Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)(=[O:30])=[O:31])=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.480 mmol) and 4-[(4-bromophenyl)sulfonyl]morpholine (147 mg, 0.480 mmol) as the starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:20]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])(=[O:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:27])(=[O:22])[CH3:21]
Reactant: COC(=O)CC(CSCCN)C(=O)c1cccnc1
Reactant: CC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CC(CSCCNC(=O)CCNC(C)=O)C(=O)c1cccnc1
Yield: 75 %

Procedure:
A solution of methyl 3-[(2-aminoethylthio)methyl]-4-oxo-4-(3-pyridyl)butanoate (747 mg), 3-(acetylamino)propanoic acid (302 mg), dicyclohexylcarbodiimide (433 mg), 1-hydroxybenzotriazole (567 mg) and N-methylmorpholine (402 mg) in dichloromethane (10 mL) were stirred at room temperature overnight. The solution was concentrated and purified by flash chromatography (SiO2, chloroform:methanol=9:1) to give the title compound in 75% yield; ESMS (M+1)+353.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N+:8]([O-])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:26][C:24](=[O:25])[C:23]([F:34])([F:33])[F:22])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Br)ccc2N1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1OC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A 9.5-g (0.027 mole) portion of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide was added portion-wise to 50 ml of trifluoroacetic anhydride, and the reaction mixture was stirred for 90 minutes. The suspended solid that formed was collected on a filter, washed thoroughly with pentane and dried in a vacuum over KOH. There was obtained 9.72 g (80%) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-one as an off-white crystalline powder: mp 175°-177° (dec.); 19F nmr (DMSO-d6) δ -74.6 ppm (s, 3F) and -112.7 ppm (m, 1F); 1H nmr (DMSO-d6) δ 6.34 ppm (s, 1H), 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]Br)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]>CN(C=O)C.ClCCl>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 54.3 %

Procedure:
In a 100 ml flask containing a solution of 2.99 g (10 mmoles) of 2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol in 30 ml of DMF, 1.38 g (10 mmoles) of potassium carbonate and 2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine are added successively. After agitation for two hours at ambient temperature, the reaction medium is diluted with 150 ml of dichloromethane and washed successively with 3×40 ml of water followed by 40 ml of brine. The organic solution is dried over sodium sulphate, filtered and concentrated under reduced pressure. The brown residue obtained is purified on a silica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethyl acetate: 8/2). After concentration of the pure fractions, 2.31 g (54%) of a brown powder is obtained. Melting point: 177.5-178.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]=2[CH2:29][CH2:28]1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CC2CCc3c(c4ccccc4n3Cc3ccccc3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 38 mg) in dry DMF (1 ml) under nitrogen. After 20 min. benzyl bromide (0.14 ml) was added and the mixture was stirred for 3 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 850 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 79:20:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (265 mg) as a solid, m.p. 78°-80°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[N+:12]([C:10]1[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[CH3:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc(C)sc2c1
Agent: O=S(=O)(O)O
Product: Cc1nc2ccc(C)c([N+](=O)[O-])c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 256.1 %

Procedure:
To a solution of 2,6-dimethylbenzothiazol (350 mg, 2.15 mmol) in Conc. H2SO4 (4 mL) was added HNO3 (69%, 0.3 mmol) at 0° C. After stirred at 0° C. for 0.5 h, the mixture was poured over ice-water. The precipitate was collected and washed with 5% sodium bicarbonate and water, recrystallized from ethanol to give 7-nitro-2,6-dimethylbenzothiazol as yellow solid (160 mg). The product (150 mg) was hydrogenated over 5% Pd/C in ethanol-THF (10:2 mL) at atmosphere pressure to give 2,6-dimethyl-benzothiazol-7-ylamine as yellow solid (120 mg). TLC single spot at Rf 0.55 (10% EtOAc/DCM); 1H NMR (270 MHz, DMSO): δ 7.07 (2H, s, ArH), 5.23 (2H, s, NH2), 2.73 (3H, s, CH3), 2.20 (3H, s, CH3).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]2)[N:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(c2nc(Cl)nc3[nH]cnc23)C1
Yield: 34.9 %

Procedure:
A solution of 2,6-dichloropurine (189 mg, 1.00 mmol), ethyl nipecotate (0.155 mL, 1.00 mmol) and DIEA (0.300 mL, 1.72 mmol) in CH3CN (5 mL) was stirred at room temperature for 20 h, during which time white solids precipitated out, which was collected to give ethyl 1-(2-chloro-9H-purin-6-yl)piperidine-3-carboxylate (108 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([CH:39]=[N:40][OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:45])[F:44])=[CH:43][CH:42]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 78.6 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.35 g, 0.66 mmol), 4-trifluoromethyl-benzaldehyde oxime (0.13 g, 0.70 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in acetone (25 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.33 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.78 (s, 1H), 8.51 (s, 2H), 8.45 (s, 1H), 8.37 (s, 1H), 8.10 (d, 1H), 7.97 (d, 1H), 7.79-7.71 (AA′BB′, 4H), 6.88 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 3.85 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:8]([OH:18])=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=O)[CH3:5].[Cl-].[OH:20][NH3+:21].C([O-])(=O)C.[Na+]>O>[OH:18][C:8]1[C:7]([C:4](=[N:21][OH:20])[CH3:5])=[CH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=1
Reactant: CC(=O)Nc1cc(C(C)=O)c(O)cc1C
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(C(C)=NO)c(O)cc1C
Yield: 86 %

Procedure:
To an ethanol (560 ml)-water (180 ml) mixed solvent were added the compound (35.46 g, 171.1 mmol) obtained in step B, hydroxylammonium chloride (19.41 g, 279.3 mmol) and sodium acetate (22.83 g, 278.3 mmol), and the mixture was heated under reflux for 70 min. The reaction mixture was cooled, water (500 ml) was added, and the solution was concentrated under reduced pressure (about 300 ml) to allow precipitation of a solid. Water (500 ml) was added hereto again, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (32.7 g, yield 86%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]([CH3:25])([CH3:24])[C:3](C1C=CC(C23CCC(CC(OC)=O)(CC2)CC3)=CC=1)=[O:4].[C:26]1([C:32]23[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:40][C:34]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:35]4)[CH2:33]2)[CH2:39]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]([CH3:25])([CH3:24])[C:3]([C:29]1[CH:28]=[CH:27][C:26]([C:32]23[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:40][C:34]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:35]4)[CH2:33]2)[CH2:39]3)=[CH:31][CH:30]=1)=[O:4]
Reactant: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Product: COC(=O)CC12CC3CC(C1)CC(c1ccc(C(=O)C(C)(C)Br)cc1)(C3)C2
Yield: 35 %

Procedure:
Prepared according to the procedure described for Intermediate 9 using methyl (3-phenyl-1-adamantyl)acetate, the title compound being isolated in 35% yield: 1H NMR (CDCl3) δ 1.66 (d, 4H), 1.71 (s, 2H), 1.77 (s, 2H), 1.87 (s, 4H), 2.04 (s, 6H), 2.18 (s, 2H), 2.20-2.22 (m, 2H), 3.65 (s, 3H), 7.41 (d, 2H), 8.12 (d, 2H); GC-MS CI m/e MH+ 433.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12](=[O:13])[CH2:11][CH2:10][C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[C:7]3=[O:18])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Yield: 72.5 %

Procedure:
To a solution of 69.4 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 109 mg (3 equivalents) of N-phenylpiperazine, and the mixture heated under reflux for 17 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 63.5 mg of the desired compound (yield 72.5%). The fumarate was obtained by converting the product to fumarate in a conventional manner, followed by recrystallization from acetoneether.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[OH-].[Na+]>O.ClC(Cl)Cl>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:1]1[CH2:3][CH2:2]1)=[O:13]
Reactant: O=C(Cl)c1ccccc1O
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1O)N1CC1
Temperature: -5 °C

Procedure:
To 690 parts of a solution of aziridine in water 0.875M are added 42 parts of sodium hydrogen carbonate while cooling in an ice-salt bath at -5° C. While stirring vigorously, there is added dropwise, during a 30 minutes period, a solution of 78.8 parts of 2-hydroxybenzoyl chloride in 150 parts of trichloromethane at a temperature below 5° C. The reaction mixture is allowed to reach 25° C while stirring, and a diluted sodium hydroxide solution is added to pH 8. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 56 parts of 1-(2-hydroxybenzoyl)aziridine as a residue.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[NH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:24])=[CH:17][CH:18]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: F[C:2]1([F:9])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C-:10]#[N:11].[K+]>CN(C)C=O>[C:10]([C:7]1[CH:6]=[C:5]([OH:8])[CH:4]=[CH:3][C:2]=1[F:9])#[N:11]
Reactant: O=C1C=CC(F)(F)C=C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O)ccc1F
Yield: 90 %

Procedure:
When 2 mmol of 4,4-difluorocyclohexadienone and 4 mmol of potassium cyanide in 0.5 ml of dimethylformamide were mixed for 10 minutes at room temperature, 3-cyano-4-fluorophenol was formed in 90% yield. The spectral data of this new compound are as follows: Mass spectrum: m/e 137 (M+); 109 (M-CO, H); 82; 57.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 60 mg), n-butyl chloroformate (0.19 mmol, 24 μL) and triethylamine (0.51 mmol, 71 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo provided Compound A48 as a white solid (40 mg, 50%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (s, 1H); 8.62 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.12 (t, 2H); 3.92 (m, 2H); 3.39 (m, 2H); 3.10 (s, 3H); 2.11 (m, 2H); 1.65 (m, 2H), 1.56 (p, 2H); 1.42 (s, 2H); 0.97 (t, 3H). Exact mass calculated for C22H27N5O5S 473.55, found 474.4 (MH+).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:35]=[C:27]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(CN1CCOCC1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CN4CCOCC4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 7 mg (8% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][N:37]([CH3:49])[CH2:38][CH2:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].CCN(CC)CC>C1COCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH2:39][CH2:38][N:37]([CH3:49])[CH3:36])(=[O:42])=[O:41])[CH2:44][CH2:45]3)[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN(C)CCS(=O)(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 293 mg (0.57 mmol) of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 9), 152 mg (0.69 mmol) of N,N-dimethyl-2-(1-piperazinylsulfonyl)ethanamine (Example 83), and 87 mg (0.86 mmol) of Et3N in 20 mL THF was stirred at room temperature for 2 hrs. The solvent was removed under vacuum. After dilution with water, the residue was extracted into CH2Cl2 and dried. Removal of the solvent gave a white solid which was recrystallized from methanol to give 0.27 g, (68% yield) of tert-butyl 2-(difluoromethyl)-1-[4-(4-{[2-(dimethylamino)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazol-6-ylcarbamate: mp 200-202° C.; 1H NMR (CDCl3) δ 8.63 (br s, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 6.62 (br s, 1H), 6.36 (d, J=1.6 Hz, 1H), 4.12-3.77 (m, 15H), 3.40 (m, 4H), 3.10 (dd, J=8.2, 6.4 Hz, 2H), 2.77 (dd, J=8.2, 6.4 Hz, 2H), (s, 6H), 1.52 (s, 9H); Anal. Calcd. for C29H42F2N10O6S: C, 50.0; H, 6.1; N, 20.1. Found: C, 50.3; H, 6.15; N, 20.1%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:59])([F:58])[C:49]1[N:57]=[C:52]2[CH2:53][NH:54][CH2:55][CH2:56][N:51]2[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:54]1[CH2:55][CH2:56][N:51]2[N:50]=[C:49]([C:48]([F:58])([F:47])[F:59])[N:57]=[C:52]2[CH2:53]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)(F)c1nc2n(n1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2nc(C(F)(F)F)nc2C1
Reaction time: 12 h
Yield: 16.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.80 g, 4.77 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 19a (560 mg, 2.92 mmol, prepared according to a known method disclosed by “patent application WO2009025784”) and N,N-diisopropylethylamine (1.4 mL, 7.95 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 19 (205 mg, yield 16.4%) as a light yellow solid.