1H, J=4.2 Hz), 1.67 (td, 1H, J=3.9 Hz, J=8.0 Hz), 2.50 (m, 3H), 3.11 (d, 1H, J=8.6 Hz), 3.31 (d, 1H, J=8.4 Hz), 6.96 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.22 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=8.3 Hz).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 3.1 g (15.6 mmol) of ethyl 2-isopropylthiazole-4-carboxylate in 50 ml of dichloromethane was cooled under N2 atmosphere to -78° C. and treated dropwise with 15.6 ml (23.4 mmol) of a 1.5M solution of diisobutylaluminum hydride in toluene over a period of 1.5 h. After being stirred for an additional 0.5 h, the solution was quenched with 5 ml of methanol followed by 15 ml of aqueous Rochelle's salt. The resulting mixture was partitioned between chloroform and aqueous Rochelle's salt, dried over Na2SO4, and concentrated to provide 1.37 g (56%) of the crude desired compound, Rf 0.47 (20% ethyl acetate in hexane). 1H NMR (CDCl3) δ1.45 (d, J=7 Hz, 6H), 3.39 (heptet, J=7 Hz, 1H), 8.07 (s, 1H), 10.00 (s, 1H). Mass spectrum: (M+H)+ =156.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4)CC3)C2)cc1OC
Yield: 90.3 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (36.3 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 45.5 mg (90.1%) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:11].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([N:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:6]2=[O:11])[S:29]([CH3:28])(=[O:31])=[O:30])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N)c2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(S(C)(=O)=O)S(C)(=O)=O)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of tert-butyl 2-(4-amino-1,3-dioxoisoindolin-2-yl)acetate (712 mg, 2.58 mmol), triethylamine (1029 μl, 7.73 mmol) and methanesulfonyl chloride (602 μl, 7.73 mmol) in 20 ml of DCM was stirred overnight at room temperature. The mixture was washed with 1N HCl, brine and finally dried over sodium sulfate and evaporated; the residue was purified by flash chromatography (Hexane/EtOAc 3/1 to 1/1) yielding tert-butyl 2-(4-(N-(methylsulfonyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate as an off-white foam (0.96 g, 2.220 mmol, 86% yield, MS/ESI+ 454.8 [MNa]+) and used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]([NH:31]C(=O)C)[S:29][CH:30]=2)=[CH:22][CH:21]=1.Cl>C(O)C>[ClH:1].[NH2:31][C:28]1[S:29][CH:30]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[Cl:1])[NH:9][C:8](=[O:12])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]4[OH:19])=[CH:21][CH:22]=2)[N:27]=1
Reactant: CC(=O)Nc1nc(-c2ccc(-c3cc4c(O)c(-c5ccccc5)c(=O)[nH]c4cc3Cl)cc2)cs1
Agent: Cl
Solvent: CCO
Product: Nc1nc(-c2ccc(-c3cc4c(O)c(-c5ccccc5)c(=O)[nH]c4cc3Cl)cc2)cs1
Temperature: 100 °C
Reaction time: 4 h
Yield: 158 %

Procedure:
To a solution of N-{4-[4-(7-chloro-4-hydroxy-2-oxo-3-phenyl-1,2-dihydro-6-quinolinyl)phenyl]-1,3-thiazol-2-yl}acetamide (Example 9) (1.7 g, 3.81 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (5.72 mL, 57.2 mmol) and the reaction mixture was stirred at 100° C. for 4 h. After cooling, the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to give the title compound 6-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-7-chloro-4-hydroxy-3-phenylquinolin-2(1H)-one hydrochloride (1.45 g, 3.01 mmol, 79% yield) as a grey powder. LCMS: (M+H)+=446; Rt=2.44 min. HRMS calculated for C24H15ClN3O2S (M−H)+: 444.0574. found: 444.0532.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9]C.B(Cl)(Cl)Cl>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[OH:9]
Reactant: COc1cc(N)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Nc1ccc(F)c(O)c1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 50 g (0.354 mol) of 4-fluoro-3-methoxy-aniline dissolved in methylene chloride (1800 ml) was treated under argon with 163.2 g (0.44 mol) of tetrabutyl-ammonium iodide, cooled to −75° C. and the treated over a period of 25 minutes with 860 ml of 1 M BCl3 in methylene chloride while keeping the reaction solution between −75° C. and −64° C. The solution was stirred for 15 minutes the cooling bath was removed and stirring was continued for 24 h under argon. The reaction solution was poured into ice water (6 l) with stirring, the layers were separated, the water layer twice extracted with methylene chloride (each 1.5 l). The combined organic layers were washed twice with water (each 2 l) and discarded. The combined aqueous layers were made basic with solid NaHCO3, saturated with NaCl, extracted 3 times with 2.5 l of ether and twice with 1.5 l of AcOEt. The combined organic layers were tried over magnesium sulphate and concentrated in vacuo to give 43.9 g (87.8%) of 4-fluoro-3-hydroxy-aniline as light brown crystalline solid. Melting point: 156-157° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:34]2[S:38][C:37]3[C:39]([C:43]4[C:48]([O:49][CH2:50][CH2:51][O:52]C5CCCCO5)=[CH:47][N:46]=[C:45]([F:59])[CH:44]=4)=[CH:40][CH:41]=[CH:42][C:36]=3[CH:35]=2)=[N:21][C:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])=[N:23][CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:34]2[S:38][C:37]3[C:39]([C:43]4[C:48]([O:49][CH2:50][CH2:51][OH:52])=[CH:47][N:46]=[C:45]([F:59])[CH:44]=4)=[CH:40][CH:41]=[CH:42][C:36]=3[CH:35]=2)=[N:21][C:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])=[N:23][CH:24]=1
Reactant: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4OCCOC4CCCCO4)c3s2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4OCCO)c3s2)n1
Temperature: 55 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
Add pyridinium p-toluenesulfonate (4.3 mg, 0.02 mmol) to a solution of 1-{2-[5-fluoro-4-(7-{2-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyridin-4-yl}-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-imidazolidin-2-one (100 mg, 0.17 mmol) in ethanol (4 mL). Stir the mixture at 55° C. overnight. Cool the solution. Concentrate the solution in vacuo to yellow oil. Purify the oil by column chromatography (methylene chloride to 10% methanol in methylene chloride) to afford the title compound (75 mg, 87%) as a light yellow solid. MS (ES) m/z 513 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH+:7]([O-:35])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:25])[F:26])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cccnc1)c1ccc(OC(F)F)c2oc3ccccc3c12
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OC(F)F)c2oc3ccccc3c12)[NH+]([O-])c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.14 mmol) (example 23) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.704 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. Chloroform was evaporated and the resulting solid was stirred in saturated sodium bicarbonate solution, filtered, dried and purified by column chromatography using 40% acetone-chloroform as the eluent to give 25 mg of of N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 252° C. (dec)
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([C:21]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=4)[CH:25]([CH2:35][Cl:36])[CH2:24]3)=[O:22])[NH:18]2)=[CH:14][CH:13]=1)=[O:11])=[O:7])CCC.O1CCOCC1>Cl>[C:6]([CH2:8][NH:9][C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([C:21]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=4)[CH:25]([CH2:35][Cl:36])[CH2:24]3)=[O:22])[NH:18]2)=[CH:14][CH:13]=1)=[O:11])([OH:7])=[O:5]
Reactant: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 78.2 %

Procedure:
A suspension of N-[(butoxycarbonyl)methyl]-2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl)indole-6-carboxamide (70 mg, 0.14 mmol) in HCl-saturated dioxane (20 mL) was stirred at 20° C. for 2 h, most of the dioxane evaporated, and the residue triturated with hot EtOAc to give N-(carboxymethyl)-2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]indole-6-carboxamide as a pale yellow powder (50 mg, 80%), mp 281° C. (dec.). 1H NMR [(CD3)2SO] δ12.57 (br s, 1H, CO2H), 12.20 (d, J=1.3 Hz, 1H, indole NH), 8.99 (d, J=2.2 Hz, 1H, H-7), 8.84 (t, J=5.9 Hz, 1H, amide NH), 8.07 (s, 1H, H-3' or H-7'), 8.05 (dd, J=8.3, 2.2 Hz, 1H, H-5), 7.79 (d, J=8.4 Hz, 1H, H-4'), 7.75 (d, J=8.3 Hz, 1H, H-4), 7.61 (dd, J=8.4, 1.3 Hz, 1H, H-5'), 7.30 (d, J=1.9 Hz, 1H, H-3' or H-7'), 4.87 (t, J=10.1Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.2 Hz, 1H, H-2), 4.19-4.08 (m, 3H, H-3 and CH2Cl), 3.95 (d, J=5.8 Hz, 2H, CONHCH2). Anal. (C23H17ClN4O6) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][C:26]([CH:35]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:35][C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 89.1 %

Procedure:
Compound 31 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH3:16])[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+]>C1COCC1.O>[OH:1][C@@H:2]([C@@H:9]([CH3:16])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](C)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Diisopropyl (2S,3R)-2-hydroxy-3-methylsuccinate (3.70 g; 15.93 mmol; 1.0 eq.) was taken in THF (55 mL), cooled to 0° C. and treated with KOH (5.36 g, 96 mmol) in water (18.5 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with Et2O (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc (continuous extraction during 20 hours). The organic phase was dried over Na2SO4 and then concentrated to give the title product (mixture of diastereoisomers) as pale yellow oil (2.4 g, quant.).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].CN1CCNCC1.C[O:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][C:24]=1[Cl:32].O>C1(C)C=CC=CC=1>[Cl:32][C:24]1[CH:25]=[C:26]([CH:29]2[CH2:30][CH2:31]2)[CH:27]=[CH:28][C:23]=1[CH:22]=[O:21]
Reactant: COC(=O)c1ccc(C2CC2)cc1Cl
Agent: CN1CCNCC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C2CC2)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.01 ml Red-Al 13.5 M (24.54 mmol) in toluene was added at 0° C. a solution of 3.0 ml 1-methylpiperazine (26.89 mmol) in 16 ml toluene over 30 min. The resulting solution was then added dropwise over 40 min to 1.1 g of 2-chloro-4-cyclopropyl-benzoic acid methyl ester (5.2 mmol) in 32 ml toluene between −5° C. and 0° C. After stirring for 30 min at this temperature, the reaction mixture was cooled to −10° C. and treated dropwise with 30 ml water. The mixture was then filtered, diluted with ethylacetate, washed with 1N—HCl, brine, dried over magnesium sulfate, filtered again and concentrated in vacuo, leading to 0.98 g of 2-chloro-4-cyclopropyl-benzaldehyde as a brown oil (100%). MS (+cEI): 180.1 (M).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CO.O>C1OCCC1>[CH3:34][C:3]1([CH3:2])[C:12]2[CH:11]=[C:10](/[C:13](/[CH3:14])=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: O=Cc1ccccc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCO2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)CCO2
Yield: 19.1 %

Procedure:
16.5 g of [1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphonium bromide and 3 g of benzaldehyde were heated under reflux in 100 ml of butylene oxide for 20 hours. The reaction mixture obtained was poured into a methanol/water mixture (6:4) and extracted with hexane. After drying and evaporating the organic phase the crude product was chromatographed (silica gel, eluting agent hexane) and recrystallized from hexane. There were obtained 1.5 g of 3,4-dihydro-4,4-dimethyl-6-[(E)-α-methylstyryl]-2H-1-benzopyran in the form of colorless crystals, melting point 64°-65° C.
Reaction SMILES: CS(O[CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1)(=O)=O.C([O-])(=[S:36])C.[K+]>CC(C)=O>[SH:36][CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)OS(C)(=O)=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCC(S)CCCCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 7.6 g. ethyl 4-(6-methanesulfonyloxyhexadecylamino)benzoate and 5.5 g. of potassium thioacetate in 200 ml. of acetone is stirred under reflux for 3 hours and evaporated. The residue is partitioned between methylene chloride and water and the organic layer is separated, dried and evaporated. Recrystallization of the residual solid from hexane affords the product as a light, tan solid. Hydrolysis of the product by the method of Example 10 affords 4-(6-mercaptohexadecylamino)benzoic acid.