Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4c(c3)OCCO4)nc2c1
Yield: 46 %

Procedure:
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 341.03; MP 307.5-309.6° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:7].C(O)(C(F)(F)F)=O.[NH:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@@H:39](C(O)=O)[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@@H:39]([NH:38][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]3[CH:3]=[CH:4][N:5]([CH3:28])[C:6]3=[O:7])[CH2:20][CH2:19]2)=[O:23])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(CN(C)C(=O)Nc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C

Procedure:
To a 150 mL round-bottomed flask equipped with stirring was added tert-butyl 4-(2-{[(2,2-dimethoxyethyl)methylamino]carbonylamino}phenyl)-piperidinecarboxylate (Step a) (1.4 g, 3.3 mmol) and a 50% aqueous TFA soln (50 mL). The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), stirred at 0° C. and treated with Boc-p-Cl-D-PheOH (Advanced ChemTech) (0.94 g, 3.15 mmol), HOBT (Novabiochem) (0.425 g, 3.15 mmol), TEA (Aldrich) (0.44 mL, 3.15 mmol) and EDC (Advanced ChemTech) (0.91 g, 4.7 mmol). The reaction was warmed to RT over 2 h and stirred at RT for 12 h. The reaction mixture was diluted with CH2Cl2 (60 mL) and the organic phase was washed with satd NaHCO3 (50 mL), and satd NaCl (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a pale yellow oil (0.55 g). MS (ESI, pos. ion) m/z: 539 (M+1). Calc'd for C29H35ClN4O4: 538.23.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]([CH3:23])=[N:11][C:10]=1[CH2:24][CH2:25][CH3:26].Br[C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH3:40])=[O:38])=[CH:18][CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[CH2:24][CH2:25][CH3:26])=[C:2]([F:1])[CH:3]=1)#[N:34]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of 3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.50 g) and methyl 2-bromo-2-methylpropanoate (1.0 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (0.72 g), and the mixture was stirred at 80° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.58 g, 96%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.59 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.69 (q, J 7.1, 1H), 7.40 (d, J 8.1, 1H), 7.65 (d, J 8.1, 1H), 7.78 (m, 2H), 8.03 (t, 1H), 8.20 (d, J 7.1, 1H), 8.47 (d, J 7.8, 1H), 8.65 (br s, 1H), 8.75 (s, 1H), 9.05 (t, J 5.8, 1H), 9.93 (s, 1H); Anal. Calcd for C20H17F3N2O+1.6HCl+1.3H2O: C, 54.58; H, 4.86. Found: C, 54.70; H, 5.10.
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)O.[CH3:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([CH3:21])([CH2:14]3)[CH2:12]1)[CH2:18]2.[CH:22]([NH2:24])=[O:23]>O.ClCCl>[CH:22]([NH:24][C:15]12[CH2:20][C:11]3([CH3:10])[CH2:18][CH:17]([CH2:19][C:13]([CH3:21])([CH2:12]3)[CH2:14]1)[CH2:16]2)=[O:23]
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Reactant: NC=O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Product: CC12CC3CC(C)(C1)CC(NC=O)(C3)C2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
In sequence, 4 mL 65% technical nitric acid and then within three hours 50 mL 98% technical sulfuric acid are added to 6.572 g (40 mmol) 1,3-dimethyladamantane at 0° C. It is stirred over night at 0° C. and the mixture is poured at 0° C. onto 100 mL formamide in a round bottom flask which is provided with a drying tube. This mixture is stirred for 30 min at 0° C. and for 90 min at room temperature and 200 mL dichloromethane and 200 mL water are added. After phase separation, the organic phase is washed with water and 2% NaHCO3-solution, is dried, over Na2SO4 and is freed from solvents at the rotary evaporator. The remaining oil is chromatographically purified (SiO2, CHCl3/acetone (20:1), Rf=0.39). 7.41 g (89.3%) of the formamide are obtained as a nearly colourless solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:47]3=[O:50])=CC=2)=CC=1.COC1C=CC(C(Cl)=O)=CC=1>>[CH3:47][O:50][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COc1ccc(C(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 103 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-methoxybenzoyl chloride. The compound of example 103 was used directly without isolation for the preparation of compound of example 104.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N#[O+].[C-:28]#[N:29].[K+].O>C(#N)C.CS(C)=O>[C:28]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:19])([CH3:20])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1)#[N:29]
Reactant: [C-]#N
Reactant: CSc1ncncc1C1c2cc(N)ccc2CC1(C)C
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: CSc1ncncc1C1c2cc(C#N)ccc2CC1(C)C
Temperature: 40 °C

Procedure:
To a mixture of 1.0 g (3.5 mmol) of 5-(6-amino-2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 25 mL of dry acetonitrile was added with stirring 1.0 g (7.0 mmol) of nitrosonium tetrafluoroborate. The brown solution was allowed to react for 10 min and was then poured, with stirring, into a solution of 2.5 g (28 mmol) of cuprous cyanide and 3.0 g (47 mmol) of potassium cyanide in 150 mL of dry dimethyl sulfoxide. The resulting mixture was heated to 40° C. to form a solution and this solution was poured into 750 mL of water. The mixture obtained was extracted with ether (2×300 mL) and the ethereal extract was washed with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 500 mg (48 percent of theory) of the title compound as a light yellow solid melting at 157°-158° C.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45](NC1C=C2C(=CC=1)NC(C(O)=O)=C2)(=[O:47])C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:45]([C:10]2[NH:15][C:14]([CH3:13])=[N:16][C:11]=2[CH3:12])=[O:47])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
HATU (365 mg, 0.96 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (99 mg, 0.32 mmol), 5-(acetylamino)-1H-indole-2-carboxylic acid (45 mg, 0.32 mmol) and diisopropylethylamine (167 uL, 0.96 mmol) in DMF (2 mL). The reaction mixture was stirred at RT overnight and was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-5% 2M NH3 solution of MeOH in DCM) and preparative TLC (5% 2M NH3 solution of MeOH in DCM) to afford the title compound (3.8 mg) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 8.82 (s, 1H) 7.53 (s, 1H) 7.30-7.38 (m, 2H) 7.21-7.26 (m, 1H) 7.13 (s, 1H) 7.01 (s, 1H) 4.61 (d, J=6.41 Hz, 2H) 2.54 (s, 3H) 2.35 (s, 3H). LCMS: m/z 433 (M+1).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23]=2[CH2:24][CH3:25])=[O:18])=[CH:5][CH:4]=1.Cl.Cl.[NH2:45][CH2:46][CH2:47][O:48][NH2:49].N1C=CC=CC=1>C(O)C>[NH2:45][CH2:46][CH2:47][O:48][N:49]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:1])[F:42])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:23]=1[CH2:24][CH3:25])=[O:18]
Reactant: NCCON
Reactant: CCc1c(C(=O)NCCCCCCC(=O)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCc1c(C(=O)NCCCCCCC(=NOCCN)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Yield: 106.8 %

Procedure:
Part C: 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid {7-[4-(trifluoromethyl)phenyl]-7-oxo-heptyl}amide (1.15 g, 1.86 mmol) was dissolved in absolute ethanol (10 ml), and O-(2-aminoethyl)hydroxylamine dihydrochloride (0.276 mg, 1.865 mol) and pyridine (0.18 ml) were successively added. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was allowed to attain room temperature. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane and washed successively with an aqueous KHSO4 solution and brine. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid [7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyl]-amide (Compound 2) (1.34 g) as a mixture of E/Z stereoisomers. Melting point: 90-95° C. 1H-NMR (400 MHz, CDCl3) δ 1.05 (t, J=7, 3H), 1.34-1.62 (m, 8H), 2.81 (br t, J=7, 2H), 2.93 (q, J=7, 2H), 3.32-3.42 (m, 4H), 4.44-4.50 (m, 2H), 7.11 (d, J=8, 2H), 7.21-7.34 (m, 5H), 7.37 (d, J=8, 1H), 7.49 (br s, 1H), 7.59 (d, J=8, 2H), 7.71 (d, J=8, 2H), 8.65 (br s, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].Br[CH2:11][C:12]1[CH:13]=[C:14]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:15]=[CH:16][CH:17]=1.O>CN(C)C=O>[CH3:23][C:21]1([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19][B:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:5][C@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:13]=2)[O:22]1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
Under argon stream, to a solution of (R)-1,1,1-trifluoropropan-2-ol (3.32 g) in N,N-dimethylformamide (43 ml) was added portionwise sodium hydride (1.16 g, 60 wt % oil dispersion) at 0° C., and the mixture was stirred for 20 minutes. Then, 2-(3-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.32 g) was added thereto, and then the mixture was stirred at room temperature overnight. To this reaction mixture were sequentially added water and a 2M aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (3.43 g).
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([OH:16])=[O:15].I[CH3:19]>CCOCC>[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([O:16][CH3:19])=[O:15]
Reactant: CI
Reactant: Cc1cccc(N)c1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3×100 ml), dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.
Reaction SMILES: N[C:2](N)=O.Cl[CH:6]([C:11]([O-:13])=[O:12])[C:7]([O:9]C)=[O:8].C(N([CH2:19][CH3:20])CC)C>CN(C=O)C>[CH3:2][C:19]1([CH3:20])[O:13][C:11](=[O:12])[CH2:6][C:7](=[O:8])[O:9]1
Reactant: CCN(CC)CC
Reactant: NC(N)=O
Reactant: COC(=O)C(Cl)C(=O)[O-]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
About 200 mg of (4) are swollen in solvent in the cold (e.g. at 0° C. in DMF) and treated with about 1 mmol of monomethyl chloromalonate. About 0.5 ml of triethylamine is added and the mixture is stirred for about 2 h at 0° C. and for 1 h at a low heat (e.g. 50° C.). After washing the resin (3) is isolated. The free derivative of the N,N′-dialkylbarbituric acid (3, Li-P=H) is then obtained by removal of the linker.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=2)[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A solution of 8.0 g (32.0 mmol) of 4-chloro-5-formyl-2-phenylimidazole (prepared according to Chem. Pharm. Bull. 24 (1976) 960-969) and 5.3 g (32.0 mmol) of K2CO3 in 200 ml of abs. DMF was stirred at RT for 20 min. A solution of 9.6 g (32.0 mmol) of 4-bromobenzyl bromide in 200 ml of abs. DMF was then added dropwise and the reaction solution was stirred at RT for 6 h. It was concentrated in vacuo, and the residue obtained was taken up in EA, washed with water, 10% strength KHSO4, 10% strength NaHCO3, and satd sodium chloride solution, and dried over Na2SO4. Chromatographic purification on SiO2 using EA/heptane (1:4) as eluent of the residue which remained after stripping off the EA yielded 11.5 g of the title compound in the form of a beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:37][N:38]=[CH:39]S(O)(=O)=[O:41]>CN(C=O)C>[C:12]([OH:17])(=[O:41])[CH3:13].[C:12]([OH:17])(=[O:41])[CH3:13].[NH2:37][N:38]=[CH:39][N:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:5][CH2:6]1
Reactant: NN=CS(=O)(=O)O
Reactant: Cc1cc(OCCN2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)O
Product: Cc1cc(OCCN2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.4 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[2-(piperazin-4-yl)ethoxy]-5-methylphenyl ester (411 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL) containing N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (85:15:2 methylene chloride:methanol:acetic acid) to give the title compound as a white solid (295 mg, 51%). 1H-NMR (300 MHz, CDCl3) δ 1.95 (s, 6H), 2.23 (s, 3H), 2.61 (t, 4H), 2.78 (t, 2H), 3.48 (t, 4H), 3.99 (t, 2H), 6.52 (s, 2H), 6.59 (s, 1H), 7.39 (dt, 1H), 7.62 (m, 2H), 7.96 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H25N4O4SCl: 453.1(M+H), 475.1 (M+Na). Found: 452.7, 474.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:24][CH2:25]2)=[CH:34][CH:33]=1)[CH2:37][CH3:38]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1
Product: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(p-propoxyphenyl)piperazine to give 1-(p-propoxyphenyl)-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]-sulfonyl]piperazine.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(O)c1
Solvent: CC(C)O
Product: Oc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 39.4 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.511 g, 2.06 mmol) and commercially available 3-aminophenol 8 (0.225 g, 2.06 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenol 32 (0.26 g, 40% yield) as a solid. MS (ES) m/z 321 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1([C:17]([C:19]2[C:20]([CH3:27])=[C:21]([CH:25]=O)[NH:22][C:23]=2[CH3:24])=[O:18])C=CN=C1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:25]\[C:21]1[NH:22][C:23]([CH3:24])=[C:19]([C:17]([NH:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:18])[C:20]=1[CH3:27]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c1C
Temperature: 62.5 °C

Procedure:
A 0.1 L flask fitted with a thermometer, condenser, beating mantle, nitrogen inlet and magnetic stirring was charged with, 3.0 g 5-Bromooxindole, 3.03 g 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde, 3.24 g N,N-Diethylethylene diamine, 4.23 g Triethylamine and 30 ml Tetrahydrofuran. The mixture was heated to 60-65° C. for 8 hours, then cooled to ambient temperature. 10 ml Tetrahydrofuran was added to aid stirring and the reaction mixture was filtered. Drying provided 3.7 g (57.7%) first crop of 5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The mother liquors are cooled to −10° C. for 6 h for an additional 1.9 g (29.6%). 1HNMR (DMSO): δ 8.08 (1H, s); 7.75 (1H, s); 7.41 (1H, s); 7.24 (1H, d); 6.81 (1H, d); 3.31 (4H, bs); 2.46 (14H, bm); 0.96 (6H, t).