Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1)(=[O:14])[CH3:13].C(N(CC)CC)C.O>O1CCCC1.C(OC(C)C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([C:12](=[O:14])[CH3:13])[N:16]=[CH:17]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(=O)n1ncc2cc(O)ccc21
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1ncc2cc(OS(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Acetyl-1H-indazol-5-yl 3-fluorobenzenesulfonate can be obtained in the following way: a solution de 0.15 g of 3-fluorobenzenesulfonyl chloride in 2 ml of tetrahydrofuran is run in dropwise into a solution, cooled to a temperature in the region of 0° C., of 132 mg of 1-acetyl-5-hydroxy-1H-indazole in 5 ml of anhydrous tetrahydrofuran and of 0.2 ml of triethylamine. The reaction medium is maintained with stirring for 3 hours at a temperature in the region of 0° C. and is then brought back to a temperature in the region of 20° C., hydrolyzed with 15 ml of distilled water and extracted with three times 15 ml of ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. A white powder is thus obtained, which powder is resuspended in diisopropyl ether, separated by filtration, washed with diisopropyl ether and dried under reduced pressure. 193 mg of 1-acetyl-1H-indazol-5-yl 3-fluorobenzenesulfonate are thus obtained in the form of a white solid (Rf=0.50, silica gel thin layer chromatography, eluent: cyclohexane/dichloromethane (1/9 by volume)).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[C:29]4[CH:48]=[CH:47][CH:46]=[CH:45][C:30]4=[C:31]([CH2:36][C:37]4[CH:38]=[N:39][C:40]([CH2:43][OH:44])=[CH:41][CH:42]=4)[CH:32]=3)[N:27]=[CH:26]2)[CH2:23][CH2:22][O:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[C:29]4[CH:48]=[CH:47][CH:46]=[CH:45][C:30]4=[C:31]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[N:39][CH:38]=4)[CH:32]=3)[N:27]=[CH:26]2)[CH2:23][CH2:22][O:21][CH2:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CO)nc3)c3ccccc32)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(C=O)nc3)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethylsulfoxide (0.040 mL, 0.56 mmol) in 2 mL of dichloromethane at −78° C. was added oxalyl chloride (0.025 mL, 0.28 mmol). After 30 min, a solution of 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one (Example 21, 0.075 g, 0.14 mmol) in 1 mL of dichloromethane. After 30 min, triethylamine (0.157 mL, 1.13 mmol) was added, and the reaction was warmed to rt. After 30 min, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with diethyl ether. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-{[3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl]methyl}pyridine-2-carbaldehyde that gave proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[NH:18][N:17]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.OO.C([O-])([O-])=[O:27].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:20]=[C:19]([CH:21]3[CH2:22][CH2:23]3)[NH:18][N:17]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH2:14])=[O:27])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A mixture of 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carbonitrile (Compound 140) (7 mg, 0.02 mmol, 1 equiv.), H2O2 (6.8 mg, 0.2 mmol, 10 equiv.) and K2CO3 (14 mg, 0.1 mmol, 5 equiv.) in DMSO (1 mL) was stirring at rt. for 1 h. The mixture was washed by water to afford 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (Compound 131) (5 mg, 69%). LC-MS (m/z)=361 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.74 (d, J=14.4 Hz, 2H), 0.98 (d, J=7.6 Hz, 2H), 1.93-1.97 (m, 1H), 6.46 (s, 1H), 7.73-7.46 (m, 1H), 7.76 (s, 1H), 8.07-8.18 (m, 1H), 8.34 (d, J=12.8 Hz, 1H), 8.45 (d, J=6.4 Hz, 1H), 9.19-9.35 (m, 1H), 12.23-12.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].Cl(O)(=O)(=O)=O.[C:21](O)(=O)C>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: CC(=O)O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CCCc1ccc(F)c(C)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The compound obtained in (1) above (172 gm) was dissolved into 700 ml of acetic acid. To the solution were added 10 ml of 40% perchloric acid and 30 gm of 10% palladium-on-carbon to effect catalytic hydrogenation under 6 atm. The catalyst was removed by filtration and acetic acid was evaporated. Upon the addition of 2 l of water, the residue was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and 1 l of methanol was added to the residue. After cooling to 0° C., 269 gm of thionyl chloride was slowly dropped to the solution, followed by the addition of 10 ml of dimethylformamide. The mixture was stirred for 12 hours at room temperature, the reaction product was concentrated, and extracted with chloroform. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 153 gm of the title compound.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:11][C:12]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1>CCOCC>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:23](=[O:24])[CH:22]=[CH:21][CH:20]([O:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:12]=2[Cl:11])=[CH:28][CH:27]=1)[CH3:26])[C:2]([O:9][CH3:10])=[O:8]
Reactant: CC(C=CC(=O)Cl)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)C(C(=O)C=CC(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OC
Reaction time: 2 h
Yield: 79.5 %

Procedure:
From 4.6 g of sodium, 26 g of dimethyl malonate and 60 ml of ether a dimethyl sodium malonate solution is prepared which is added dropwise under stirring to a mixture of 37 g of 4-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-2-pentenoyl chloride and 50 ml of ether. The reaction mixture is heated to boiling for 2 hours and worked up as described in Example 1. Thus 37 g of the faint yellow crystalline desired compound are obtained, yield 79%, mp.: 60°-63° C.
Reaction SMILES: [NH2:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].C(N1C(=O)C(C)(N2[C:35](=[O:36])[C:34]3[C:29](=[C:30]([F:40])[C:31]([F:39])=[C:32]([F:38])[C:33]=3[F:37])[C:28]2=[O:41])C(=O)NC1=O)C>>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([CH3:17])([N:1]3[C:28](=[O:41])[C:29]4[C:34](=[C:33]([F:37])[C:32]([F:38])=[C:31]([F:39])[C:30]=4[F:40])[C:35]3=[O:36])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Product: CC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 19h was prepared from 5-amino-1-cyclohexyl-5-methylbarbituric acid (0.36 g, 1.50 mmol) using the same procedure described for 19f. The crude product was recrystallized from EtOH to give 1-cyclohexyl-5-methyl-5-(tetrafluorophthalimido)barbituric acid (19h) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16](O)=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:3]=1[C:28]#[N:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH2:55][C@@H:56]([OH:59])[CH2:57][OH:58].C(N(CC)C(C)C)(C)C>CN(C=O)C.O1CCCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:54][CH2:55][C@@H:56]([OH:59])[CH2:57][OH:58])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:3]=1[C:28]#[N:29]
Reactant: NC[C@@H](O)CO
Reactant: N#Cc1c(N)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2cccc(C(=O)NC[C@@H](O)CO)c2)c(C#N)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
50 mg (0.12 mmol) of 3-({[6-amino-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]sulfanyl}methyl)-benzenecarboxylic acid Example 14 were initially charged in 1.2 ml of DMF. The reaction solution was cooled to 0° C. After addition of 94 mg (0.25 mmol) of HATU, the mixture was stirred at 0° C. for 20 min. 22.5 mg (0.25 mmol) of (R)-3-amino-1,2-propanediol and 32 mg (0.25 mmol) of N,N-diisopropylethylamine were added, and the reaction solution was stirred at RT overnight. Water and tetrahydrofuran were added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2C)c2ccccc2C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2C)c2ccccc2C)c1

Procedure:
0.55 g of amorphous compound 72 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.63 g of ethyl 4-(2-aminophenoxy)butyrate and 0.56 g of 3-[1-[2,2'-dimethylbenzhydryl)indol-5-yl] isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:33]=[N:32][C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=3)[N:25]=2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([N:32]=[CH:33][C:24]([S:23][CH2:22][CH2:21][N:18]3[CH2:17][CH2:16][CH:15]([NH2:14])[CH2:20][CH2:19]3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
Trifluoroacetic acid (5.41 mL, 70.2 mmol, 15.0 eq) is added at 0° C. to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (2.0 g, 4.68 mmol, 1.0 eq) in dichloromethane (200 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and water (50 mL) and the pH value adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine as an orange oil (1.40 g, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCCC2)c1
Reaction time: 16 h
Yield: 6.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and cyclopentylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (27 mg, yield 6%). MS calcd for (C20H24BN3O5S): 429.2. MS found (ESI negative): (M−H)−=428.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.44 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 6.46 (s, 1H), 6.35 (d, J=8 Hz, 1H), 5.94 (bs, 2H), 4.87 (s, 2H), 4.02 (q, J=6.4 Hz, 1H), 3.77 (s, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H), 1.39 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:12]1([C:10]2[N:9]=[CH:8][N:7]=[C:6]([C:4]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:5])[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cc(-c2ccccc2)ncn1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cc(-c3ccccc3)ncn2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of 38b (0.243 g, 1 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.6 mL, 1.4 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1b (52.3%). 1H NMR (CDCl3) δ 9.40 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=1.5 Hz), 8.22-8.18, 7.57-7.54 (m, 5H), 7.46 (s, 2H), 3.96 (s, 3H), 3.91 (s, 6H); MS (ESI) m/z 351.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9]([Cl:16])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(Cl)nc2cccc(Br)c21
Temperature: 110 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.20 g, 9.69 mmol) was dissolved in 30 mL of phosphorous oxychloride and the mixture was heated at 110° C. for 2 days. The reaction allowed to cool to room temperature, poured into water with an ice, and stirred for 1 h. The aqueous solution was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.32 g of the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.F[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-n2cc3ncnc(SC)c3n2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (100 mg) and methyl 4-fluorobenzoate (102 mg) in 1-methyl-2-pyrrolidone (2 mL) was added potassium carbonate (125 mg), and the mixture was stirred at 120° C. for 3 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (90 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([N:41]1[CH2:42][CH2:43][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][CH2:40]1)=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)N2CCN(c3ccccn3)CC2)cc(OC)c1OC
Yield: 67.8 %

Procedure:
8 g of 3',4',5'-trimethoxy-flavone-3-carboxylic acid with 5.5 g 4-dimethylaminopyridine and 2.2 ml mesylchloride in 100 ml absolute dichloromethane were converted into the mixed anhydride analogously to Example 1 (a), and this was then reacted with 3.6 g 1-(2-pyridyl)-piperazine analogously to Example 1 (b). The working up of the reaction mixture and the purification of the crude title compound obtained were carried out analogously to Example 1 (b). 7.5 g of 3',4',5'-trimethoxy-3-{[4-(2-pyridyl)-piperazin-1-yl]-carbonyl}flavone were obtained.
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:35])[CH3:34])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[CH:1]1([C:7]2[N:16]3[C:10]([C:11](=[CH:46][C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[NH:37][CH:38]=4)[C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:34])[CH3:35])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Yield: 64 %

Procedure:
Following the procedure described for Example 1 (A), Step A, 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 8(A)) (90 mg, 0.184 mmol) was condensed with 1H-indole-3-carbaldehyde (32 mg, 0.221 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 72.5 mg of 2-[1-cyclohexyl-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.63 (s, 1H), 8.16 (m, 1H), 7.88-7.96 (m, 1H), 7.45-7.76 (m, 2H), 7.12-7.44 (m, 6H), 6.83 (m, 1H), 5.10 (m, 1H), 4.11-4.35 (m, 1H), 3.94 (t, 2H), 3.84 (dd, 1H), 2.94 (m, 1H), 2.25 (m, 1H), 1.99 (m, 2H), 1.70 (m, 6H), 1.35 (m, 3H), 1.15 (m, 6H); MS 616.4 (M+1), 614.3 (M−1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH:22]([OH:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=[O:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanol (1.40 g, 4.28 mmol) in Methylene chloride (24.5 mL, 383 mmol) was added Dess-Martin periodinane (3.2 g, 7.6 mmol) and was stirred at room temperature for 1 hour. After pass through si gel plug, the solvent was concentrated down to give product as an oil (1.29 g, 93%). LCMS 2.28 min at m/z 326.20 ([M+1], 100%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:36][C:37]1[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH2:41])=[O:40].C(O)(C)C>CN(C)C=O.N1C=CC=CC=1>[C:39]([C:38]1[C:37]2[N:36]=[C:17]([C:16]3[CH:15]=[CH:14][C:13]([CH:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:21][CH:20]=3)[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1)(=[O:40])[NH2:41]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)cc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
N-Boc-4-pyrrolidin-2-ylbenzoic acid (0.29 g) in dimethylformamide (DMF, 1 mL) and pyridine (1 mL) at 40° C. was stirred for 10 minutes, treated with CDI (0.17 g) stirred for 30 minutes, treated with 2,3-diaminobenzamide dihydrochloride (0.22 g), stirred at ambient temperature for 3.5 hours, treated with isopropanol (2 mL), stirred at ambient temperature for 16 hours, treated with isopropanol (5 mL) and hexanes (40 mL) and decanted. The residue was stirred in water (3 mL) at ambient temperature with 2 drops 50% NaOH for 5 hours and filtered. The filtrant was stirred in acetic acid (3 mL) at reflux for 7.5 hours, cooled and concentrated. The concentrate was stirred in dichloromethane (5 mL) and hexane (15 mL) and filtered. 1H NMR (DMSO-d6) δ 13.35 (br, 1H), 9.35 (br, 1H), 8.18 (br d, J=7.8 Hz, 2H), 7.87 (d, J=7.4 Hz, 1H), 7.75 (br, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.40 (br d, J=8.5 Hz, 2H), 7.34 (t, J=7.8 Hz, 1H), 4.79 (brm, 1H), 3.55 (m, 2H), 2.36 (m, 1H), 1.80 (m, 3H), 1.41 (s, 4H), 1.12 (s, 5H).