Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].ON1C2C=CC=CC=2N=N1.[NH2:30][CH:31]([CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=1)[C:32]([NH:34][CH:35]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:16]([NH:30][C@H:31]([C:32]([NH:34][CH:35]([CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:33])[CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:53]=1)=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CC(NC(=O)C(N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(O)C(=O)OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
To a mixture of 1.1 g (4 mmol) of N-[(1,1dimethylethoxy)carbonyl]-L-phenylalanine and 0.568 g (4.2 mmol) of 1-hydroxybenzotriazole in 5 ml of dimethylformamide at 0° C. is added 2.4 g (4.1 mmol) of 3-[[2-amino-1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester (mixture of [2R-[2R*,3S*(S*)]] and [2S-[2R*,3R*(R*)]]-isomers) in 15 ml of dimethylformamide. The solution is stirred for five minutes, treated with 0.867 g (4.2 mmol) of dicyclohexylcarbodiimide, stirred at 0° C. for one hour, warmed to room temperature, stirred overnight, filtered and the dimethylformamide evaporated in vacuo. The resulting oil is dissolved in ethyl acetate and washed successively with 30 ml of 1N citric acid solution, 30 ml of saturated solution of sodium bicarbonate and 30 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and evaporated in vacuo to a foam. The foam is chromatographed over 250 g of silica gel (230-400 mesh), eluted with 5% methanol 95% chloroform, the combined fractions evaporated in vacuo and the residue dried under high vacuum overnight to afford 2.3 g of the title compound as a white foam.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31](Cl)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCCN1CCCCC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCCCN2CCCCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-piperidin-1-yl-propan-1-ol (0.85 mmol, 121 mg) in THF at room temperature, NaH (1.2 mmol, 29 mg) was added and stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.42 mmol, 150 mg) was added. The resulting mixture was stirred at 50-55° C. over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 4-(4-Benzyloxy-phenyl)-3-butyl-6-(3-piperidin-1-yl-propoxy)-pyridazine.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:19]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>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>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:2][C:3]3[N:4]=[C:5]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[S:6][C:7]=3[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1CBr
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (109.4 mg, 0.326 mmol), 1,4-benzodioxane-6-boronic acid (91.0 mg, 0.506 mmol), tetrakis(triphenylphosphine)palladium(0) (43.0 mg, 0.0372 mmol), cesium carbonate (430 mg, 1.3 mmol), 1,4-dioxane (2.19 mL, 28.0 mmol) and water (43.8 uL, 2.43 mmol) were combined in a vial equipped with a stirbar. The vial was sealed and the atmosphere was replaced with nitrogen. The vial was sonicated for 1 minute then heated at 90° C. (heating block temperature) with stirring for 1 hour. The reaction was cooled to room temperature, the vial was opened and the contents were quenched into stirring saline. The quench mixture was transferred to a separatory funnel and extracted twice with ethyl acetate. The extracts were combined, washed with saline, dried over sodium sulfate, filtered, and concentrated in vacuo to leave an orange oil. The crude residue was purified by silica gel chromatography (gradient elution: ethyl acetate/hexane from 0/100 to 100/0) to give ethyl 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (60 mg, 47% yield) as a white powder. LC/MS (FA) ES+ 391; 1H NMR (300 MHz, DMSO-d6) δ: 6.67-6.74 (m, 3H), 4.20 (q, 2H, J=7.1 Hz), 4.17 (s, 4H), 4.07 (s, 2H), 3.69-3.65 (m, 4H), 3.46-3.43 (m, 4H), 1.24 (t, 3H, J=7.1 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[C:24]([Br:26])[C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[C:6]=1[Cl:27])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[Br:26][C:24]1[C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:11][C:7]=2[C:6]([Cl:27])=[C:5]([C:3]([OH:4])=[O:2])[CH:25]=1
Reactant: COC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester (520 mg, 1.16 mmol) is dissolved in THF (6 ml). Lithium hydroxide hydrate (190 mg, 4.64 mmol) in water (6 ml) is added. After addition of methanol (2 ml) the reaction is heated to reflux for 5 hours. After cooling the organic solvents are evaporated and the reaction is diluted with water, acidified with 1N aqueous HCl solution and extracted with ethyl acetate. The combined organic layers are washed with brine, dired over sodium sulfate and filtered. The solvent is evaporated in vacuo. The residue is stirred with n-hexane. The product precipitates as a white solid (350 mg, 70%), which is filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([O-])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.N1C=CC=CC=1>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([Cl:25])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reaction time: 2 h

Procedure:
Sodium N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate (0.92 g, 3 mMol) is suspended in dry CH2Cl2 (25 ml) and cooled in an ice-water bath. Oxalyl chloride (0.38 g, 3 mMol) and 2 drops of pyridine are added. The resulting mixture is stirred in the cold for 2 hours, and then filtered. The filtrate, which contains N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycyl chloride, is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:22]2[CH:21]=[N:20][CH:19]=[CH:18][C:17]=2[C:16]([NH2:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:10]([NH:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:11])=[C:17]2[C:22]=1[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: Nc1ccc(Br)c2cnccc12
Reactant: O=C=NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(Br)c2cnccc12

Procedure:
The title compound was prepared using 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%) MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.[H-].[Na+]>>[Cl:9][C:10]1[N:15]=[C:14]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(Sc2ccnc(Cl)n2)cc1

Procedure:
The 2-chloro-4-(4-methylphenylsulphanyl)pyrimidine was prepared in a similar manner to the analogous starting material of Example 1, from p-thiocresol (838 mg, 6.71 mmol), 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) and sodium hydride [60% dispersion in oil] (295 mg, 7.4 mmol), m.p. 80-81°. δH (CDCl3) 8.15 (1H, d, J 5.4 Hz), 7.46 (2H, d, J 8.0 Hz), 7.30 (2H, d, J 8.0 Hz), 6.59 (1H, d, J 5.4 Hz) and 2.43 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]=[C:18]([CH3:20])[CH3:19]>S(=O)(=O)(O)O.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:4]
Reactant: C=C(C)C
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Temperature: -78 °C
Reaction time: 144 h
Yield: 62 %

Procedure:
Concentrated sulfuric acid (10 drop) was added to a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 2.15 mmol) in 20 ml of dioxane/chloroform (2:3) in a sealed tube. After cooling the solution at −78° C., put 20 ml of isobutene gas. The sealed tube was closed and then the reaction mixture was stirred for 6 days at 60° C. The solvent was removed and then partitioned between 15 ml of sat. Na2CO3 solution and 15 ml of EtOAc. The organic layer was separated, the aqueous phase was washed twice with ethyl acetate and the combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (5% EtOAc/Hexane) to obtain 385 mg (62%) of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65 ppm (d, 2H, Haro); 7.44-7.38 ppm (m, 3H, Haro); 7.07 ppm (s, 1H, Haro); 3.86 ppm (s, 3H); 1.48 ppm (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][CH:11]=[CH:12][C:5]=2[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.N1C=CC=CC=1.[C:25]12([CH2:35][C:36](Cl)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>C(Cl)Cl.CCOC(C)=O>[C:25]12([CH2:35][C:36]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[N:9]=[CH:10][CH:11]=[CH:12][C:5]=4[C:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:3]3)=[O:37])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: Nn1nc(-c2ccccc2)c2cccnc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2cccnc2c1=O
Yield: 72.6 %

Procedure:
A mixture of Example 7B (34.8 mg, 0.146 mmol), pyridine (0.014 mL, 0.18 mmol), and (adamantan-1-yl)acetyl chloride (35.2 mg, 0.165 mmol) in CH2Cl2 (0.45 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (3% MeOH/CH2Cl2) to give the title compound (43.9 mg, 0.106 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.15 (dd, 1H), 8.16 (dd, 1H), 7.94 (dd, 1H), 7.65-7.54 (m, 5H), 2.08 (s, 2H), 1.95 (s, 3H), 1.74-1.53 (m, 12H); MS (DCI) M/Z 432.2 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]([C:15]4[CH:16]=[C:17]([OH:26])[CH:18]=[CH:19][C:20]=4[N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40].O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:13]([C:15]4[CH:16]=[C:17]([O:26][C:43](=[O:44])[NH:42][CH:39]([CH3:41])[CH3:40])[CH:18]=[CH:19][C:20]=4[N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[N:14][C:10]=3[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)n1c(-c2cc(O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)Oc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a stirred solution of 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-phenol (100 mg, 0.23 mmol) in THF (3 mL) is added potassium carbonate (65 mg, 0.47 mmol) followed by isopropyl isocyanate (25 ul, 0.26 mmol). The resulting mixture is stirred at room temperature for 3 hours and then is warmed to 60° C. for 18 hours. The reaction is cooled to room temperature, poured into water and the product extracted into EtOAc (2×10 mL). The combined organics are dried with MgSO4 (500 mg), filtered, and concentrated. The remaining residue is purified by silica gel flash column chromatography (12 g silica gel, 0-5% MeOH/DCM). Product-containing fractions are combined and concentrated to give the title compound (15 mg, 13%). LCMS (ESMS): m/z 512.5 (M++1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1SC.CCN(CC)CC>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]3[N:29]([CH3:28])[CH2:33][CH2:32][N:31]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: CSC1=NCCN1C
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CCN=C1NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To the boiling solution of 2-methylthio-2-imidazoline hydriodide (1 g, 8.4 mmol) in methanol (10 mL) was added MeI (0.78 mL, 12.6 mmol, 1.5 equiv.) dropwise. The reaction mixture was stirred at reflux temperature for 1 hr, concentrated and crystallized with ether to give 1-methyl-2-methylthio-2-imidazoline (1.1 g, 100%). MS found for C5H10N2S (M+H)+: 131. Step 2: A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (74 mg, 0.195 mmol), 1-methyl-2-methylthio-2-imidazoline (25 mg, 0.195 mmol), NEt3 (2 mL) and pyridine (5 mL) was stirred at 80° C. overnight, concentrated and HPLC (C18 reversed phase)eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[(1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide (52 mg, 65%). MS found for C24H23ClN6O2 (M+H)+: 463.
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 91.2 %

Procedure:
In 300 ml of toluene was suspended 9.0 g of sodium amide in a nitrogen stream, and 21.3 g of 2-pyrrolidinone was slowly added thereto dropwise. After stirring the mixture at 60° to 70° C. for 2 hours, 19.7 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by allowing to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The precipitated crystals in the aqueous layer were recovered by filtration and dried under reduced pressure to obtain 22.4 g (91%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][N:17]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([C:19]1[O:18][N:17]=[C:16]([NH:15][C:12]([C@@H:9]2[CH2:10][CH2:11][N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:14])[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)[C@@H]1CCN1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold solution (0° C.) of (S)-1-(4-Chloro-phenyl)-azetidine-2-carboxylic acid (100 mg; 0.472 mmol) and 3-amino-5-t-butylisoxazole (66 mg; 0.472 mmol) in pyridine (1.5 mL) is added phosphorus oxychloride (0.043 m; 0.48 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with diluted NH4Cl aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 334 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30](F)=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C-:34]#[N:35].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(F)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C#N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (444 mg, 0.899 mmol) was dissolved in DMF (5 mL). KCN (300 mg, 4.6 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. Additional KCN (110 mg, 1.7 mmol) was then added and the reaction was stirred for another 2 hours. The solvent was removed under reduced pressure and the resulting brown oil purified by column (1:4 EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield). MS calc'd for C24H24ClN4O4S (MH+): 499.1. found 499.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (28 mg, 0.11 mmol) in diphenyl ether (1 ml) was stirred at 220° C. for 1.5 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole (12 mg, 54%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN(C=O)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1nc(-c2ccco2)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A solution of 2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (4.1 g, 21.8 mmol) in DMF (20 mL) was treated with PdCl2(PPh3)2 (772 mg, 0.17 mmol) and 2-(tributylstannyl)-furan (6.9 mL, 21.8 mmol), stirred at room temperature for 16 h, diluted with diethyl ether and filtered to give the title compound (2.94 g, 61%) as a pale orange solid.
Reaction SMILES: [H-].[Na+].[CH:3](=[N:10][N:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[ClH:23].[ClH:23].[C:4]1([CH:3]=[N:10][N:11]2[CH2:17][C:15](=[O:16])[N:14]([CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:4]1([CH:3]=[N:10][N:11]2[CH2:17][C:15](=[O:16])[N:14]([CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCCCCBr
Reactant: O=C1CN(N=Cc2ccccc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C1CN(N=Cc2ccccc2)C(=O)N1CCCCCl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1-Phenylmethylenamino-3-(4-chlorobutyl)-2,4-imidazolidinedione dihydrochloride is prepared by adding 60% sodium hydride in mineral oil (7.8 g, 0.1944 mole) over 1 hour to a stirred solution of 1-(benzylideneamino)hydantoin [prepared as described by J. Gut, A Novacet, and P. Fiedler, Coll. Czech. Chem. Commun., Vol. 33, pp. 2087-2096 (No. 7). 1968 hereby incorporated by reference herein] (39.5 g, 0.1944 mole) in dimethylformamide (1000 ml). After complete addition, the solution is heated at steam bath temperature (approximately 100° C.) for 1.5 hours. The resulting mixture is allowed to cool to ambient temperature (30° C.). While stirring at ambient temperature, 1-bromo-4-chlorobutane (100 g, 0.5832 mole, 3 eq) is added in one portion. The mixture becomes exothermic reaching around 35° C. in approximately 30 minutes. The near-solution is heated at approximately 80° C. by steam bath for four hours, cooled and stirred for approximately eight hours at ambient temperature (30° C.). The cloudy mixture is filtered, removing a small amount of insoluble solid. The filtrate is concentrated under reduced pressure to a semi-solid residue. This residue is triturated with H2O (400 ml), collected, recrystallized from acetonitrile, and then air-dried to give 43.1 g (0.1467 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4-imidazolidinedione.