Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: Nn1c(COc2ccccc2)nc2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(COc2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenoxymethyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.50-1.64 (m, 9H), 1.84 (br s, 3H), 2.03-2.15 (m, 2H), 4.96-5.07 (m, 2H), 6.94-7.03 (m, 3H), 7.27-7.34 (m, 2H), 7.59-7.64 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.87-7.92 (m, 1H), 8.18 (dd, J=8.0, 1.2 Hz, 1H), 10.91 (s, 1H) ppm; MS (DCI/NH3) m/z 444 (M+H)+; Elemental Analysis Calculated for C27H29N3O3.H2O: C, 70.26; H, 6.77; N, 9.10. Found: C, 70.17; H, 6.71; N, 9.23.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14](Cl)=[O:15])[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14]([OH:15])=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:9]
Reactant: CCOc1cc(C(=O)Cl)ccc1OC
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(O)=C(C#N)C#N)ccc1OC
Reaction time: 1 h

Procedure:
NaH (2.2 g, 56 mmol, 60% dispersion in paraffin oil) was added to a solution of malononitrile (1.85 g, 28 mmol) in THF (30 mL) on ice. 3-ethoxy-4-methoxybenzoyl chloride (25.5 mmol) was dissolved in THF (50 mL) and added the first solution dropwise by syringe at 0° C. The ice was then removed and the reaction was allowed to proceed at RT for 60 min. 1N HCl (100 mL) was added and the solution was extracted three times with EtOAc. The organic phase was dried with MgSO4, filtered, and concentrated in vacuo to give an orange solid that was taken onto the next step without further characterization.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[Br:33].CC(C)([O-])C.[Na+].O>C1COCC1>[Br:33][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:25]=1[NH:24][C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1
Reactant: N#Cc1ccc(N)c(Br)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (225 mg, 0.67 mmol) and 4-amino-3-bromobenzonitrile (197 mg, 1 mmol) were dissolved in anhydrous THF (4.5 mL). Sodium tert-butoxide (96 mg, 1 mmol) was added in one portion. After 1.5 h, the reaction was poured into H2O (25 mL) and extracted with EtOAc (3×30 mL). The organics were washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The tan solid was purified via flash column chromatography (30% EtOAc/hexanes) to provide tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (106 mg, 32%) as a pale yellow solid. LCMS (ES): >90% pure, m/z 497 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.C[I:33].[C:34](OCC)(=O)C>CN(C=O)C>[I-:33].[CH3:34][N+:21]1([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:27]=[CH:28][CH:29]=[C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:31][CH:30]=4)[CH:9]=3)=[CH:15][CH:16]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(COc2cccc(C(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(COc2cccc(C(=O)Nc3ccc(C[N+]4(C)CCCCC4)cc3)c2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 3-(4-methylbenzyloxy)-4′-(piperidinomethyl)benzanilide (900 mg) dissolved in DMF (5 ml) was added methyl iodide (405 μl), and the resulting mixture was stirred at room temperature for 15 hours. Ethyl acetate (200 ml) was added to this reaction mixture, and the resulting precipitate was collected by filtration to obtain 1-methyl-1-[4-[3-(4-methylbenzyloxy)benzoylamino]benzyl]piperidinium iodide (compound 88) (1.05 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=O.CN>O1CCCC1>[N+:11]([C:10]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]([NH:17][CH3:15])=[O:6])=[CH:8][C:9]=1[CH3:14])([O-:13])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Reaction time: 3 h
Yield: 93.8 %

Procedure:
3,5-Dimethyl-4-nitrobenzoic acid (1 g, 5.12 mmol) is suspended in dry tetrahydrofuran (10 mL) and 1,1′-carbonyldiimidazole (0.91 g, 5.64 mmol) is added. The mixture is stirred for 3 hours then methylamine (2 M solution in tetrahydrofuran, 7.7 mL, 15.4 mmol) is added and the mixture stirred for 30 minutes. The solvent is removed, the residue suspended in EtOAc and washed with 0.2 M aqueous HCl solution, saturated sodium bicarbonate solution and brine, dried and the solvent removed under vacuum to give the title compound (Yield 1.0 g).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:31])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:35])(C)=O>C(OCC)(=O)C.CO>[ClH:35].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[NH:5][C@:4]([CH3:31])([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@@]1(C)C(N)=O
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-methyl-1-pyrrolidinecarboxylate (D11, 306 mg, 0.69 mmol) in a mixture of ethyl acetate (5 ml) and methanol (0.5 ml) was added AcCl (130 μl, 2.5 eq) at 0° C. The mixture was stirred for 1 hour at room temperature. A further addition of AcCl (130 μl) was made and stirred for 30 min rt. The reaction mixture was kept overnight at −18° C. Then AcCl (another 100 μl) was added at 0° C., stirring for 15 mins, then for 1 hour at rt. The reaction was then complete (as shown by HPLC). The mixture was evaporated to afford the title compound as a white solid (246 mg, 95%); Rt (HPLC) 3.62 min; Chiral HPLC: Column: chiralpak AD-H 5 um, 250×4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200400 nm; Analysis time: 20 min; ret. time: 14.3 min; MS: (ES/+) m/z: 329 [MH+]; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.87 (br. s., 1H), 8.24 (br. s., 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.56 (t, 1H), 7.39-7.47 (m, 3H), 7.21-7.30 (m, 2H), 7.11 (d, 2H), 5.16 (s, 2H), 4.60-4.76 (m, 1H), 2.42-2.54 (m, 1H), 2.23-2.34 (m, 1H), 1.99-2.11 (m, 1H), 1.84-1.97 (m, 1H), 1.65 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69](O)(=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C.C(OCC)(=O)C>[C:69]([N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]1[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:3]=1[O:2][CH3:1])[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:9])=[O:8])=[CH:11]2)(=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C(=O)c4ccccc4)cccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (Intermediate NN, 0.033 g, 0.065 mmol) and HBTU (0.037 g, 0.097 mmol) were dissolved in DMF (0.324 mL). Hunig's base (0.034 mL, 0.194 mmol) and benzoic acid (0.016 g, 0.130 mmol) were added and the reaction was stirred for four hours at room temperature. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (12 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 5-(1-benzoylpyrrolidin-2-yl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as an off-white solid. m/z (ESI) 614.3 (M+H)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:32]1[CH:36]=[C:35](CO)[C:34]([N+:39]([O-:41])=[O:40])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([N:32]1[CH:36]=[C:35]([CH2:1][Br:5])[C:34]([N+:39]([O-:41])=[O:40])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbon tetrabromide (3.67 g, 11.1 mmol) and triphenylphosphine (2.43 mL, 11.1 mmol) were added to a solution of C3 (1.29 g, 5.53 mmol) in dichloromethane (150 mL), and the reaction was allowed to stir at RT for 18 hours. After being washed with water, the reaction mixture was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) afforded C4 as a solid. Yield: 951 mg, 3.21 mmol, 58%. LCMS m/z 297.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 4.60 (d, J=0.6 Hz, 2H), 5.32 (s, 2H), 7.28-7.32 (m, 2H), 7.36-7.41 (m, 3H), 7.52 (br s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:30])[CH:21]=[CH:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]=[C:20]([O:30][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:21]=[CH:22][S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C(C=CSc1ccccc1)Nc1ccc2c(c1)CCC2
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C(=CC(=Nc1ccc2c(c1)CCC2)Oc1ccccc1)Sc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 164.8 %

Procedure:
Thionyl chloride (1.53 mL) and DMF (catalytic amount) were added to a solution of N-(5-indanyl)-3-(phenylthio)acrylamide (2.47 g) in toluene (80 mL), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added anhydrous THF (40 mL). To a solution of phenol (1.18 g) in anhydrous THF (20 mL) was added sodium hydride (60%) (0.769 g) under a nitrogen atmosphere under ice-cooling, and then stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was added to the above-described reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added ethyl acetate (200 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain phenyl N-(5-indanyl)-3-(phenylthio)acrylimidate (2.56 g) as a orange oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:30]=[CH:29][C:14]3[C:15]([CH3:28])=[C:16]([C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[O:17][C:13]=3[CH:12]=2)[CH:6]=1.CO.O.[OH-].[Li+]>O1CCCC1>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:18]([C:16]1[O:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=3)[CH:30]=[CH:29][C:14]=2[C:15]=1[CH3:28])=[O:27]
Reactant: COC(=O)Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CC(=O)O)c3)ccc12
Temperature: 50 °C

Procedure:
{3-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid methyl ester (3160 mg, 6.97 mmol) was dissolved in tetrahydrofuran (50 mL), methanol (20 mL), water (10 mL), and lithium hydroxide (2650 mg, 110.65 mmol) was added to the solution. The mixture was heated at 50° C. for 3 h then cooled to room temperature. The volatile components were removed under vacuum and the pH of the resulting aqueous component was adjusted to 1 with HCl (1N). The aqueous layer was extracted several times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and condensed under reduced pressure. The crude residue was purified by MPLC with a gradient of 0 to 30% methanol/dichloromethane to give {3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid as a brown solid (2540 mg, 52% two steps). MS LC-MS (MH+439.1/441.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[C:21]([C:22](O)=[O:23])=[C:20]([CH3:25])[O:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:22]([C:21]2[C:17]([CH3:16])=[N:18][O:19][C:20]=2[CH3:25])=[O:23])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 3,5-dimethyl-isoxazole-4-carboxylic acid. LC-MS (acidic): tR=0.93 min; [M+H]+=336.2. 1H-NMR (CDCl3): δ=0.51 (bs, 1H); 0.81-0.87 (m, 1H); 1.49 (s, 9H); 1.50-1.56 (m, 1H); 1.74 (bd, J=13.5 Hz, 1H); 2.47 (s, 3H); 2.52-2.62 (m, 1H); 2.64 (s, 3H); 3.05-3.11 (m, 1H); 3.57-3.65 (m, 2H); 4.32-4.40 (m, 1H); 7.95 (bs, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cnc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
At room temperature, to a solution of 189h (90 mg, 0.13 mmol) in i-propanol/THF (1:1, 5 mL) and water (0.5 mL) was added lithium hydroxide (126 mg, 2.9 mmol). The reaction mixture was stirred at 35° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified with by reverse-phase prep-HPLC to afford 189 (60 mg, 71%) as yellow solid. MS-ESI: [M+H]+ 638.3. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 6.89 (s, 1H), 5.04-5.01 (m, 1H), 4.72-4.50 (m, 6H), 4.32-4.30 (m, 1H), 4.15-4.09 (m, 2H), 3.88-3.86 (m, 1H), 3.72 (s, 3H), 3.57-3.49 (m, 5H), 2.61-2.43 (m, 8H), 1.92-1.78 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[C:32]1([CH3:42])[C:33]([S:38]([Cl:41])(=[O:40])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[ClH:41].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH3:42])(=[O:40])=[O:39])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and o-toluenesulfonylchloride (51 mg, 0.269 mmol) to give 18 mg as purple solid. M+1 501.3 Calcd 501.15. 1HNMR δ 7.78-7.17 (m, 9H), 6.68-6.35 (m, 3H), 3.63-3.10 (m, 8H), 2.59 (s, 3H), 2.09-2.01 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCC
Yield: 65 %

Procedure:
As described in Example 50 the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.117 g, 0.4 mmol) was reacted with 4-chloro-6,7-diethoxyquinazoline (0.101 g, 0.4 mmol) from Example 13A, and Cs2CO3 (0.130 g, 0.4 mmol) in isopropanol (10 mL) at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.131 g, 65%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.03 (s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 7.33 (m, 2H), 7.29 (d, 1H), 6.49 (s, 1H), 4.26 (m 4H), 1.45 (m, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].O.[Cl-].[Na+]>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]1([N:3]=[C:2]=[S:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N=NC1(N=C=S)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 91.5 grams (1.05 moles) of sodium thiocyanate in 450 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 203.2 grams (1.0 moles) of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 900 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 173 grams (75% crude yield) of a yellow liquid. The product had a broad band at approximately 2040 cm-1 in its infrared spectrum which is indicative of the isothiocyano band in these compounds. There was no band at 2170 cm-1 (thiocyano band).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[H][H].S(O[CH2:24][CH2:25][O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:25][O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC2CC2)cc1
Reactant: Oc1ccc(Cl)nc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCCOCC2CC2)cn1

Procedure:
A solution of 12.9 g (0.1 mol) of 2-chloro-5-hydroxypyridine in 50 cc of dry dimethylformamide is added to a suspension of 4.8 g (0.1 mol) of sodium hydride (a 50% dispersion in mineral oil) in 200 cc of dimethylformamide. When the evolution of hydrogen has ceased, a solution of 27 g (0.1 mol) of 2-cyclopropylmethoxy-ethanol tosylate in 50 cc of dimethylformamide is added and the mixture is heated at 50°-60° C. for 5 hours. It is then cooled and poured into water; extraction is carried out with diethyl ether and the organic phase is washed with water. After drying, filtration and evaporation of the ether phase, an oil is obtained, which is distilled. Its boiling point (0.1 mm Hg) is 136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH2:25]([N:28]=[C:29]=S)[CH2:26][CH3:27].[Cl-].[NH4+].IC.Cl>CO.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:29]([NH:28][CH2:25][CH2:26][CH3:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: CCCN=C=S
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CI
Solvent: CO
Product: CCCNc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 2 ml of methanol, the solution was mixed with 90 μl of propylisothiocyanate, and the mixture was heated for 3 hours to 50° C. After cooling, it was mixed with saturated ammonium chloride solution, diluted with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 140 mg of a thiourea derivative, which was dissolved in 1.5 ml of methanol, was obtained. 0.16 ml of iodomethane was added to this solution, and it was refluxed for 4 hours. After cooling, it was mixed with IN aqueous hydrochloric acid, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 72 mg was obtained.