Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(SCCc2ccccc2)cc1
Yield: 66.8 %

Procedure:
A mixture of 2-phenylethylmercaptan (72.3 mmol, 10.0 g), 4-bromobenzaldehyde (79.6 mmol, 14.7 g) and potassium carbonate (116 mmol, 16 g) were stirred in dimethylformamide (100 ml) at 110° C. for 48 hours. The solution was cooled and diluted with water (200 ml). The aqueous was extracted with ether (3×200 ml) and the combined ether layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica gel using hexane:ethyl acetate (9:1) as eluant to afford 11.7 g (67%) of present title product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2].S(=O)(=O)(O)O.ON1[C:32]2C=CC=C[C:31]=2N=N1.Cl.[CH3:38]N(C)CCCN=C=NCC>C(N(CC)CC)C.C(O)(C)C>[CH:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[C:8]([O:10][CH2:31][CH3:32])=[O:9])([CH3:38])[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)OC(C)C)c1
Temperature: 25 °C

Procedure:
Sonicate a mixture of 5-(methyl-propyl-carbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), isopropanol (0.75 mL) and concentrated sulfuric acid (25 μL) then stir the resulting solution at room temperature for one month. Add 1-hydroxybenzotriazole (68 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol), and triethylamine (100 μL). Stir overnight at room temperature. Add dichloromethane (25 mL) and wash with 0.1 N citric acid (5 mL), saturated aqueous sodium bicarbonate (10 mL), saturated aqueous sodium chloride (10 mL), dry (magnesium sulfate) and concentrate (149 mg, 89%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:18])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:3])[CH3:2].O([CH2:40][CH2:41][O:42][CH3:43])S(C(F)(F)F)(=O)=O.[H-].[Na+]>ClCCl.CN1CCCC1=O>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:40][CH2:41][O:42][CH3:43])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: COCCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N1c2c(ccn3cc(C)nc23)[C@@H](O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=1.19(s, 9H), 2.15(s, 3H), 2.38(s, 3H), 3.27(s, 3H), 3.45–3.57(m, 2H), 3.83–3.93(m, 2H), 4.60(d, 1H), 5.31(t, 1H), 5.79(d, 1H), 6.94 (s, 1H), 7.20(s, 5H); 7.74(s, 1H), 8.43(d, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[C:20](OCC)(OCC)(OCC)[CH3:21].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=[C:20]1[CH3:21]
Reactant: Nc1cnc2ccccc2c1NCCCCCCCl
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3ccccc3c2n1CCCCCCCl
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
N4-(6-Chlorohexyl)quinoline-3,4-diamine (5 g, 18 mmol), triethyl orthoacetate (2.92 g, 18 mmol), toluene (75 mL), and a catalytic amount of pyridine hydrochloride were combined in a pressure vessel and heated to 140° C. After about 1.5 hours the reaction mixture was allowed to cool and then it was concentrated under reduced pressure to provide 3.8 g of 1-(6-chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a dark orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O>O1CCCC1.C1C=CC=CC=1>[Cl:17][C:9]1[C:10]([OH:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2)on1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Oc1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3-hydroxyisoxazole (50.0 g) in dry tetrahydrofuran (300 ml), a solution of sulfuryl chloride (34.5 g) in dry benzene (50 ml) was added dropwise with stirring at 5° C. The resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour and further refluxed for 3 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the solid thus obtained was recrystallized from ethanol to obtain the title compound (44.2 g, 76.8%) as colorless needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([Cl:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1Cl
Yield: 75.5 %

Procedure:
The product was prepared by the alkylation of 2-chloro-4-nitrophenol (17.35 g) in DMF (150 mL) with ethyl bromoacetate (16.7 g) in the presence of potassium carbonate (13.8 g) to afford 19.6 g (75.6%) of ethyl 4-nitro-2-chlorophenoxyacetate as a white solid, m.p. 73°- 74° C.; hydrogenation of the latter (10.0 g, 38.5 mmol) in ethanol (200 mL) on a Parr hydrogenator in the presence of 5% platinum on carbon (sulfided) (200 mg) afforded 8.1 g (92%) of ethyl 4-amino-2-chlorophenoxyacetate, m.p. 59°-62° C., after recrystallization from tert-butylmethylether, and finally, treatment of the latter (7.3 g, 31.8 mmol) in CH2Cl2 (75 mL) at 5° C. with pyridine (3.0 mL, 38.7 mmol) and methanesulfonyl chloride (2.29 mL) to afford N-[4-(ethoxycarbonylmethoxy)-3-chlorophenyl]methanesulfonamide, m.p. 87°-88° C. after recrystallization from tert-butylmethylether.
Reaction SMILES: O.O.Cl[Sn]Cl.[N+:6]([C:9]1[CH:10]=[C:11]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([NH2:6])[CH:10]=2)[NH:15][N:16]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(C(F)(F)F)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc2[nH]nc(C(F)(F)F)c2c1
Yield: 102.6 %

Procedure:
SnCl2.2H2O (1.3 g, 5.7 mmol) was added to 5-nitro-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.19 g, 0.82 mmol) in ethyl acetate (20 mL). The resulting solution was heated to reflux for 3 hours. The cooled yellow solution was treated with dilute aqueous sodium bicarbonate. The resulting slurry was filtered through celite, and the filter cake was washed with ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-amine (0.17 g, 99%) as a film.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=[O:10].[N:41]1([CH2:46][C@@H:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[CH2:45][CH2:44][CH2:43][CH2:42]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:48]2[CH2:49][CH2:50][CH2:51][C@H:47]2[CH2:46][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:10])[C:15]=1[CH3:16])(=[O:28])=[O:29]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (120 mg, 0.2 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (31 mg, 0.2 mmol) to give the titled compound.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C.C(Cl)Cl>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: [S-]c1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 mL of DMF was heated at 50° C. with 4-chloro-3-nitrotoluene (2.65 mL, 20 mmol) with stirring for 2 days. Cooled to room temperature and diluted with CH2Cl2. Washed with water and dried the organic layer over Na2SO4. Filtered and concentrated under vacuum giving the title compound (4.29 g, 87%) 1H NMR (300 MHz, CDCl3) δ ppm: 2.36 (s, 3 H) 6.76 (d, J=8.09 Hz, 1 H) 7.16 (d, J=8.46 Hz, 1H) 7.45 (m, 3 H) 7.58 (m, 2 H) 8.03 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:23]3[CH2:31][C:30]4[C:25](=[C:26]([N+:32]([O-])=O)[CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:35])[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[C:24](=[O:35])[N:23]([CH:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:14])[F:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:7]=1)[CH2:17][C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:31]2
Reactant: [H][H]
Reactant: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc(N)c2C1=O
Yield: 97.4 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-propionamide (330 mg, 0.67 mmol) in ethyl acetate (100 ml) was added 10% Pd on carbon (100 mg). The suspension was shaked under about 50 psi hydrogen atmosphere at room temperature overnight. The suspension was filtered through a pad of celite. The solvent was removed and the resulted oil was purified by HPLC (CH3CN:water=40:60) to give 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (300 mg, 65%): mp 70–72° C.; 1HNMR (CDCl3): δ 0.31–0.37 (m, 2H), 0.58–0.65 (m, 2H), 1.21–1.28 (m, 1H), 2.90(s, 3H), 3.05 (dd, J=6.3, 15.8 Hz, 1H), 3.09 (s, 3H), 3.52 (dd, J=8.5, 15.3 Hz, 1H), 3.85 (d, J=7 Hz, 2H), 4.20 (d, J=16.8 Hz, 1H), 4.35 (d, J=16.8 Hz, 1H), 5.20 (broad, 2H), 5.56 (dd, J=6.3, 8.5 Hz, 1H), 6.52–6.63 (m, 2H), 6.59 (t, JH-F=75 Hz, 1H), 6.90–6.98 (m, 1H), 7.09–7.26 (m, 3H); 13C NMR (CDCl3): δ 10.8, 36.2, 37.0, 38.1, 49.8, 54.3, 114.0, 114.9, 116.3, 116.9, 120.1, 121.0, 123.3, 133.4, 139.4, 140.5, 143.4, 146.6, 151.3, 170.4, 170.9; Anal. Calcd. for C24H27F2N3O4 +0.18 H2O: C, 62.30; H, 5.96; N, 9.08; H2O 0.7. Found: C, 62.30; H, 5.89; N, 9.02; H2O, 0.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10][C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1.[Se](=O)=[O:21].OO.O>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1)=[O:21]
Reactant: Fc1cccc(Cl)c1CSc1nc2cnccc2[nH]1
Reactant: O=[Se]=O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(Cc1c(F)cccc1Cl)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[(2-Chloro-6-fluorophenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine (2.6 g, 0.0089 mol) was dissolved in 140 mL of methanol containing 20 mL of ethyl acetate. An oxidizing solution was prepared by heating 0.99 g (0.0089 mol) of selenium dioxide in 40 mL of methanol and adding 1.01 g (0.0089 mol) of 30% hydrogen peroxide and 0.65 mL of water. The oxidizing solution was added dropwise with stirring to the sulfide solution. The reaction mixture was stirred overnight at room temperature. Approximately 1/2 the solvent was removed in a rotary evaporator and the reaction mixture was chilled in ice. The resulting precipitate was collected and amounted to 1.08 g. An analytical sample, m.p. 180°-183° C., was obtained by recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=C[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.BrC1C=[N:19]C(C#N)=NC=1.BrC1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[N:15])=[N:19][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cn1
Reactant: N#Cc1ncc(Br)cn1
Agent: OB(O)c1ccc(Br)cc1
Product: N#Cc1ncc(-c2ccc(Br)cc2)cn1
Yield: 58 %

Procedure:
The same procedure described for 5-(4′-bromophenyl)-2-pyridinecarbonitrile was used by employing 5-bromo-2-cyanopyrimidine and 4-bromophenylboronic acid to furnish 84 in 58% yield; mp 202-204° C. 1H NMR (DMSO-d6): δ 7.79 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])(O)[CH3:9])=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])([C:24]2[C:23]3[C:27](=[C:19]([CH2:18][S:17][CH3:16])[CH:20]=[CH:21][CH:22]=3)[NH:26][CH:25]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg (0.68 mmol) of the compound from Example 75A and 120 mg (0.68 mmol) of the compound from Example 8A were introduced into 4 ml of dichloromethane at 0° C., 157 mg (0.71 mmol) of indium(III) chloride were added, and the mixture was stirred at RT for 1 h and under reflux for 0.5 h. After cooling, 0.05 ml (0.68 mmol) of trifluoroacetic acid was added, and the mixture was stirred under reflux for 5 min. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 117 mg (45% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22].Cl>O1CCOCC1.CO.O1CCOCC1.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Temperature: 100 °C
Reaction time: 54 h

Procedure:
A mixture of 1.5 g of 2-chloro-3-nitro-pyridine, 3.39 g of (4-amino-2-methyl-phenyl)-acetic acid methyl ester and 6.9 ml of an 4 N solution of HCl in dioxane in 30 ml of MeOH/dioxane (1:1, v/v) is stirred for 54 hours at 100° C. The mixture obtained is allowed to cool to rt and concentrated in vacuo. The concentrate obtained is dissolved in EtOAc, the mixture obtained is washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate obtained is subjected to silica gel column chromatography. [2-Methyl-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester is obtained. ES-MS: 302.1 [M+H]+; tR=4.79 min (System 1); Rf=0.43 (CH2Cl2).
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1)=[C:14]=[O:15]>>[C:10]([O-:12])(=[O:11])[CH3:9].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:13][C:14](=[O:15])[NH:1][C@H:2]([CH2:9][C:10]([OH:11])=[O:12])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])=[CH:17][CH:18]=1)(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Reactant: O=C=Nc1ccc(C(=O)c2ccccc2)cc1
Product: CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)O)NC(=O)Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
According to the method described in example S11, aminocarnitine (40 mg) was reacted with (4-isocyanatophenyl)(phenyl)methanone to yield the title compound as a white solid (13.4 mg). 1H NMR (400 MHz, CD3OD): δ=7.76-7.68 (m, 4H), 7.66-7.55 (m, 3H), 7.55-7.48 (m, 2H), 4.66 (brs, 1H), 3.78 (dd, J=9.20 Hz, 13.60 Hz, 1H), 3.60-3.50 (m, 1H), 3.24 (s, 9H), 2.65-2.50 (m, 2H), 1.98 (s, 3H); MS ESI [M+H]+, calcd for [C21H26N3O4+H]+ 384.4 found m/z 384.2 (100)
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]3[NH:24][C:23](=[O:25])[CH2:22][CH2:21]3)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:24]1[CH:20]([C:11]2[O:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)[CH2:21][CH2:22][C:23]1=[O:25]
Reactant: COc1cccc(CCl)c1
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.9 %

Procedure:
To a solution of NaH (60% oil, 28 mg), 5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.15 g) and sodium iodide (catalytic amount) in THF (1 ml) was added a solution of 3-methoxybenzyl chloride (0.11 g) in THF (2 ml). After being stirred for 4 days at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-methoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.14 g). MS (m/z): 425 (M+ +1) NMR (CDCl3, δ): 2.32-2.96 (4H, m), 3.65 (3H, s), 4.32 (1H, d, J=14.8 Hz), 4.70 (1H, d, J=14.8 Hz), 4.78 (1H, m), 6.68-6.82 (3H, m), 7.13 (1H, t, J=7.8 Hz), 7.33-7.48 (6H, m), 7.56-7.61 (4H, m)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.[ClH:52]>CCOCC.CO>[ClH:52].[CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 66 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in HCl in ether/methanol (2/3 ml) to afford 120 mg (66% yield) of the titled compound. MS: m/z=605.2 (M+1).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28]C)=O)[CH2:22][C@@H:21]2[CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].[NH3:36]>C(O)C>[ClH:9].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][C@H:23]([C:26]([NH2:36])=[O:28])[CH2:22][C@@H:21]2[CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: N
Reactant: COC(=O)[C@H]1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@@H](CN2CCCC2)C1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: Cl
Product: NC(=O)[C@H]1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@@H](CN2CCCC2)C1

Procedure:
A solution of the product of Example 3 as the free base (0.25 g) in a mixture of ethanol (5 ml) and liquid ammonia (50 ml) was heated at 100° for 3 days in an autoclave. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane/methanol/ammonia 100:10:2 as eluent to give the free base of the title compound as an oil (0.14 g). A solution of the oil in a mixture of diethyl ether and methyl acetate was treated with ethereal hydrogen chloride. The resulting solid was washed with diethyl ether and dried to give the title compound as a solid (0.065 g) T.l.c. Silica, Dichloromethane/ethanol/ammonia (75:10:2) Rf 0.45.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.C(Cl)Cl.O.[CH3:22][CH2:23]O>>[CH2:22]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:23]
Reactant: O=C(O)Cc1cc(Cl)cc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)cc(Br)c1

Procedure:
(3-Bromo-5-chloro-phenyl)-acetic acid (14 g, 56 mmol) in EtOH (150 mL) was treated with sulfuric acid (2 mL) at 50° C. for 2 hours. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was concentrated to give the title compound.