Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:18]2[S:17][C:16]([NH:15][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[CH3:9])[N:3]=3)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=2)=[CH:29][CH:28]=1
Reactant: CC(c1cccc(Br)n1)N1CCCC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Product: CC(c1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)N1CCCC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-bromo-6-(1-pyrrolidin-1-ylethyl)pyridine (200 mg, 0.78 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (204 mg, 0.86 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:25]=[CH:26][CH:27]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(OC(=O)c2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OC(=O)c2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzoyloxybenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-benzoyloxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 274-275° C. (decomposition).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:32](=[O:34])[CH3:33])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with triethyl amine (0.051 mL, 0.366 mmol) followed by acetyl chloride (0.0173 mL, 0.244 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.075 g) were purified by flash chromatography on silica gel eluting with a solvent gradient of 30% to 50% ethyl acetate in hexanes to provide 0.035 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (d, J=8.09 Hz, 1H) 7.49 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.99 (dd, J=3.68, 0.74 Hz, 1H) 5.09-5.20 (m, 1 H) 4.63 (heptet, J=5.88 Hz, 1H) 1.85 (s, 3H) 1.45 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:10]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:10])[CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1cccnc1C
Solvent: CC(=O)O
Product: COc1ccc[n+]([O-])c1C
Reaction time: 3 h
Yield: 60 %

Procedure:
15.3 g (0.124 mol) of 3-methoxy-2-methylpyridine are dissolved in 100 ml of glacial acetic acid, and 40 ml of 30% strength hydrogen peroxide are added in 4 portions at 80° C. in the course of 6 hours. The mixture is stirred for a further 3 hours and then concentrated in vacuo (1.5 kPa), and two 50 ml portions of acetic acid are added, the mixture being concentrated completely after each addition. Following negative detection of percompounds, the mixture is distilled in a bulb tube oven. The fraction which distils at 120° C. (1.5 Pa) is extracted by stirring in a little diethyl ether and the solid is filtered off and dried. 12 g (60% of theory) of 3-methoxy-2-methylpyridine 1-oxide are obtained in the form of colourless crystals of m.p. 72°-78° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](=[S:19])[N:16]([CH3:20])[C:15]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:10][CH:9]=1.Cl[CH2:32][C:33]([N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])=[O:34]>CC(C)=O>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([C:15]2[N:16]([CH3:20])[C:17]([S:19][CH2:32][C:33]([N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])=[O:34])=[N:18][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)[nH]c(=S)n2C)ccn1
Reactant: O=C(CCl)N(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nc(SCC(=O)N(CCO)CCO)n2C)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (3.1 mmol/0.34 g) is added to undissolved N-{4-[5-(4-fluorophenyl)-3-methyl-2-thioxo-2H-imidazol-4-yl]pyridin-2-yl}acetamide (2.23 mmol/0.8 g), and the mixture is then suspended in 100 ml of absolute acetone. 2-Chloro-N,N-bis(2-hydroxyethyl)acetamide (2.3 mmol/0.455 g) is then added, and the mixture is stirred at room temperature for 24 h. The mixture is then heated under reflux for 3 h, the precipitate is filtered off and the filtrate is concentrated under reduced pressure using a rotary evaporator. The oily residue is separated on a column (mobile phase: CH2Cl2/EtOH, 9.5:0.5).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:15](=[O:18])[CH2:16][CH3:17].C(O)(=O)C>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([CH3:17])[CH:15]=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108.5 g of p-tert.butyl-benzaldehyde are added under nitrogen gasification to a solution of 1.4 g of potassium hydroxide in 100 ml of methanol and 39.2 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. Subsequently, the mixture is further stirred at 40° C. for 1 hour, 1.5 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-acrolein of boiling point 165° C./11 Torr.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2].[S:63]([O-])(=[O:66])(=[O:65])[CH3:64]>>[C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][O:26][S:63]([CH3:64])(=[O:66])=[O:65])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CS(=O)(=O)[O-]
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 85.3 %

Procedure:
Compound 24 (570 mg, 0.66 mmol) was converted into its methane sulfonyl derivative exactly as described for the preparation of 10 to give 25 (530 mg, 85.3%) as a syrup after chromatography on silica gel using (hexane:ethyl acetate; 3:2) as eluant; [α]D +76.6° (c 0.57, chloroform). 1H-n.m.r. (CDCl3): δ5.19(t, 1H, J2,3 =J3,4 10.0 Hz, H-3), 4.90(d, 1H, J1',2' 3.8 Hz, H-1'), 4.82(d, 1H, J1,2 3.8 Hz, H-1), 3.57(s, 3H, OCH3), 3.00(s, 3H, CH3SO2), 2.23 and 2.03(s, 3H each, 2×Ac).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([C:20]([NH2:22])=[O:21])=[C:12]3[CH2:13][NH:14][C:15]4([CH2:18][CH2:17]4)[CH2:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.O>[C:23]([NH:27][C:28]([N:14]1[C:15]2([CH2:18][CH2:17]2)[CH2:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:19]([C:20]([NH2:22])=[O:21])=[C:12]2[CH2:13]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC1(CC1)C2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.3 %

Procedure:
To a solution of Intermediate 350H (30 mg, 0.094 mmol) in THF (2 mL) was added TEA (0.026 mL, 0.187 mmol) and tert-butyl isocyanate (0.022 mL, 0.187 mmol) and the resulting solution was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 350 as an off-white solid (10 mg, 25%). HPLC retention times 9.363 min. and 13.023 min. (Methods A and F respectively). MS(ES): m/z=420 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.68 (ddd, J=8.63, 4.80, 2.20 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.30 (br. s, 1H), 7.16 (br. s, 1H), 4.78 (br. s, 2H), 4.10 (br. s, 2H), 1.26 (s, 9H), 1.09 (s, 4H).
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][N:9]2[CH:14]=[O:15].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1.C[O-].[Na+]>CO>[OH:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][N:9]2[CH:14]=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCC2CCN(CC(O)COc3cccc4c3CCN4C=O)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OCC2CCN(CC(O)COc3cccc4c3CCN4C=O)CC2)cc1

Procedure:
3.3 g. 4-{2-Hydroxy-3-[4-(4-aminophenoxymethyl)-piperidino]-propoxy}-1-formylindoline (preparation see Example 15b) are stirred with a mixture of 25 ml. acetic anhydride and 25 ml. pyridine for 10 hours at ambient temperature, then evaporated in a vacuum and the residue dissolved in water and dichloromethane. After neutralization with sodium bicarbonate, the organic phase is distilled and the residue obtained is converted in methanol with sodium methylate solution into the desired compound. By shaking out between dichloromethane and water and evaporating the organic phase, there is obtained 1.0 g. (27% of theory) 4-{2-hydroxy-3-[4-(4-acetamidophenoxymethyl)-piperidino]-propoxy}-1-formylindoline; m.p. 177°-179° C.
Reaction SMILES: [C:1]([C:3]1([CH3:18])[CH2:8][CH2:7][CH:6]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH3:18])([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C#N)CCC(CN)CC1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 366A (480 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum and was used directly in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 56.5 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}-2-methylpropan-1-one (30 mg, 0.068 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (17 mg, 0.100 mmol) to afford the desired product (18.9 mg, 56%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.75 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.06-7.99 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.54-3.41 (m, 3H), 3.23-3.11 (m, 6H), 3.03 (d, J=6.8 Hz, 2H), 2.11-1.93 (m, 7H), 1.74-1.62 (m, 2H), 1.26 (d, J=6.9 Hz, 6H); ESI MS m/z 492 [C29H34ClN3O2+H]+; HPLC>99% (AUC), tR=10.93 min.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:34][O:35][C:36]([C:38]1[CH:43]=[N:42][C:41](Cl)=[CH:40][N:39]=1)=[O:37].C(N(CC)CC)C>CN(C)C=O>[CH3:34][O:35][C:36]([C:38]1[N:39]=[CH:40][C:41]([N:17]2[CH2:16][CH2:15][N:14]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:13]([C:11](=[O:12])[NH:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:33][CH:32]=3)[CH2:18]2)=[N:42][CH:43]=1)=[O:37]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)cn1
Temperature: 60 °C
Reaction time: 14 h
Yield: 102.7 %

Procedure:
A mixture of the compound (61 mg) obtained in Example 1, 5-chloropyrazine-2-carboxylic acid methyl ester (25 mg) and triethylamine (42 μl) in N,N-dimethylformamide (0.3 ml) was stirred at 60° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (5% methanol/chloroform) to give the title compound (75 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[N:6]=[C:5]1Cl.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(O)C>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:21]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH2:3][CH2:2]1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3
Reactant: NCc1ccccc1Cl
Reactant: O=c1c2cc(Cl)ccc2nc(Cl)n1CCCl
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Cl)ccc2nc2n1CCN2Cc1ccccc1Cl

Procedure:
A solution of 1.0 g. of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g. of 2-chlorobenzylamine in 50 ml. of ethanol and 1.0 ml of dimethylacetamide is stirred and heated at reflux for 12 hours. The solvent is removed by evaporation in vacuo and the residue dissolved in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chloride/pentane and filtered to obtain 1-(o-chlorobenzyl)-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 173°-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=1>COCCOC.[Zn].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>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CSc1ccc(CBr)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: COCCOC
Product: CSc1ccc(CC(=O)c2ccc(Br)cc2)cc1F
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
To the mixture of 4-bromobenzoyl chloride (10.81 g, 49.26 mmol), zinc (4.40 g, 67.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.99 g, 2.586 mmol) in DME (250 mL) was added dropwise the solution of 4-(bromomethyl)-2-fluoro-1-(methylsulfanyl)benzene (12.16 g, 51.72 mmol) in DME (120 mL) at room temperature. After 2.5 hour, the mixture was filtered through celite, the filtrate was evaporated, diluted with ethyl acetate (300 mL), washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was washed with ethyl acetate-isopropylether, to give the subtitle compound (12.16 g, 73% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[C:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:32])=[O:33])=[CH:29][CH:30]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-acetylbenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(4-acetylbenzenesulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 300 mg (0.76 mmol) of N-(4-acetylbenzenesulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 170 mg of the above-identified compound (yield 59.1%). Properties: colorless crystal, Melting point: >250° C. (decomposition), PMR (δppm, DMSO-d6):2.64 (3H,s), 7.10 (1H,s), 7.24 (1H,q), 7.85 (1H,d), 8.17 (2H,d), 8.27 (2H,d).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: C[C@H](Nc1cncc(-n2cnc3ccc(NC(=O)c4ccncc4)cc32)n1)c1ccccc1
Yield: 23 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and isonicotinoyl chloride hydrochloride (20 mg, 0.11 mmol) furnished the product (10 mg, 23%) after chromatography.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][C:11](=O)[CH3:12])=[CH:5][CH:4]=1.C([O-])(=O)C.[C:20]([NH:24][S:25]([C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[C:38]([C:40]([NH2:42])=[NH2+:41])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([C:40]3[N:42]=[C:11]([CH3:12])[CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=4)[N:41]=3)[N:39]=2)[CH:29]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(N)=[NH2+])n2)c1
Reactant: CC(=O)C#Cc1ccc(C(F)(F)F)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Yield: 75.8 %

Procedure:
Condensation reaction: The above described 4-(6-trifluoromethyl-pyridin-3-yl)-but-3-yn-2-one (53 mg, 0.25 mmol), 6-(3-tert-butylsulfamoyl-phenyl)-pyridine-2-carboxamidinium acetate (Example 26, amidine part, steps 1 to 4) (118 mg, 0.3 mmol) and sodium carbonate (64 mg, 0.6 mmol) were dissolved in acetonitrile (2 ml) and treated by microwave irradiation at 120° C. for 60 min. The reaction mixture was extracted with ethyl acetate and water, the organic layers were combined, dried over MgSO4, filtered and the solvents were evaporated to give a crude product, which was purified by flash chromatography with n-heptane and ethyl acetate to give the title compound as a light brown foam (100 mg, 76%). MS (ISP) 528.2 [(M+H)+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([O:13][C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=O)=[CH:2]1.O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:13])=[CH:2]1
Reactant: O=C1OC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)maleic anhydride (100 mg, 0.3 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (10 mL) and water (10 mL) was added benzylamine (0.13 mL, 1.2 mmol), and the whole was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF, and the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 2,3-bis(1H-indol-3-yl)-N-benzylmaleimide (110 mg, 86.6%) as red solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:23][CH2:24]2)=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 23.9 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide (343 mg, 0.95 mmol), 4-chloropyridine hydrochloride (709 mg, 4.73 mmol), triethylamine (479 mg, 4.73 mmol), and ethanol (3 mL) yielded 100 mg (24%) of the title compound.