Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]2[CH2:47][C@@H:42]1[CH2:43][NH:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C:4]2[N:3]=[C:2]([N:44]3[CH2:43][C@H:42]4[CH2:47][CH:45]3[CH2:46][N:41]4[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Reactant: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C[C@@H]1CN2c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)-phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (820 mg, 2.0 mmole), potassium carbonate (ca. 1.0 g) and (−)-2-(tert-butoxycarbonyl)-(1R, 4R)-2,5-diaza-bicyclo[2.2.1]heptane (436 mg, 2.2 mmole) in 10 ml of DMF was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and precipitate was filtered and washed with water and dried under vacuum to give product as off white solid; MS m/z (M)+ 572.3; C27H25ClF3N7O2 requir. 572.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][O:34]S(C)(=O)=O)[C:30]5[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2.[C:43]([O-])([O-])=O.[K+].[K+].O.[C:50]([O:53][CH2:54][CH3:55])(=O)[CH3:51]>C(O)(C(F)(F)F)=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][O:34][CH:54]5[CH2:55][CH2:43][CH2:51][CH2:50][O:53]5)[C:30]5[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOS(C)(=O)=O
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(2R,4R)-tert-butyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(methylsulfonyloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (65 mg, 0.11 mmol) was dissolved in TFA (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to removed TFA, the residue was dissolved in DMF (1 mL) and K2CO3 (30m g, 0.22 mmol) was added to it, the resulting mixture was stirred at 60° C. for over night. Water and ethyl acetate were added to reaction mixture, the organic layer was separated and dried over MgSO4 and concentrated. Purification was done by Companion (ReadSep, 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1-5% to give a white solid 30 mg (60%) as title compound. LC-MS: 405.2 (t=1.4 min).
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][C:15]([O:17]C)=O)=[C:12](Cl)[N:11]=[C:10]([CH3:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([CH2:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([CH2:28][NH:29][C:12]1[C:13]2[CH2:14][C:15](=[O:17])[N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=[C:10]([CH3:20])[N:11]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Nc1ccccc1
Product: Cc1nc(NCCc2ccccc2)c2c(n1)N(c1ccccc1)C(=O)C2
Temperature: 160 °C
Yield: 44.6 %

Procedure:
A mixture of 4-anilino-6-chloro-2-methylpyrimidine-5-acetic acid, methyl ester (5.0g, 17.2mM) and benzylmethylamine (2.22ml, 17.2mM) was heated at 160° C. for 3.5 hours. The mixture was cooled and then partitioned between methylene chloride (50ml) and 2M hydrochloric acid (50ml). The organic layer was separated, washed with a solution of sodium hydroxide (2M, 50ml), water, dried and the solvent evaporated. The residue was purified by flash column chromatography on silica (Merck 9385), eluting with ethyl acetate/hexane (20:80, v/v) to give 4-(N-benzylmethylamino)-2-methyl-6-oxo-7-phenyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine (2.64g, 44.6%) m.p. 81°-84° C.; microanalysis, found; C, 73.0; H, 6.0; N, 16.3%; C21H20H40 requires C, 73.3; H, 5.8; N, 16.3%; NMR: DMSOd6 : 2.3(3H, s, pyrimidine-CH3), 3.2(3H,s,N-CH3), 3.95(2H,s,COCH2), 4.85(2H,s,N-CH2), 7.2-7.55(10H, complex, aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][S:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid (3.33 g, 13.07 mmol), 4-(methylsulfonyl)benzohydrazide (3.08 g, 14.38 mmol) and anhydrous THF (200 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.77 g, 13.07 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.76 g, 19.61 mmol) at −15° C. followed by triethylamine (2.73 mL, 19.61 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 17 h, the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4) and concentrated to furnish a light brown solid (5.82 g). This crude product was chromatographed [100% EtOAc as eluent] to afford a pale yellow solid (5 g). The crude product was used directly in the next step.
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (94 mg, yield 90%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24][CH3:25])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:26].OO>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24]([CH3:25])=[O:26])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CSCCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: CS(=O)CCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 14 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-5-(methylthio)pentanoic acid (2.5 g) was added to water (15 ml) and acetic acid (5 ml) and 30% H2O2 (10 ml) . The oxidation was allowed to proceed for 14 hours after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.51 (m, 4H), 1.56 (m, 2H), 2.0(m, 2H), 2.18 (s, 3H), 2.90 (m, 4H), 2.71 (m, 2H), 4.10 (m, 1H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.10 (bs, 2H), 9.25 (bs, 2H); MS (FAB) m/e 382 2 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:6]1[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=[C:5]1[CH2:1][CH:2]([CH3:4])[CH3:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of the 6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 26) (11 g, 49 mmol) in 60 ml of anhydrous DMF at 0° C., was added 13.8 g (100 mmol) of anhydrous K2CO3 followed by benzyl bromide (9.3 g, 54 mmol) and the mixture was stirred at 0-20° C. overnight. The TLC of the reaction mixture showed the complete disappearance of the SM. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×100 ml). The combined extracts were washed with water (100 ml), brine (100 ml), dried (Na2SO4) and concentrated. The TLC and the 1H NMR showed the presence of two products N alkylated as well as O-alkylated products in a ratio of 75:25. The products were separated by column (silica gel) chromatography using 10% EtOAc in hexanes. The major N-alkylated product 5-benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one was isolated as white crystalline solid (10.8 g, 70%). 1H NMR (300 MHz) δ 0.94 (d, 6H), 2.23-2.37 (m, 1H), 2.64 (d, 2H), 2.82 (s, 3H), 5.38 (s, 2H), 7.10-7.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:45])(=O)=O.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][Cl:45])[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-dihydro-3-quinolinecarboxamide (197 mg) from Preparation No. 41 in DMF (1 mL) is added 2,4,6-collidine (0.14 mL) and DMAP (8 mg). The solution is cooled to 0° C., and methanesulfonyl choride (69 μL) is added. After 18 h, the mixture is added to 20 mL of rapidly stirred water containing 0.75 mL of 1N HCl. The resulting precipitate is filtered, washed well with water, and dried in vacuo to afford 183 mg of N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-dihydro-3-quinolinecarboxamide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1C[O:23][CH2:22][CH2:21]1>>[F:13][C:14]1[C:19]([C:22](=[O:23])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: C1CCOC1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.13 mL (30.90 mmol) of freshly distilled diisopropylamine in 10 mL of anhydrous THF under nitrogen cooled to −78° C. was treated dropwise with 19.31 mL (30.90 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting solution was stirred at −78° C. for approximately 20 minutes, and was briefly (5-10 minutes) warmed to −40° C., then recooled to −78° C. At 30 minutes post addition, 3.00 g (30.90 mmol) of 2-fluoropyridine was added dropwise to the reaction. The resulting solution was stirred at −78° C. for 30 minutes. The reaction was treated dropwise with a solution of 3.16 mL (30.90 mmol) of the Weinreb amide in 30 mL of THF. The resulting solution was stirred 18 hours, allowing the bath to slowly evaporate and the reaction temperature to rise to room temperature. The reaction was treated with 5 mL of 1N HCl, and was concentrated to remove most of the THF. The residue was extracted twice with EtOAc, and the combined extracts were washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, and were dried over anhydrous MgSO4. Filtration and concentration of the filtrate provided a crude orange oil, which was purified by flash chromatography over silica gel with 3:1 Hexanes/EtOAc to provide 1.10 g of the title product as an orange oil. 1H NMR (CDCl3): 2.72 (s, 3H), 7.33 (m, 1H), 8.34 (m, 1H), 8.41 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 90 %

Procedure:
A solution (0.5 M) of 3-cyclohexenyl-1H-indole-6-carboxylic acid (from Step 1) in THF/MeOH (0.5 M, 1:1, v/v) was hydrogenated for 14 h over Pd(OH)2/C (0.1 eq., 20%) at 60 psi. The catalyst was removed by filtration on a pad of Celite™ and the filtrate evaporated to dryness to afford 3-cyclohexyl-1H-indole-6-carboxylic acid (90%) as a white solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.20-1.53 (m, 5H), 1.70-1.87 (m, 3H), 1.90-2.02 (m, 2H), 2.69-2.86 (m, 1H), 7.40 (s, 1H), 7.55-7.65 (m, 2H), 8.0 (s, 1H), 11.40 (s, 1H); MS (ES+) m/z 244 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:1][CH:2]([CH2:6][OH:7])[C:3]([O:5][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[O:4]
Reactant: O=C(O)C(Cl)CO
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)C(Cl)CO
Reaction time: 40 h

Procedure:
2-chloro-3-hydroxypropionic acid (4.80 g, 0.03 mol), dodecanol (6.00 g, 0.03 mol) were taken with 5 mL dry benzene in a (50 mL) RB, with a dean-stark apparatus and condenser; 25 mg (0.26 mmol) para-Toluene sulfonic acid (pTSA) was added to it and the mixture was stirred at 75° C.-80° C. for 40 h. 1H-NMR showed 85% conversion. More 2-chloro-3-hydroxypropionic acid (1.00 g, 8.00 mmol) was added to it and heated at 75° C.-80° C. for 20 h. 1H-NMR showed almost complete conversion. After cooling it down, the product was added with 100 mL of CH2Cl2. Organic phase was washed twice with 50 mL of dil. NaHCO3 aq. sol. and once with 50 mL of sat. NaCl aq. sol. and then dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, yield=7.76 g (78%). It was used for the next reaction without further purification. 1H-NMR (CDCl3, 7.27 ppm): 2.18-2.40 (broad, —OH), 3.97 (m, —CH2OH), 4.21 (m, —CO2CH2), 4.39 (m, —CHCl).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[O:20]=[C:17]1[N:16]=[C:15]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH2:19][S:18]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of glycinamide hydrochloride (5.00 g) and triethylamine (6.30 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.02 g), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.50 g).
Reaction SMILES: NC1C(C(O)=O)=CN(C2N=CC3CC[C:14]4[CH:20]=[C:21]([O:24][CH3:25])C=C[C:13]=4[C:12]=3[N:11]=2)N=1.Br[C:27]1[CH:39]=[CH:38][C:30]2[NH:31]C(C(Cl)(Cl)Cl)=[N:33][C:29]=2[CH:28]=1>CC(N(C)C)=O>[NH2:33][C:29]1[CH:28]=[C:27]([C:20]2[C:21]([O:24][CH3:25])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:39]=[CH:38][C:30]=1[NH2:31]
Reactant: ClC(Cl)(Cl)c1nc2cc(Br)ccc2[nH]1
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(N)c(N)c1

Procedure:
A solution of salicylaldehyde derivative 1 (0.5 mmol) and diamine 2 (0.176 g, 0.5 mmol) in dimethylacetamide (4 mL) was stirred at 100° C. for 12 h. Solvent was evaporated and the residue was purified by preparative HPLC to give benzimidazole derivative 3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=1.C([Li])CCC.B(OC)(OC)[O:20]C.CC(O)=O.OO>C1COCC1.O>[OH:20][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cnccc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(pyridin-3-yl)-2,2-dimethylpropanamide (8.90 g, 50.0 mmol) in THF (200 mL) at −78° C. was added n-Butyllithium (50 mL, 125 mmol) dropwise over 30 min. After addition, the reaction mixture was warmed to 0° C. and stirred an additional 3 h. The reaction was then cooled back to −78° C. and trimethyl borate (14.2 mL, 125 mmol) in THF was added dropwise over 15 min. After addition, the reaction mixture was warmed to 0° C. and stirred an additional 2 h. Glacial AcOH (10.8 mL, 188 mmol) was added to the reaction, followed by dropwise addition of 30% H2O2 (14.3 mL, 138 mmol). The reaction mixture was warmed to rt and stirred overnight. The mixture was diluted with H2O and concentrated in vacuo. The residue was extracted three times with 10% iPrOH/CHCl3, the combined extracts treated with activated charcoal, and the slurry filtered through Celite. The organic layer was washed three times with H2O, once with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (3–10% MeOH/CHCl3) to give N-(4-hydroxypyridin-3-yl)-2,2-dimethylpropanamide as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 11.58 (br s, 1H), 8.76 (br s, 1H), 8.67 (s, 1H), 7.68 (d, 1H), 6.26 (d, 1H), 1.22 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.NC1C(C(N)=O)=NC(C2C=CC(F)=CC=2)=CC=1>>[NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1nc(Cl)ccc1N
Reactant: OB(O)c1cccc(F)c1
Agent: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Product: NC(=O)c1nc(-c2cccc(F)c2)ccc1N
Yield: 92 %

Procedure:
was synthesized from 3-amino-6-chloropyridine-2-carboxylic acid amide and 3-fluorophenylboronic acid in 92% yield as a white solid, using the procedure described for the synthesis of 3-amino-6-(4-fluorophenyl)-pyridine-2-carboxylic acid amide. The mass spectrum was as follows: MS (m/z): 232 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([NH:37][C:38](=[O:48])[C@@H:39]([NH2:47])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:35][CH:36]=1)=[O:31].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([NH:37][C:38](=[O:48])[C@@H:39]([NH:47][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]3[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]3)=[CH:15][CH:14]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:35][CH:36]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
(R)-tert-Butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid (280 mg, 0.73 mmol), 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (203 mg, 0.66 mmol) (prepared as described in example 10, step 1), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (191 mg, 1.0 mmol) and 1-hydroxybenzotriazole hydrate (135 mg, 1.0 mmol) were combined in dichloromethane (5 mL) and stirred overnight at room temperature. The resulting solution was poured into ethyl acetate and washed with 0.2 M aqueous hydrochloric acid, water, brine and dried over magnesium sulfate. The solvents were removed and the crude was purified by chromatography over silica gel gradient eluted between 40% and 50% v/v ethyl acetate in hexane to give 2-((S)-2-{(R)-2-tert-butoxycarbonylamino-2-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a foam (170 mg, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)=[O:12])([O-:3])=[O:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)[C:11](=[O:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Product: CCOc1ccc(N(C(=O)CCl)C(=O)Nc2ccccc2[N+](=O)[O-])cc1Br

Procedure:
A solution containing N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea (5.76 g) and chloroacetyl chloride (40 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo, diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N'-(2-chloroacetyl)-N-(2-nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a white solid.