Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>ClCCl>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[O:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl
Yield: 82.2 %

Procedure:
to a solution of 4-(4-phenyl-5-(trifluoromethyl)oxazol-2-yl)benzenamine (178 mg, 585 μmol) and pyridine (473 μl, 5850 μmol) in 5 mL dichloromethane at room temperature was added 2-chlorobenzoyl chloride (78.0 μl, 614 μmol) all at once by pipet. After one hour the reaction was concentrated under reduced pressure then taken up in 25 mL dichloromethane and washed with 25 mL saturated aqueous sodium bicarbonate solution. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow oil. The product was isolated by chromatography on silica gel, eluting with 15-40% ethyl acetate in hexane, to yield a colorless foamy solid (213 mg, 82%). ESI+ m/z=443.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:41][OH:42].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:38](=[N:41][OH:42])[NH2:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a suspension of N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.050 g, 0.086 mmol) in 80% ethanol-water (2.5 mL) was added an aqueous solution (0.50 mL) containing 6.65 mg of hydroxylamine hydrochloride (1.1 equivalents) and 4.61 mg of sodium carbonate (0.5 equivalents). The resulting solution was heated at 80° C. for 20 hours. Solid was collected by filtration and treated with hot (80° C.) 80% ethanol-water (2 mL×5). Solid was collected and dried under vacuum at 45° C. overnight to afford 25 mg (48%) of the title compound as a yellow solid. M.p.=272-273° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.52 (s, 1H), 8.70 (bs, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.73 (m, 3H), 7.67-7.66 (m, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.38 (d, J=4.4 Hz, 1H), 5.68 (s, 2H), 3.94 (br. s, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.49-2.48 (m, 1H), 2.35 (t, J=8.8 Hz, 1H), 1.95-1.84 (m, 2H), 1.60-1.5 (m, 1H), 1.46-1.30 (m, 1H). LCMS: 610 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: OC1CCc2cc(F)ccc21
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncn1C1CCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-indan-1-ol (0.293 g, 1.925 mmol) and methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.163 g, 1.290 mmol) in THF (10 mL) at 0° C. is added pMe2NPhP(Ph)2 (0.619 g, 1.925 mmol) and diisopropyl azodicarboxylate (94%, 0.414 g, 1.925 mmol). After 1 hour the mixture is warmed to room temperature and after 18 hours it is diluted with ethyl acetate and extracted with 1M aqueous HCl. The extracts are cooled to 0° C., and the pH is adjusted to ca. 9 with ice-cold 4M aqueous NaOH. The basic aqueous phase is extracted three times with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered through a cotton plug, and concentrated. The resulting residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 1:0 to 99:1 to 49:1) to afford 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 261.0 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 2.06-2.20 (m, 1 H), 2.71-2.85 (m, 1 H), 2.87-3.00 (m, 1 H), 3.00-3.14 (m, 1 H), 3.87 (s, 3 H), 6.47 (dd, J=7.7, 4.7 Hz, 1 H), 6.88-6.97 (m, 1 H), 7.01 (dd, J=8.6, 2.3 Hz, 1 H), 7.16 (dd, J=8.6, 5.1 Hz, 1 H), 7.19 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.CC(O)C.N(OCCC(C)C)=O>C1COCC1>[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[CH:2]=[N:3][C:4]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[N:5]2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1-c1ccnc(Cl)c1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of 250 mg of 4-[5-amino-1-(2-chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide (0.686 mmol, 1 equiv) in 40 mL of 1:1 THF:iPrOH, 160 mg of isoamyl nitrite (1.37 mmol, 2 equiv) was added. The dark yellow solution was stirred for 12 h at 25° C. and then heated under reflux for 6 h. The reaction mixture was cooled and concentrated in vacuo. The resulting yellow solid was triturated with methanol and filtered to give the title compound as a yellow solid (118.9 mg, 50%); 1H NMR (400 MHz, (CD3)2SO) δ 10.20 (1H, s), 9.42 (1H, s), 8.55 (1H, d, J=5.6), 8.07 (1H, m), 7.95 (1H, dd, J=5.6 and 1.8), 7.77 (4H, m) and 7.18 (2H, s); MS (ES+) m/e 351.36, (ES−) m/e 349.48
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([C:15]([NH2:17])=[S:16])[NH2:14].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:3]1([N:17]=[C:15]2[S:16][C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:14][N:13]2[CH3:12])[CH2:11][CH2:10][CH2:6][CH2:5][CH2:4]1
Reactant: CN(N)C(N)=S
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CCCCC1
Temperature: 95 °C
Yield: 76.2 %

Procedure:
To a mixture of 4-cyanobenzoic acid (74.8 mmol, 11 g), 2-methylthiosemicarbazide (5a) (74.8 mmol, 13.42 g) in anhydrous dioxane (110 mL) at 70° C., POCl3 (89.65 mmol, 76.76 mL) was added, and the mixture was warmed at 95° C. for 4 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The aqueous phase was extracted with dichloromethane. The organic layer was washed with water and saturated solution of NaCl, dried over magnesium sulfate, filtered, and distilled to give a residue which was purified by silica gel chromatography (eluted with a gradient of cyclohexane/ethyl acetate finishing with the ratio 90:10) to afford 8.5 g of the title compound. Yield: 42%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=1[NH2:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:19]([C:4](=[O:5])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:18]1[C:17]([F:20])=[CH:16][N:15]=[CH:14][C:13]=1[F:12])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Nc1c(F)cncc1F
Solvent: c1ccncc1
Product: O=C(c1c(F)cccc1Cl)N(C(=O)c1c(F)cccc1Cl)c1c(F)cncc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Chloro-6-fluorobenzoyl chloride (13.6 g, 71.6 mmol) was added dropwise, over 10 minutes, to a solution of 3,5-difluoro-pyridin-4-ylamine (7.7 g, 59.3 mmol) in pyridine (100 mL) at 0° C. under argon and the reaction mixture was stirred at 0° C. for 3 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with 1N HCl (100 mL). The resultant suspension was stirred at room temperature for 2 hours and then the solid was collected by filtration, washing with water. A mixture of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide, LCMS (Method E): RT=2.83 min, m/z: 287 [M+H+], and of 2-chloro-N-(2-chloro-6-fluorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide LCMS (Method E): RT=3.96 min, m/z: 443 [M+H+], (23 g) was obtained which was used in the following step without further purification.
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cc(NC(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)ncn1
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.32 g, 1.1 mmol), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (XLI) (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 min. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.40 g of 3-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLII).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1>[C:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (300 mg, 1.01 mmol) in tetrahydrofuran (15 ml) was added benzoyl chloride (145 mg, 1.03 mmol) and triethylamine (101 mg, 1.00 mmol) and the mixture was stirred at room temperature overnight. After reaction, the reaction mixture was filterated and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-benzamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (279 mg, 69% yield): mp 147°-147.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23]Br)=[CH:22][C:16]=2[CH:15]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: Oc1cccnc1
Reactant: COC(=O)c1cc2cc(CBr)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(COc3cccnc3)ccc2s1

Procedure:
3-Hydroxypyridine (0.40 g.) was dissolved in dry N,N-dimethylformamide (10 ml.) and sodium hydride (0.20 g. of 50% dispersion in mineral oil) was added portionwise with stirring and the resulting mixture was stirred at room temperature for 30 minutes. 5-(Bromomethyl)benzo[b]thiophene-2-carboxylic acid methyl ester (1.20 g.) in a few mls of dry N,N-dimethylformamide was then added and the mixture was stirred at room temperature for 30 minutes, and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of chloroform and toluene (1:1) first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid (0.40 g.) which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 5-(3-pyridyloxymethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, m.p. 106°-107° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:53][C@H:52]([CH2:51][O:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH2:54][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(Nc2ncccc2NC(=O)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1)c1ccccc1
Yield: 32.8 %

Procedure:
N-{2-[4-(2-Aminoethyl)anilino]-3-pyridinyl}benzamide (0.1 g, 0.30 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.107 g, 0.265 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.064 g, 0.087 mmol).
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][CH2:11][C@H:12]([C:38](=[O:40])[NH2:39])[NH:13][C:14](=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29](=[O:30])[C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26](=[O:35])[C:25]=1[CH3:36])C1C=CC=CC=1>CO.O.[Pd]>[CH3:32][O:31][C:28]1[C:29](=[O:30])[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][C@@H:12]([C:38](=[O:40])[NH2:39])[CH2:11][CH2:10][C:9]([OH:41])=[O:8])=[O:37])=[C:25]([CH3:36])[C:26](=[O:35])[C:27]=1[O:33][CH3:34]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)=C(C)C1=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](CCC(=O)O)C(N)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
10-(2,3-Dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine benzyl ester (3.42 g, 6 mmol) was dissolved in methanol (12 ml) and, the solution was hydrogenated with palladium black at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol (25 ml). A solution of ferric chloride (2.43 g, 15 mmol) in water (5 ml) was added and the mixture was stirred at room temperature for 10 minutes. The solvent was then distilled off and the residue was dissolved in ethyl acetate (30 ml), washed with water (15 ml×4) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on a silica gel column. Elution with chloroform-methanol (9:1, v/v), chloroform-acetone-methanol (10:3:2, v/v) and chloroform-methanol-acetic acid (18:2:1, v/v) in that order gave a crude product. The product was recrystallized from ethanol-ethyl ether-petroleum ether to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine (1.61 g), melting at 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc(Cl)sc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)sc1CBr
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate (Intermediate 179, 2.8 g; 13.6 mmol) was dissolved in CCl4 (25 ml). NBS (2.3 g; 13 mmol) and AIBN (2.12 g; 13 mmol) were added in a single portion and the resultant reaction mixture was heated to reflux for 24 hours. Additional NBS (690 mg; 0.3 equiv.) and AIBN (636 mg; 0.3 mmol) were added to push the reaction to completion. Continued to heat for another 4 hours. Cooled to room temperature, filtered and concentrated the mother liquor. Redissolved in minimal DMSO (7 ml) and purified by Gilson HPLC (5-95% ACN/0.1% TFA; run time=35 min). Isolated 1.15 g of desired product in 29% yield MS (ES) MH+: 284, 286, 288 for C7H7BrClNO2S.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=[O:12])=O.C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[C:11]1(=[O:12])[C@H:6]2[C@H:5]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:3][O:13]1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC[C@H]2CCCC[C@@H]12
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Into a 25 mL jacketed vessel cooled to below 0° C. was placed a solution of (1S,2R)-2-(methoxycarbonyl) cyclohexane carboxylic acid (3, 880 mg, 4.72 mmol) and triethylamine 659 μL, 4.72 mmol) in THF (6.6 mL). A solution of ethyl chloroformate (512 μL, 4.72 mmol) in 1.2 mL of THF was added slowly over a few minutes and the resulting mixture was stirred for 30 minutes. The precipitated triethylamine hydrochloride salt was removed by filtration and the filtrate was added drop-wise to a suspension of sodium borohydride in 4.6 mL of water at 12° C. After the addition was complete, the reaction mixture was stirred at 20° C. for a further 3.5 hours. The reaction mixture was then cooled to below 10° C., acidified to pH 4 with 2M HCl solution, and extracted with 2×15 mL of dichloromethane. The combined organic extracts were dried over magnesium sulfate and solvent was removed under reduced pressure, to yield 450 mg of a colorless oil. The material was purified by short path distillation to yield 170 mg of colorless oil with e.e.=98% and [α]D20=−39.3° (c 1, methanol).
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[BrH:38].C(O)(=O)C>C(OCC)C>[BrH:38].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodononane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[N:8][C:4]=2[CH:3]=1.[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC>C1(C)C=CC=CC=1.CCOC(C)=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>[CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:7]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]3[CH:28]=[CH:29][C:2]([CH:30]=[CH2:31])=[CH:3][C:4]=3[N:8]=2)[C:11]1=[O:22])([CH3:21])[CH3:20]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(Br)ccc21
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Yield: 32.3 %

Procedure:
A mixture of 1-[5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (90 mg, 0.2 mmol), tributylvinyltin (76 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene (4 mL) was heated to reflux for 4 h. After cooling, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 4:1 to 2:1) to give 26 mg (32%) of 1-isopropyl-3-[1-(3-methyl-butyl)-5-vinyl-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one as a off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: COc1ccnc(CSCCN)c1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: COc1ccnc(CSCCN=C(NC#N)SC)c1
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-4-methoxypyridine (3.15 g) in ethanol (25 cc) was added over 1 hour to a stirred solution of dimethyl N-cyano-dithioimidocarbonate (2.215 g) in ethanol (30 cc) at 22° and the mixture was allowed to stand overnight at room temperature. Nitrogen was passed through the suspension and the mixture was filtered to give N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea m.p. 91.5°-92.5°. (3.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CCO>[C:7]([C:11]1[N:12]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Yield: 87.4 %

Procedure:
piperazine (7.54 g, 87.57 mmol) was dissolved in EtOH, 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (3.28 g, 14.60 mmol) was added dropwise at 80° C. over 10 min The solution was refluxed overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (3.5 g, 87%).