Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].OOS([O-])=O.[K+].[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:21])(=[O:31])=[O:29])[C:3]=1[CH3:22]
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: [O-2]
Agent: O=S([O-])OO
Agent: [Al+3]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 65 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (300 mg, 0.893 mmol) was dissolved in chloroform (8 mL) and Oxone™ (1.65 g, 2.68 mmol) and wet aluminum(III) oxide (910 mg, 8.90 mmol) was added. The heterogeneous mixture was stirred vigorously at 65° C. and refluxed for five h. Another portion of Oxone™ (1.65 g, 2.68 mmol) and aluminum(III) oxide (910 mg, 8.90 mmol) was added and the reaction was stirred vigorously overnight at 65° C. The reaction was cooled to rt and slurried in DCM and filtered. The filtrate was concentrated and the crude product was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=368.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:9]O.[ClH:11]>>[NH2:1][CH:2]([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:9])=[O:4].[ClH:11]
Reactant: CO
Reactant: C=CCC(N)C(=O)O
Agent: Cl
Product: C=CCC(N)C(=O)OC
Yield: 79.2 %

Procedure:
A solution of α-Allyl-Gly-OH (1.00 g, 7.75 mmol) in MeOH/HCl (20 mL) was heated at reflux for 3 hrs. After TLC showed the reaction was complete, the mixture was evaporated to give α-Allyl-Gly-OMe HCl (1.10 g, 79.2%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:29]([C:15]2([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-fluoro-benzylamine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[C:41]=1Cl>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:17][CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:41]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCC3)cc1F

Procedure:
4-{[1-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 523.22 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride, yielding 4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1
Reactant: OCCSc1ccc2nccn2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Product: c1cn2nc(SCCOC3CCCCO3)ccc2n1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
In 30 ml of 1,2-dichloroethane is suspended 1.5 g of 6-(2-hydroxyethylthio)imidazo[l,2-b]pyridazine and with stirring at room temperature, 1.94 g of dihydropyran and 193 mg of pyridinium p-toluenesulfonate are added. The mixture is stirred at 65° C. for 4 hours, after which 1.5 g of dihydropyran and 100 mg of pyridinium p-toluenesulfonate are further added. The mixture is stirred for an additional 4 hours. After cooling, the reaction mixture is washed with 30 ml portions of water three times, dried over sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel (100 g) column chromatography and elution is carried out with ethyl acetate. The eluate is concentrated under reduced pressure to give 1.85 g of 6-[2-(2-tetrahydropyranyloxy)ethylthio]imidazo[l,2-b]pyridazine as colorless crystals melting at 60° to 62° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][O:14][CH:15]([CH:36]([OH:37])[C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COCC(=O)OC
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.25 h

Procedure:
To tetrahydrofuran (50 ml), cooled to -78° C. under argon, was added diisopropylamine (5.7 ml, 0.041 mole) followed by n-butyllithium (16 ml, 0.041 mole) slowly. After 15 minutes, methyl methoxyacetate (4.25 g, 0.041 mole) in tetrahydrofuran (10 ml) was added dropwise. The resulting solution was stirred for 30 minutes after which a solution of 2-(8-phenyloctyl)benzaldehyde in tetrahydrofuran (10 ml) was added dropwise. After 2 hours the reaction mixture was quenched with a solution of saturated ammonium chloride and then diluted with ice water. The aqueous layer was extracted with ether. The combined ether extract was washed with 10% sodium hydroxide (ice cold), dried over magnesium sulfate, filtered and evaporated to give the desired product.
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.Cl.N1C=CC=CC=1>O>[F:30][CH:2]([F:1])[C:3]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: COc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(CCCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(O)cc1)C(F)F

Procedure:
27.22 g (65.68 mmol) 1,1-Difluoro-5-(4-fluoro-3-phenoxyphenyl)-2-(4-methoxyphenyl)-2-methylpentane was heated with 75.92 g (657 mmol) pyridine hydrochloride at 180° C. for 7 hours. It was then added to water, extracted with ethyl acetate, and the organic phase washed until it was neutral, dried over Na2SO4 and evaporated. After chromatography on silica gel, using toluene/ethyl acetate, 24.5 g of the desired product remained i.e. 93.1% of theory. Refractive index nD20 : 1.5571.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2)cc1

Procedure:
4-Phenylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and phenyl isocyanate: 1H NMR (CD3SOCD3, 300 MHz, ppm) 8.72-8.64 (m, 2H), 7.44 (d, 2H), 7.36 (d, 2H), 7.28 (d, 2H), 7.16 (d, 2H), 6.96 (t, 1H), 3.52 (s, 2H); m/z 272.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.[N-:12]=[C:13]=[O:14].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]([NH2:12])=[O:14])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N)cc1
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1ccc(NC(N)=O)cc1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 31.4 g of p-n-propylaniline dissolved in 116 ml of acetic acid and 232 ml of water was added dropwise into 200 ml of a mixed solution comprising 130 g of sodium isocyanate and 900 ml of water, and then stirred in an ice-bath for 30 minutes. The crystals precipitated were filtered, washed with water and dried to give 38.88 g of 4-n-propylphenylurea. After the 4-n-propylphenylurea was added in portions into 107.6 ml of 20% fuming sulfuric acid, the reaction was carried out at 60° C. for 2 hours. Under cooling in an ice-bath, about 400 ml of ice was added into the reaction mixture, followed by heating under reflux for 4 hours. The crystals precipitated by cooling were filtered, washed with water and then dried to give 30.09 g of the above title product (yield: 64.1%). Melting point: 30 261.7°-262.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)[O:7][C:8](=[O:9])[C:4]=2[CH:3]=1.C[Si](C)(C)[NH:15][Si](C)(C)C>ClC1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:15][C:8]2=[O:9]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: Clc1ccccc1
Product: Cc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 10.5 h

Procedure:
1.00 g of 5-methyl-2-benzofuran-1,3-dione was suspended in 10 mL of chlorobenzene, to which 1.3 mL of 1,1,1,3,3,3-hexamethyldisilazane was added at room temperature, and this suspension was stirred for 10.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and resultant precipitate was filtered out therefrom to yield 0.169 g of 5-methyl-1H-isoindole-1,3(2H)-dione as light yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])[CH:13]=[N:12]2)[C:8]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.1 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21, 200.4 mg, 0.50 mmol) in methylene chloride (5.0 mL, 0.10 M) at 25° C. was treated with N,N′-diisopropylcarbodiimide (80 μL, 0.51 mmol) and 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol). The solution was stirred at 25° C. for 45 min. After this time, the reaction was added to a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 95.3 mg, 0.61 mmol) in methylene chloride (2.0 mL) at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 1-4% methanol/methylene chloride) followed by silica gel column chromatography (AnaLogix 40 g, 1-3% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide (144.2 mg, 53%) as a white solid; ES+-HRMS m/e calcd for C26H30N5O4F3 [M+H+] 534.2323, found 534.2321. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.27-1.77 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.53-7.63 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[N:17]=[C:16]([CH3:21])[N:15]=1>>[Br:20][C:18]1[N:17]=[C:16]([CH3:21])[N:15]=[C:14]([NH:13][C:2]2[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:19]=1
Reactant: CC(C)OC(=O)c1cnc(Cl)s1
Reactant: Cc1nc(N)cc(Br)n1
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)OC(C)C)s2)n1
Yield: 76.9 %

Procedure:
Prepared from isopropyl 2-chlorothiazole-5-formate and Compound 9: isopropyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 76.9%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:12]=[N+]=[N-])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12]
Reactant: [N-]=[N+]=NCCOCCOCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCOCCOCCN
Yield: 96.8 %

Procedure:
The diazide (17) (3.55 g, 17.85 mmol) in THF (10mL) was added dropwise into a cold (-5° C.) stirred mixture of lithium aluminum hydride (1.83 g, 48.2 mmol) in THF (20 mL). The reaction mixture was kept at -5° C. and carefully quenched with water (10 mL). The THF layer was filtered to remove the inorganic salts, dried over Na2SO4, and evaporated in vacuo to afford the diamine (18) (2.56 g, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:22]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][C:21]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)=[O:22])([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: COC(=O)CCCCC(=O)n1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(5-Carbomethoxypentanoyl)-3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl 5-(chloroformyl)pentanoate.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:26])([F:25])[C:15]([NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16]>>[CH:7]1([N:6]2[C:2]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:18]([NH:17][C:15](=[O:16])[C:14]([F:25])([F:13])[F:26])[CH2:19][CH2:20]3)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[N:5]2)[CH2:9][CH2:8]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(C2CC2)c1Cl
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Yield: 61 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.105 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 6.55-6.38 (m, 1H), 4.30-4.15 (m, 1H), 3.65-3.53 (m, 1H), 3.55-3.25 (m, 4H), 2.25-2.05 (m, 6H), 1.35-1.05 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)SCC(CC(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 1-[3-(acetylthio)-2-methoxycarbonylmethylpropanoyl]-L-proline tert-butyl ester (3.7 g) in methanol (60 ml), N sodium hydroxide (40 ml) is added. After four hours, the reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. This last ethyl acetate layer is dried and concentrated to dryness in vacuo. The residue is dissolved in a mixture of pyridine and acetic anhydride (3:1) and the solution is stored at room temperature overnight. The reaction mixture is diluted with ethyl acetate (200 ml) and washed with 10% potassium bisulfate. The organic layer is dried and concentrated to dryness in vacuo to yield 1-[3-(acetylthio)-2-carboxymethylpropanoyl]-L-proline tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Reactant: NCCN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol) by a procedure similar to Example 10 and was isolated as white powder (27 mg, 54%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m, 4H).
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[N:4][C:5]([O:11][CH3:12])=[C:6]([C:9]=1[CH3:10])[C:7]#[N:8].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:12][O:11][C:5]1[N:4]=[C:3]([CH3:13])[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH3:10])[C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(C)c(I)c(C)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1nc(C)c(-c2ccccc2)c(C)c1C#N
Yield: 78.6 %

Procedure:
5-iodo-2-methoxy-4,6-dimethyl-nicotinonitrile (1.6 g, 5.554 mmol), Pd(PPh3)4 (642 mg, 0.555 mmol), phenyl boronic acid (1.05 g, 8.331 mmol), and anhydrous potassium carbonate (1.54 g, 11.11 mmol) were suspended in the mixed solution of 60 mL of anhydrous toluene and 3 mL of anhydrous ethanol, and then heated to reflux for about 72 hours under the nitrogen atmosphere. The mixture was filtered, added with 100 mL of a saturated solution of ammonium chloride and then extracted twice with 100 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and then concentrated. A silica gel column chromatography (5% EtOAc/Hexanes) was performed on the resulting residue and 1.04 g (78%) of 2-methoxy-4,6-dimethyl-5-phenyl-nicotinonitrile was obtained in pale yellow solid.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[C:7]([F:13])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:2][O:3][CH3:4])[C:7]=1[F:13]
Reactant: COCCl
Reactant: Oc1cccc(Br)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloro(methoxy)methane (11.8 mL) was added at 0 C to a THF (150 mL) solution of 3-bromo-2-fluorophenol (15.0 g) and N,N-diisopropylethylamine (41.1 mL). The reaction mixture was stirred overnight at room temperature in a nitrogen atmosphere and then filtered through celite. The obtained filtrate was washed with 1 M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in this order, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (NH, hexane/ethyl acetate), and the solvent was distilled off under reduced pressure to obtain the title compound (17.9 g)
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(#N)C>[O:1]([CH2:8][CH2:9][O:10][S:13](=[O:15])(=[O:14])[NH:12][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)OCCOc1ccccc1

Procedure:
This compound was prepared according to the procedure used in Example 112. Thus, a mixture of 14.8 g (0.1 mole) of 2-phenoxyethanol (Matheson, Coleman, and Bell), 15.6 g (0.12 mole) of methylsulfamoyl chloride and 12.3 g (0.12 mole) of triethylamine in 150 ml of acetonitrile gave a viscous oil that solidified upon standing. The solid was recrystallized from benzene-petroleum ether (30°-60° C.) to yield 15.4 g (67%) of shiny, white flakes, mp 66°-68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH2:19][CH3:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: CCC(=O)CC
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 3-pentanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 3 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (100 mL, 50 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was purified by column chromatography (40 g, silica, Combiflash, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate. The precipitate was collected by filtration to afford the title compound (0.040 g, 28%) as a yellow solid: