Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21]C(OC(C)C)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][Cl:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)=[O:21])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)=[O:21])=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc2cc(Br)ccc12
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc2c(C)noc2c1
Yield: 52.9 %

Procedure:
Example 6 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 17, 16 mg) to give the title compound as an oil (8.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[CH:14][N:15]=[C:8]1[N:7]=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[CH:14][N:15]=[C:8]1[NH:7][CH:6]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)c(-c1ccccc1)nc1nccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccccc1)Nc1nccn1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a suspension of 1.38 g of 7-methoxy-5-phenylimidazo[1,2-a]quinazoline in 25 ml of tetrahydrofuran was added 0.38 g of lithium aluminum hydride, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise 1 ml of water with ice-cooling, and the resulting precipitate was filtered off and washed with tetrahydrofuran. The filtrate was evaporated under reduced pressure and the residue was recrystallized from ethylacetate-isopropyl ether to give 1.1 g of 4,5-dihydro-7-methoxy-5-phenylimidazo[1,2-a]quinazoline, m.p. 178°-179° C. (decomp.).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:18][S:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:43])=[O:42])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
L-phenylalanyl-L-proline benzylester hydrochloride (1.94 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-L-phenylalanyl-L-proline benzylester (yield: 2.14 g, 86.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[S:26][N:25]=[CH:24][N:23]=5)(=[O:20])=[O:19])=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)=[C:4]([O:27][CH3:28])[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
A vial was charged with 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide (Example 524; 0.050 g, 0.115 mmol), (3-fluorophenyl)boronic acid (0.032 g, 0.230 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.365 mg, 5.76 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (4.36 mg, 5.76 μmol), and potassium phosphate (0.073 g, 0.346 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (0.524 ml) and Water (0.052 ml) were added in sequence. The vial was sealed and microwaved at 80° C. for three hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(3′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.47 (s, 1H), 8.39 (d, J=1.7 Hz, 1H), 8.34 (s, 1H), 8.00-7.97 (m, 1H), 7.91-7.87 (m, 1H), 7.75-7.72 (m, 1H), 7.72-7.68 (m, 2H), 7.61-7.49 (m, 4H), 7.31-7.23 (m, 1H), 3.81 (s, 3H). m/z (ESI) 494.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:65]([O:84][NH2:85])([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>ClCCl>[C:65]([O:84][NH:85][C:19](=[O:21])[C@H:18]([NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:16])[CH2:22][CH2:23][CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (304 mg, 0.593 mmol) and NMM (0.330 mL, 3.00 mmol) in 10 mL of dichloromethane is treated with 1-hydroxy-7-azabenzotriazole (89 mg, 0.654 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) at RT. After stirring for 30 min, O-tritylhydroxylamine (489 mg, 1.776 mmol) is added, and the reaction is stirred for 16 h. The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water. The organic solution is washed with 30 mL of 1M aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 4/6—ethyl acetate/hexane) affords 293 mg (64%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide as a waxy solid: NMR(CDCl3) 0.62-0.76 (br m, 1H), 1.08-1.24 (br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J=8.7), 5.31 (d, 1H, J=9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J=8.4), 7.59 (d, 2H, J=8.5), 7.70 (d, 4H, J=8.3), 7.91 (d, 2H, J=8.3), 8.27 (s, 1H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH:29][NH2:30].N1C=CC=CC=1>O>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([N:29]([CH3:28])[NH2:30])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: CNN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CN(N)c1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a mixed liquid of methylhydrazine (32 mg) and pyridine (0.5 ml), and the mixture was stirred at room temperature for 3 hours. Water (5 ml) was added. At this time, the pH of the reaction mixture was about 5. Solids formed were collected by filtration and subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the resultant residue to conduct filtration, thereby obtaining the title compound (60 mg) as a brown powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13]>C1CCCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][C:11]([F:10])([F:24])[CH:12]([F:13])[F:14])[CH:17]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cc(F)ccc1F
Solvent: C1CCCCC1
Product: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
EX-661A) A mixture of 2,5-difluoroaniline (2.58 g, 20 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (4.44 g, 20 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0° C., then sodium borohydride was added (1.32 g, 35 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 5.7 g (86%) of the desired N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=336 [M+].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH3:34][O:35][CH2:36]Br.O>CN(C)C=O>[CH3:34][O:35][CH2:36][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C(=O)Nc1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 2.5 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (150 mg, 0.31 mmol) in anhydrous dimethyl formamide (DMF, 1.5 mL) at ambient temperature was added NaH (6.6 mg, 0.28 mmol, 60% dispersion in mineral oil). After stirring 20 minutes a solution of bromomethyl methyl ether (35 mg, 0.28 mmol) in anhydrous DMF (0.5 mL) was added. After 2.5 h the reaction was judged complete by TLC analysis. To the reaction was carefully added H2O (2 mL). The reaction was extracted with EtOAc (10 mL). The EtOAc solution was washed with H2O (3×7 mL) followed by brine (7 mL). The organics were dried (Na2SO4), filtered and evaporated to give crude product. The crude material was purified by silica gel chromatography (0 to 8% EtOAc in pet ether) to afford 3-(methoxymethyl)-3-(4,6-bis(2,2,2-trifluoro ethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (4) as an off white solid (18 mg, 11%), mp 118-119° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.84 (s, 1H), 7.41-7.28 (m, 1H), 6.66 (dd, J=4.1, 0.9 Hz, 1H), 6.18 (s, 1H), 5.54 (s, 2H), 5.02 (q, J=8.6 Hz, 4H), 3.27 (s, 3H); ESIMS m/z 527 ([M−H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-fluoronicotinic acid (255 mg, 1.32 mmol) in methanol (5 mL) at room temperature was added (trimethylsilyl)diazomethane (4.0 mL, 2 M in diethyl ether, 8.0 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. Methyl 6-fluoronicotinate (129 mg, 47%) was used without further purification: NMR (600 MHz, DMSO-d6) δ 8.79 (d, J=2.6 Hz, 1H), 8.47 (td, J=7.9, 2.6 Hz, 1H), 7.35 (ddd, J=8.5, 2.6, 0.6 Hz, 1H), 3.88 (s, 3H); ESIMS calcd 156.0 (M++H), found 156.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 31 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.42 (m, 1H), 7.33–7.24 (m, 7H), 6.94 (d, 1H, J=7.1 Hz), 6.58–6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.56–2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz), 2.03–1.87 (m, 6H), 1.83–1.76 (m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]1([CH2:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F-].[K+]>CS(C)=O>[CH2:18]([NH:19][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cnc2ccc(NCc3ccccc3)nn12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
3-Bromo-6-chloroimidazo[1,2-b]pyridazine (20.0 g), phenylmethanamine (11.3 ml), and potassium fluoride (12.0 g) were dissolved in dimethyl sulfoxide (400 ml), and the solution was stirred at 130° C. for 24 hours. After standing to cool to room temperature, the reaction solution was poured into ice water (2.0 L). The resulting solid was collected by filtration and dried under reduced pressure. The obtained solid was dissolved in hot ethyl acetate, and the insoluble matter was filtered under heating. After distilling off the solvent, the solid was recrystallized from ethyl acetate to obtain the title compound (21.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[O:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CCO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:16]3[O:19][C:13]([CH3:12])=[CH:14][CH:15]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)o1
Reaction time: 0.08 h
Yield: 50 %

Procedure:
7.70 g (0.05 mole) of 4-nitro-2-aminophenol and 5.50 g (0.05 mole) of 5-methylfurfural are dissolved in 400 ml of 95% EtOH and refluxed overnight. The ethanol is removed and the resulting dark red oil is recrystallized from CH3CN yielding golden plates of the Schiff Base, mp 190°-193°. This material is then dissolved in CH3CN (200 ml) by heating and 22.2 g (0.05 mole) of lead tetraacetate added. Heating is continued for 5 min and then solution is diluted with an equal volume of water. The dark brown precipitate is collected, washed with water and recrystallized from CH2Cl2 and Darco G-60 yielding 6.1 g of product (50%), mp 182°-184°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: N#C[O-]
Reactant: COc1ccc(Cl)c(N)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cl)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A solution of 2-chloro-5-methoxyaniline (5 g, 25.76 mmol) and potassium cyanate (5.22 g, 64.41 mmol) in a mixture of acetic acid (125 mL) and water (12.5 mL) was stirred at room temperature overnight. The solvent was evaporated, and the residue taken into a mixture of CH2Cl2 and an aqueous saturated solution of NaHCO3. The layers were separated, the aqueous one being extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography on silica gel (cyclohexane/EtOAc/MeOH:80/20/2) to give 2.06 g (40%) of intermediate 5.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl.CN.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH:14]1[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(c2ccncc2)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCC(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Acetic acid (0.2 ml) was added catalytically to an ice-cooled (0° C.) solution of 4-(pyridin-4-yl)cyclohexanone (500 mg, 2.857 mmol, 1 eq) and methylamine hydrochloride (957 mg, 14.28 mmol, 5 eq) in MeOH (10 ml), and stirring was carried out for 1 h at RT. NaCNBH3 (358 mg, 5.714 mmol, 2 eq) was added at 0° C. and stirring was carried out for a further 14 h at RT. The reaction mixture was concentrated, diluted with dichloromethane (100 ml) and washed with sat. sodium hydrogen carbonate solution (60 ml) and sat. NaCl solution (60 ml). The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox neutral, 6% MeOH in dichloromethane). The desired amine was obtained in the form of a light-yellow solid. Yield: 27% (150 mg, 1.26 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27](=[O:29])[CH3:28].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cccc(C)c1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1cccc(C)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (71 mg; 0.295 mmol) and 90 mg (0.592 mmol) of 1-(2-fluoro-3-methylphenyl)ethanone were added to a solution of 82 mg (0.732 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 5 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 6 mg (yield: 5%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.C(N(CC)CC)C.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:5]1([O:4][CH2:3][CH2:2][O:1][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2nccs2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3nccs3)CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 16 h

Procedure:
To an ambient solution of tert-butyl 3-(2-hydroxyethoxy)-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (1.92 g, 6.11 mmol) in dichloromethane (20 mL) was added triethylamine (1.70 mL, 12.21 mmol), 4-dimethylaminopyridine (0.075 g, 0.611 mmol), and para-toluenesulfonyl chloride (1.28 g, 6.72 mmol). The reaction was stirred for 16 hours and was quenched by the addition of saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product, which was used without further purification. MS ESI(+) m/z 468.8 [M+H]+.