Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCCC1>[SH:14][C:13]1[NH:10][C:5]2[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Yield: 64.5 %

Procedure:
4-trifluoromethyl-benzene-1,2-diamine (0.5 g, 2.84 mmol) and 1,1′-thiocarbonyldiimidazole (0.84 g, 4.73 mmol) in 5 ml of tetrahydrofuran are stirred at room temperature for 48 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 10 ml ethyl acetate and washed with water (2×3 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is then purified on a silica gel column (32 g) eluted with dichloromethane. The fractions containing the expected product are concentrated under reduced pressure to yield 400 mg of 2-mercapto-6-trifluoromethyl-1H-benzimidazole. Yield=65%. Analytical LC/MS (method B): retention time=3.14 min., m/z=218.98 (positive ion mode).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:57]=[CH:56][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH:16]1[C:17]2[C:18](=[CH:19][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:38]5[CH:57]=[CH:56][C:41]([CH2:42][N:43]6[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:47][CH2:48]6)=[CH:40][CH:39]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:12][CH:13]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
Intermediate B (131 mg) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate (136 mg) were suspended in 2 mL of acetonitrile and treated with 2 mL of 1 M sodium carbonate solution and dichloro-bis-(triphenylphosphine)-palladium(II) (10 mg). The resulting mixture was heated in a microwave reactor cell for 20 minutes at 150° C., resulting in de-tosylated material which was purified by MPLC chromatography (0-3% methanol) to provide an analytical sample of the title compound (50 mg, 508 M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([NH:17][C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])=[S:19])=[O:16]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: CNC(=O)c1ccccc1N
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1C
Yield: 93.4 %

Procedure:
To a stirred mixture of 5.4 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 6.67 g of 2-methylbenzoyl isothiocyanate in 100 ml of ether over 15 minutes. After several hours, the solid was collected, giving 11 g of the desired product as light grey crystals, mp 172°-175° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([Cl:16])=[O:6])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cccc(C)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-ethyl-6-methylbenzoic acid (49 mg, 0.30 mmol) in dichloromethane (3 mL) containing DMF (1 drop) was treated with oxalyl chloride (0.14 mL, 1.6 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Nc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
Into a 2-L three-neck flask were put 25 g (0.15 mol) of 4-bromoaniline, 25 g (0.15 mol) of 1-naphthaleneboronic acid, 450 mL of toluene, and 150 mL of ethanol. While the pressure was reduced, this mixture was degassed by being stirred. After the degassing, the atmosphere in a system was replaced with nitrogen. Into the solution was added 220 mL (2.0 mol/L) of a potassium carbonate solution. The obtained mixture was degassed by being stirred while the pressure was reduced, and then, the atmosphere in the system was replaced with nitrogen. To this mixture were added 0.48 g (2.1 mmol) of palladium(II) acetate and 2.4 g (7.9 mmol) of tris(2-methylphenyl)phosphine, and the obtained mixture was stirred under a nitrogen stream at 80° C. for three hours. After the stirring, this mixture was allowed to cool to room temperature, and an aqueous layer of this mixture was extracted three times with toluene. The extracted solution and an organic layer were combined and washed twice with water and washed twice with saturated saline. Into this mixture was added magnesium sulfate, and the mixture was dried for 18 hours. The obtained mixture was subjected to natural filtration to remove magnesium sulfate, and the filtrate was concentrated to obtain an orange liquid. This orange liquid was dissolved in toluene, and this solution was filtrated through Celite, alumina, and Florisil. The obtained filtrate was concentrated to give 33 g of an objective orange liquid in a yield of 99%.
Reaction SMILES: [CH:1]1([N:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C@H:8]2[CH2:12]C[NH:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29]N1CC(NC2CCCCC2)C1)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)(=O)C(C)C>[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29][N:10]1[CH2:9][CH:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[CH2:12]1)=[O:28])([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1
Agent: CC(C)C(=O)Cl
Product: CC(C)C(=O)N(C1CCCCC1)C1CN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 36 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and isobutyrylchloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[C:24]([OH:31])[CH:23]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[K+].[Br-]>>[NH2:35][C:34]1[CH:33]=[CH:32][C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([OH:31])[CH:23]=4)=[CH:19][CH:20]=3)(=[O:13])=[O:14])=[CH:8][CH:7]=2)=[CH:3][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(S(=O)(=O)c3ccc(Oc4ccc([N+](=O)[O-])c(O)c4)cc3)cc2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc(S(=O)(=O)c3ccc(Oc4ccc(N)c(O)c4)cc3)cc2)cc1O
Yield: 83.5 %

Procedure:
Bis(4-(4-amino-3-hydroxyphenoxy)phenyl)sulfone was synthesized in a manner analogous to Example 2 from bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)sulfone. Yield: 83.5%; mp 228˜231° C.; IR (KBr): 3318, 1577, 1511 cm−1; MS (EI) m/z 464 (M+, 100); Elemental Anal. Calcd. for C24H20N2O6S: C, 62.07; H, 4.31; N, 6.03. Found: C, 61.83; H, 4.39; N, 5.96.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][O:3]1.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:1][C:2]([CH3:5])([OH:3])[CH3:4])=[CH:9][C:8]=1[CH3:15]
Reactant: CC1(C)CO1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C

Procedure:
In a microwave vial 2,2-dimethyloxirane (2.2 g) is added to a suspension of 4-bromo-3,5-dimethylphenol and K2CO3 (11 g) in N,N-dimethylformamide (6 mL). The vial is sealed and the mixture is heated for 48 hours to 120° C. After cooling to room temperature the mixture is partitioned between saturated aqueous Na2CO3 solution and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 2.9 g; LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=273 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCc2ccc(OC)cc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCc2ccc(OC)cc21
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(6-methoxy-indan-1-ylidene)-acetic acid ethyl ester (3.18 g, 14.5 mmol) was dissolved in MeOH (30 ml). A catalytic amount of 10% Pd/C was added and the reaction was stirred under an atmosphere of hydrogen (balloon) for 2 h. The reaction mixture was filtered through Celite to provide pure (6-methoxy-indan-1-yl)-acetic acid ethyl ester (2.98 g, 94%) as a clear oil. LCMS: 235.0 (M+1)+.
Reaction SMILES: C1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30]C)[C:25](=[C:32]([S:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2)C>C(N(CC)CC)C>[CH3:16][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[C:25](=[C:32]([S:35][CH2:36][CH:37]([O:45][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:38][N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2
Reactant: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(=C(C#N)SCC(CN1CCOCC1)OC(=O)c1ccccc1)NCC2

Procedure:
After adding 40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride to 4.06 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile, the reaction mixture is refluxed for 45 minutes, then cooled down and filtered. After evaporating the filtrate, the residue crystallizes out on adding ethyl acetate to obtain the named product in a yield of 3.25 g, m.p.: 144° C. (from isopropanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH3:14].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c(Br)cc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)c(Br)cc1C(F)(F)F
Temperature: 25 °C
Yield: 56.6 %

Procedure:
1-Bromo-4-methoxy-2-methyl-5-trifluoromethyl-benzene (1.0 g), 2,2′-azobisisobutyronitrile (61 mg) and N-bromosuccinimide (795 mg) are dissolved in carbon tetrachloride (15 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give 1-bromo-2-bromomethyl-4-methoxy-5-trifluoromethyl-benzene (732 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][N:4]=1)=[O:28]
Reactant: CSc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(-c2nc(=O)c3ccccc3s2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
2-[2-(Methylthio)-4-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.096 g, 32%) as pale yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].CS(C)=O.[CH:9]1[C:14](N=C=S)=[CH:13][C:12]2[C:18]([O:20][C:21]3([C:31]4[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=4[O:29][C:23]4[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]3=4)[C:11]=2[CH:10]=1)=[O:19]>O>[CH:9]1[CH:14]=[CH:13][C:12]([C:18]([OH:20])=[O:19])=[C:11]([C:21]2[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[O:29][C:30]3[C:31]=2[CH:32]=[CH:33][C:34]([CH:35]=3)=[O:36])[CH:10]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The HA-HZ as obtained above (Example 10-1) was dissolved in distilled water (Milli Q water), resulting in a concentration of 20.0 mg/ml. Thereafter, a 0.25 M carbonate buffer (pH 9.0; 4.84 ml) and a DMSO solution (2.42 ml) that contained 101.3 mg/ml FITC were added to the above obtained solution, and the obtained mixture was gently shaken in the dark at room temperature for 1 hour. Thereafter, the resultant was dialyzed against an excessive amount of PBS for purification. The external dialysis solution was exchanged with distilled water (Milli Q water), followed by further dialysis and purification (Spectrapore 4; molecular weight cut off (MWCO): 12 k-14 kDa). The obtained aqueous solution was freeze-dried, so as to obtain fluorescein-labeled HA-HZ (227.63 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)#[CH:11]>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([C:10]#[C:11][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:13]=[N:14][CH:15]=1
Reactant: C#Cc1cncc(OC)c1
Reactant: N#Cc1cccc(I)c1
Product: COc1cncc(C#Cc2cccc(C#N)c2)c1
Yield: 68 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-iodobenzonitrile (681 mg, 3.0 mmol) and 3-ethynyl-5-methoxypyridine from PREPARATION 10 (415 mg, 3.1 mmol) at room temperature for 16 h to give the title compound (564 mg, 68%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]([CH:20]=[CH:21]N(C)C)=O)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH3:26])[CH:7]=1)=[O:5])C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[NH2:30][C:29]1[N:31]=[C:18]([C:11]2[CH:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:25][CH3:26])=[CH:13][C:12]=2[F:17])[CH:20]=[CH:21][N:28]=1
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccnc(N)n3)cc21
Yield: 35.9 %

Procedure:
To 900 mg (2.5 mmol) of the 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 15 ml of t-butanol at 50° C. was added 580 mg (2.5 eq) of guanidine hydrochloride that had been previously treated with 1.35 g (5 eq) of potassium t-butoxide at 50° C. in t-butanol for 30 minutes. The final mixture was stirred for 24 hours at 60° C. It was poured into 8% aqueous acetic acid and extracted into chloroform. The chloroform was extracted three times with water. The chloroform was dried magnesium sulfate and concentrated. The residue was purified by column chromatography and gave 295 mg of 7-(2-amino-4-pyrimidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 245°-247° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:46][CH2:47][C:48]([CH2:50][F:51])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:48]([CH2:50][F:51])[CH2:47][F:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(CF)CF
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added 1,3-difluoroacetone (139 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[N:12]1[C:17]2[NH:18][C:19]3[CH:44]=[CH:43][CH:42]=[CH:41][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](N4C=CC(C)=N4)=[CH:27][C:26]=3[C:37]([F:40])([F:39])[F:38])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[N:12]1[C:17]2[NH:18][C:19]3[CH:44]=[CH:43][CH:42]=[CH:41][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[CH:8]=[CH:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]4)=[CH:27][C:26]=3[C:37]([F:39])([F:40])[F:38])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Yield: 58.4 %

Procedure:
Sodium hydride (60% suspension in oil, 0.17 g, 4.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-trifluoromethyl pyrazole (0.34 g, 2.5 mmol ) was added in one portion. After the gas evolution subsided stirring was continued at room temperature. The (5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)- (4-fluoro-2-trifluoromethyl-phenyl)methanone of Example 4, Step B (0.75 g, 1.94 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) overnight. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was crystallized from ethanol to yield the title compound (0.57 g, 57.3%) as an off-white solid, m.p. 127-129° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:19][C:20]1[C:27]([O:28]C)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.CC([O-])=O.[Na+]>CC(O)=O>[OH:19][C:20]1[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c2ccccc2nc(C=Cc2cccc(O)c2O)n1-c1ccccc1
Yield: 80.5 %

Procedure:
A mixture of compound 27 (0.7 g, 003 mol), 9 (0.64 g, 0.004 mol) and NaOAc (0.233 g, 0.002 mol) in AcOH was heated under reflux for 10 hours. After cooling, the precipitate formed was washed with water, dried and recrystallized from EtOH to yield 75 (0.85 g, 75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:32])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[C:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:33])=O)(C)(C)C>Cl.O1CCOCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C:24]#[C:23][C:19]2[N:18]=[C:17]([C:15]3[N:14]([CH3:32])[C:11]4[CH2:12][CH2:13][NH:8][C:9](=[O:33])[C:10]=4[CH:16]=3)[CH:22]=[CH:21][N:20]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cn1c(-c2ccnc(C#Cc3cccc(Cl)c3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(-c2ccnc(C#Cc3cccc(Cl)c3)n2)cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A suspension of 2-[2-(3-chloro-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.018 g, 0.05 mmol) in 4M HCl in dioxane (3.0 ml) was stirred at room temperature for 2 h. The solvent was removed under vacuum and the crude was purified by column chromatography over silica gel, using DCM/MeOH (9.8:0.2) as eluent, affording 2-[2-(3-Chloro-phenylethynyl)-pyrimidin-4-yl]-1-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one as a yellow solid (0.007 g, 0.02 mmol, 50%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N+:23]([O-:39])=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Solvent: ClCCl
Product: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)cc[n+]1[O-]

Procedure:
To a solution of 370 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)acetamide obtained in stage b) of Example 7 in 20 mL of dichloromethane are added, under argon, and with stirring, 704 mg of 3-chloroperbenzoic acid. After stirring for 1 hour 30 minutes at a temperature in the region of 20° C., 156 mg of 3-chloroperbenzoic acid are added. The solution is stirred overnight and then diluted with dichloromethane and washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. After chromatography on a column of silica, eluting with a dichloromethane/methanol/28% aqueous ammonia mixture (gradient from 100/0 to 90/9/1 by volume), 280 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}-1-oxidopyridin-2-yl)acetamide are obtained in the form of a yellow wax, the characteristics of which are as follows: