Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)(=O)=O.[CH2:29]([NH2:31])[CH3:30]>C1COCC1>[CH2:29]([NH:31][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:30]
Reactant: CCN
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)OCC)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl (4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25–1.45 (3H, m), 1.55–1.65 (2H, m), 1.70–1.80 (1H, m), 2.05–2.15 (1H, m), 3.25–3.35 (2H, m), 3.79 (1H, t), 3.90–3.95 (2H, m), 4.10–4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0 M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP—HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[S:24])[N:16]([CH2:25][C:26]([O:28]CC)=[O:27])[C:15]1=[O:31].Cl.S(=O)(=O)(O)O>O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[S:24])[N:16]([CH2:25][C:26]([OH:28])=[O:27])[C:15]1=[O:31]
Reactant: CCOC(=O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 64.3 %

Procedure:
Into 10 ml of acetic acid were dissolved 500 mg of ethyl 1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2-oxo-4-thioxo-3(2H)-quinazolineacetate, and, after added 3 ml of concentrated hydrochloric acid and then 0.5 ml of concentrated sulfuric acid, the mixture was refluxed for 1 hour. After cooling by allowing to stand, the reaction mixture was poured into 200 ml of water and the deposits were collected by filtration. They were recrystallized from acetic acid to obtain 300 mg of title compound. m.p. 220°-221° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].B.O1CCCC1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[CH2:7][OH:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
To a solution of 3,5-dinitrobenzoic acid (213.0 g, 1.00 mol) in anhydrous THF (1500 mL) at 0° C. was added borane-tetrahydrofuran complex (1.5 L of 1M in THF, 1.50 mol) over 1 h. The resulting heterogeneous mixture was stirred at 0° C. for 3 h and at 25° C. for 18 h. The resulting homogeneous solution was quenched with H2O and concentrated in vacuo until solids were present. The solids were filtered, washed with H2O and dissolved in EtOAc. The aqueous filtrate was extracted with EtOAc. The combined organics were washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 176.0 g (89%) of the sub-title compound as a solid which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[N:25]3[CH3:32])=[O:23])=[N:12]2)=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3)cc2-c2ccccn2)cn1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3C)cc2-c2ccccn2)cn1
Reaction time: 0.25 h
Yield: 16 %

Procedure:
60% Sodium hydride (142.4 mg) was added to the above-obtained 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopyrazolidine (0.542 g) in N,N-dimethylformamide (5 mL) at room temperature, followed by stirring for 15 minutes. Subsequently, methyl iodide (0.828 mL) was added to the resultant mixture, followed by stirring for 10 days. Potassium carbonate (0.614 g) and methyl iodide (0.276 mL) were added to the reaction mixture. The resultant mixture was stirred at 60° C. for 2 hours, and then cooled in air. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate-hexane), to thereby give the title compound as a solid (89.8 mg, 15%).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I.[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:32].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.CO.ClCCl>[CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:46][CH2:47]2)([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](c1ccccc1)N1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(F)cc4)CCN([C@@H](C)c4ccccc4)C3=O)CC2)nc2ccccc21
Reaction time: 16 h

Procedure:
Combine 1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (Rf=0.59 silica gel, ethyl acetate) (0.67 g, 1.59 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.86 g, 1.59 mmol), and N,N-diisopropylethylamine (1.24 mL, 7.13 mmol) in acetonitrile (20 mL). Heat to reflux. After 16 hours, cool and evaporate in vacuo to give a residue. Combine the residue and ethyl acetate, extract twice with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting sequentially with with 15% methanol/dichloromethane and then 15% methanol/dichloromethane/1.0% concentrated aqueous ammonia to give a diastereomer of the title compound.
Reaction SMILES: [CH2:1]([C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:5])[CH2:2][CH3:3].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:4]([C:6]1[S:10][C:9]([NH:11][C:20]([CH:17]2[CH2:19][CH2:18]2)=[O:21])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:5])[CH2:1][CH2:2][CH3:3]
Reactant: CCCC(=O)c1sc(N)nc1-c1ccco1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCC(=O)c1sc(NC(=O)C2CC2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 55.5 %

Procedure:
Compound 384 (79.8 mg, 0.338 mmol) and N,N-dimethylaminopyridine (2.10 mg, 0.0172 mmol) were dissolved in pyridine (1.5 mL), and cyclopropanecarbonyl chloride (0.0521 mL, 0.570 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 5.5 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 385 (57.1 mg, 55%) as a white solid.
Reaction SMILES: C1(CC[N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)CCCCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:29][CH2:30]Cl>O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:29][CH2:30][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36]
Reactant: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Reactant: COc1cc(CCCl)cc(OC)c1OC
Solvent: O
Product: COc1cc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc(OC)c1OC

Procedure:
Prepared in exactly the same way as for the compound of Example 1 except that 3,4,5-trimethoxyphenethyl chloride was used in place of cyclohexylethyl bromide. The title compound was obtained as a monohydrate (1.2 g.), m.p. 193°-4° C. (Found: C, 66.7; H, 7.6; N, 6.9. C20H30N2O4. H2O requires C, 66.4; H, 7.5; N, 6.7%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[N:34]1([CH2:6][CH:7]2[O:11][C:10](=[O:12])[N:9]([C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:32])([F:31])[F:33])[NH:19][C:20]4=[O:23])=[CH:15][CH:14]=3)[CH2:8]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C1OC(CN2CCOCC2)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 49 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (20.0 mg, 0.0415 mmol) obtained in step C of Example 1-30 was dissolved in acetonitrile (0.1 ml). Thereafter, morpholine (3.6 μl) was added to the obtained solution, and the obtained mixture was stirred under heating to reflux for 22 hours. Thereafter, the reaction solution was cooled to a room temperature, and it was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1), so as to obtain 7-(5-morpholin-4-ylmethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (9.7 mg; yield: 49%) in the form of a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30][CH2:31]Br>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:29][CH2:30][CH3:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCn1cc(C(=O)OCC)c(=O)c2cc(F)c(-n3cccc3)cc21
Yield: 70.1 %

Procedure:
A mixture of 3 g (0.01 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate, 2.8 g (0.02 mol) of potassium carbonate and 6 g (0.04 mol) of n-propyl bromide is heated for 5 hours at 80°-90° C. and left to cool, water is added and the precipitate formed is filtered off, washed with water and recrystallized from ethanol to give 2.4 g of a solid melting at 128°-130° C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:33][NH2:34])[CH2:31][CH3:32]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:34][N:33]2[CH2:30][CH2:31][CH3:32])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CCCNN
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: CCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 52.8 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and propylhydrazine oxalate (0.164 g, 1.0 mmol) to give 0.075 g of product as a pink solid.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:9]1([C:2]2[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Fc1ncccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ncccc1C1CC1
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-2-fluoropyridine (1.56 g, 8.86 mmol), cyclopropylboronic acid (990 mg, 11.5 mmol), potassium phosphate (6.59 g, 31.0 mmol) and tricyclohexylphosphine (249 mg, 0.89 mmol) in a mixed solvent of toluene (40 mL) and water (2 mL) under a nitrogen atmosphere was added palladium(ii) acetate (99.5 mg, 0.443 mmol). The reaction mixture was heated at 100° C. for 3 h. The mixture was allowed to cool to RT, filtered through a pad of Celite™ and washed with EtOAc. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 10% EtOAc in hexane, to provide 3-cyclopropyl-2-fluoropyridine as light-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH2:18][CH:17]2[N:20]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:21][CH:22]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:16]12)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:19][CH2:18][CH:17]2[N:20]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:21][CH:22]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:16]12)=[O:14]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a solution containing 38 (0.28 g, 0.53 mmol) in DCM (10 mL) was added TFA (3 mL) at ambient temperature. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 218 mg of 39 which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotamers: δ9.31 (s, 0.5H), 8.24 (s, 0.5H), 7.86 (dd, J=5.4, 8.7 Hz, 0.5H), 7.54 (dd, J=5.4, 8.7 Hz, 0.5H), 7.28 (s, 1H), 7.00 (dd, J=2.4, 9.9 Hz, 0.5H), 6.96-9.6.91 (m, 1H), 6.86-6.79 (m, 0.5H), 4.98 (app t, J=8.1 Hz, 0.5H), 4.80 (app t, J=7.8 Hz, 0.5H), 4.16-4.09 (m, 0.5H), 3.94-3.81 (m, 1.5H), 3.54-3.45 (m, 1H), 3.29-3.06 (m, 2H), 2.90-2.70 (m, 2H), 2.26-2.21 (m, 0.5H), 2.12-2.05 (m, 0.5H), 1.90-1.68 (m, 4H), 1.60-1.50 (m, 4H), 1.16 (br s, 2H), 0.80 (s, 4.5H), 0.21 (s, 4.5H) ppm. Mass spectrum, m/z [427.3] (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[I:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][C:19]=1[CH3:33]>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([I:17])=[C:19]([CH3:33])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c(-c2ccc(I)c(C)c2)o1

Procedure:
Following general procedure A, starting from 2-((4-(1,1-difluoroethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 07: tR=1.03 min; [M+H]+=555.03.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[S:18])[N:11]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH2:29])=[S:18])[N:11]=1
Reactant: Nc1ccccc1N
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNC(=S)Nc2ccccc2N)cs1

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-isothiocyanatobutyl)thiazole (0.33 g.) and o-phenylenediamine in alcohol (5 ml.) was heated under reflux for 2 hours. Evaporation of the reaction mixture to dryness gave 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]-thiazole as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:13][CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=2)=[O:6])=[C:7]([Cl:11])[CH:8]=[CH:9][N:10]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ncc(C(F)(F)F)cc1Cl)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.22 g of the acid from Step C was refluxed in thionyl chloride for 1 hour followed by removal of the solvent under vacuum to give an oil. The oil was dissolved in 1 mL of methylene chloride and added to a solution of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride (0.25 g) and triethylamine (0.20 g) in 9 mL of methylene chloride at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered through silica gel, eluting with 100% methylene chloride. Removal of the solvent under vacuum provided the title compound as a solid, m.p. 122-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:35]1[CH2:42][S:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38]>>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:35]2[CH2:42][S:41][CH2:40][C@H:36]2[C:37]([OH:39])=[O:38])=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: O=C(O)[C@@H]1CSCN1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N2CSC[C@H]2C(=O)O)=C(C)C1=O
Yield: 32.1 %

Procedure:
Using p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (474 mg, 1 mmol) and L-thioproline (266 mg, 2 mmol) and following the procedure of Example 13, there was obtained 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-L-thioproline (150 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH2:19][CH:18]=[CH:17]3.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.S(=O)(O)[O-].[Na+].C(C1C=C(C(C)(C)C)C=C(C(O)=O)C=1O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1)CCCCCCCCCCC>[Cu].C1(C)C=CC=CC=1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=[CH:29][C:24]([CH:19]2[CH:20]=[C:21]3[C:16](=[CH:15][C:4]4[CH:5]=[C:6]5[C:14]([C:2]([CH3:22])([CH3:1])[C:3]=43)=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[N:7]5)[CH:17]=[CH:18]2)=[CH:25][CH:26]=1
Reactant: CC1(C)C2=C(C=C3C=CCC=C32)C=C2N=c3ccccc3=C21
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCCCCCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)C2=C(C=C3C=CC(c4ccc(-c5ccccc5)cc4)C=C32)C=C2N=c3ccccc3=C21
Temperature: 190 °C
Reaction time: 26 h
Yield: 88.9 %

Procedure:
12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 1 (35.5 g), 4-bromobiphenyl (35.0 g), sodium bisulfite (6.0 g), a copper powder (2.4 g), 3,5-di(tert-butyl)salicylic acid (9.4 g), potassium carbonate (31.2 g), and dodecylbenzene (52 ml) were added to a nitrogen-substituted reaction vessel, heated, and stirred at 190° C. for 26 hours. After cooled to 120° C., the mixture was stirred after adding toluene (35 ml), and a crude product was collected by filtration. After adding toluene (1.6 L) to the crude product, the crude product was heated and extracted at 110° C. After cooled to a room temperature, the crude product was concentrated under reduced pressure. The product was crystallized with methanol (120 ml) to obtain a white powder of 10-(biphenyl-4-yl)-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (48.5 g; yield 88.1%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:15].Br[C@H:17]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@@H:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>CN(C=O)C.CCOC(C)=O.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C@@H:17]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@@H:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@H](Br)c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)cc2c(O)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@@H](Oc1ccnc2c(C)cc(Cl)cc12)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60 wt % in mineral oil, 15.5 mg, 0.387 mmol) was washed with hexanes (2 mL), then a solution of 6-chloro-8-methylquinolin-4-ol (50.0 mg, 0.258 mmol) in DMF (2 mL) was added. Once gas evolution had ceased, the product of Step A (170 mg, 0.387 mmol) was added in one portion, then the mixture was stirred at 120° C. overnight. After being allowed to cool to room temperature, the mixture was diluted with EtOAc (20 mL) and water (15 mL), then the organic layer was concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 8.51 (d, J=5 Hz, 1H); 7.93 (d, J=8.5 Hz, 2H); 7.89 (d, J=2.5 Hz, 1H); 7.47 (s, 1H); 7.26 (dd, J=6.5, 6.0 Hz, 4H); 7.12 (d, J=8.5 Hz, 2H); 6.43 (d, J=5 Hz, 1H); 5.44 (d, J=6.5 Hz, 1H); 3.29-3.23 (m, 1H); 2.69 (s, 3H); 1.90-1.80 (m, 1H); 1.74-1.64 (m, 1H); 1.58 (s, 9H); 1.30-1.10 (m, 2H); 0.83 (t, J=7.5 Hz, 3H); LC4 2.78 min. (M+H)+ 550.