Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1 mL, 13.3 mmol) was added to a cooled (0° C.) solution of 4-(benzyloxy)butan-1-ol (2 g, 11.1 mmol) and triethylamine (1.9 mL, 13.3 mmol) in DCM (20 mL) and it was stirred at 0° C. for 1 h. HCl (1M) was added to the reaction mixture and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 4-(benzyloxy)butyl methanesulfonate as a yellow oil. LCMS [M+1]+ 259.5.
Reaction SMILES: [CH2:1]([CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:16]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([C:26]1[CH:27]=[C:28]([CH2:37][CH2:38][C:39]([NH:41][NH2:42])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC=CC=1>O>[C:33]([C:30]1[CH:29]=[C:28]([CH2:37][CH2:38][C:39]([NH:41][N:42]2[C:19](=[O:21])[CH2:20][CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:16]2=[O:18])=[O:40])[CH:27]=[C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:31]=1[OH:32])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 70 °C
Yield: 84.4 %

Procedure:
A mixture of 2-tetradecylsuccinic anhydride (17.2 g, 52.5 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (15.4 g, 52.5 mmol) and 40 ml of toluene was refluxed for about one hour under a nitrogen atmosphere with the azeotropic removal of water. The bulk of the solvent was then allowed to distill off. Residual solvent was removed by placing the heated mixture (140° C.) under vacuum for 15 minutes. The bath used to heat the mixture was cooled to 70° C. and the vacuum was released. The resulting viscous melt was dissolved in 120 ml of acetone and suction filtered to remove mechanical impurities. The filtrate was diluted to 700 ml with acetone. This solution was cooled in an ice/water bath to precipitate the product which was collected by vacuum filtration. The filtrate was then re-cooled in a -20° C. acetone/dry ice bath to obtain additional product which was also collected by filtration. The collected solids were combined, air dried on a sheet of paper and finally high vacuum dried to give 25.3 g of a white solid having a melting range of 70°-77° C.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:18]([F:19])=[CH:17][C:12]2[NH:13][C:14](N)=[N:15][C:11]=2[CH:10]=1.[ClH:20]>CC(C)=O.[Cu](Cl)Cl>[Cl:20][C:14]1[NH:13][C:12]2[CH:17]=[C:18]([F:19])[C:9]([F:8])=[CH:10][C:11]=2[N:15]=1
Reactant: Nc1nc2cc(F)c(F)cc2[nH]1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC(C)=O
Product: Fc1cc2nc(Cl)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. To a mixture of copper(II) chloride (795 mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL, 4.43 mmol). The reaction mixture was stirred at rt for 20 minutes, 5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added, and the mixture was heated at reflux for 2 h (with additional portions of tert-butyl nitrite added every 0.5 h). The reaction mixture was then cooled to rt, treated with 2 N HCl, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%), which was used without further purification in the next step. LC-MS m/z 189.2 (MH+), ret. time 1.96 min; 1H NMR (300 MHz, DMSO-d6) δ 7.62 (t, 2H), 13.5 (br s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([O:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)(=[O:36])[CH3:35]
Reactant: NC(=O)COc1cccc(C(O)C(c2ccccc2)C2SCCCS2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(c1cccc(OCC(N)=O)c1)C(c1ccccc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5 (192 mg, 0.5 mmol) in 10 mL THF was added DMAP (2 mg), triethylamine (70 mL, 0.5 mmol), and acetic anhydride (94 mL, 1.0 mmol). The solution was stirred at room temperature for 4 h, and then partitioned between ethyl acetate (50 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with water (3 X 5 50 mL), dried with Mg2SO4, and evaporated to yield a colorless oil. Yield 205 mg (98%). IR: 3479, 3331 (br), 1747, 1694, 1589, 1 443, 1224, 1033, 910, 718 cm-1. 1H NMR (CDCl3, TMS) d 7.740 (dd, J=8.15, 1.55 Hz, 2 H), 7.348-7.281 (m, 3 H), 7.111 (t, J=7.96 Hz, 1 H), 6.801 (dd, J=8.18, 2.53 Hz, 1 H), 6.686 (d,J=7.59 Hz, 1 H), 6.521 (s, 2 H), 6.312 (s, 1 H), 6.136 (s, 1 H), 4.238 (s, 2 H), 2.751-2.597 (m, 4 H), 2.104 (s, 3 H), 1.933-1.857 (s, 1 H). 13C NMR (CDCl3, TMS) d 171.080, 169.318, 156.012, 136.974, 130.771, 128.402, 128.045, 127.738, 122.586, 115.072, 114.635, 79.890, 66.982, 63.133, 27.270, 27.109, 24.568, 20.848. Anal. Calcd. for C21H23NO4S2 : C, 60.41; 11, 5.55; N, 3.5. Found: C, 5 9.92; H, 5.76; N, 3.14.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1.Br[CH:16]([OH:18])[CH3:17].C(Cl)Cl.[OH-].[Na+]>O>[OH:18][CH2:16][CH2:17][NH:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCNC1CCc2cc3c(cc2C1)OCC3

Procedure:
7.7 g of 7-amino-2,3,5,6,7,8-hexahydronaphtho-[2,3-b]furan, 5 g of bromoethanol, 40 ml of methylene chloride, 12 ml of 40% strength sodium hydroxide in water and 1 g of Triton B are stirred vigorously at room temperature for 48 hours. After separation following settling, the methylene chloride is evaporated off in the cold and the residue is taken up with ethyl ether, which is exhaustively extracted with hydrochloric acid. The alkalinized acid phases yield an oil having the expected structure.
Reaction SMILES: [C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Cl)[CH:15]=[CH2:16].O>C1COCC1>[C:1]1([C:6]2([CH2:16][CH:15]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:2][CH2:3][CH2:4][CH:5]=1
Reactant: C=CCCl
Reactant: O=C1CCCC1=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(C2=CCCC2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a stirring solution of 2-cyclopentylidenecyclopentan-1-one (62.5 g, 0.417 moles) in dry THF (450 mL) at room temperature under nitrogen, was added NaH (60% oil dispersion, 20.0 g, 0.5 moles) in one portion. The mixture was stirred at room temperature for 30 min and then a solution of allyl chloride (38.3 g, 0.5 moles) in THF (100 mL) was added dropwise over 30 min. When the addition was complete, the reaction was warmed gently to approximately 40° C. It was determined by TLC and GC that the reaction was complete after 18 hours. Water was added to the reaction mixture and the layers were separated, with the organic layer being washed successively with 10% HCl (aqueous), saturated NaHCO3 (aqueous), and brine. The resulting organic layer was dried with MgSO4, filtered, and concentrated. The brown oil was distilled under vacuum to give 2-cyclopent-1-enyl-2-prop-2-enylcyclopentan-1-one (54.5 g, 69.0% yield).
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:2])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 115.5 %

Procedure:
To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in N,N-dimethylformamide (50 ml) were added sequentially 1,2,3,4-tetrahydroisoquinoline (322 mg, 1.1 eq), 1-hydroxybenzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to Yield 1.24 grams of a dark oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[CH3:12][C:13]1[N:18]=[C:17]([C:19](O)=O)[CH:16]=[C:15]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:14]=1>>[CH3:19][C:17]1[N:18]=[C:13]([C:12]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[CH:14]=[C:15]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH:16]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C(=O)O)n1
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(N)nc3)no2)n1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.113 g, 0.53 mmol) and 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.11) (0.10 g, 0.36 mmol) according to the general procedure V. Obtained as an off-white solid (0.045 g, 31%). MS (ISP) 398.1 [(M+H)+]; mp 163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH:19]=O)=[CH:14][N:13]=1>>[C:2]1([CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[C:5]([NH2:6])=[N:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[CH:14][C:15]=2[CH:19]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1ccccc1CC#N
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1N

Procedure:
The title compound was prepared according to Example 1, starting from 2-methylbenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 300-302° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO[C:22](OC)([CH3:24])[CH3:23].CC(C)=O>CCCCCC>[CH3:23][C:22]1([CH3:24])[O:3][CH:2]2[CH:4]([CH:6]([CH2:7][OH:8])[O:9][CH:1]2[N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:5]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: COC(C)(C)OC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC1(C)OC2C(CO)OC(n3cnc4c(N)ncnc43)C2O1
Reaction time: 3 h

Procedure:
A solution of adenosine (43 g) and 2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated with D-camphorsulphonic acid (1 eq) at and the resulting reaction was allowed to stir for 3 hr. The reaction mixture was concentrated in vacuo and diluted with a mixture of saturated aqueous NaHCO3 (250 mL) and ethyl acetate (250 mL). The resulting solution was transferred to a separatory funnel and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide a solid residue. The solid residue was suspended in hexane, filtered, washed with hexane and dried to provide 2′,3′-Isopropylidene-adenosine (43 g). 1H NMR (DMSO-d6, 300 MHz): δ 4.12-4.17 (m, 1H), 4.22-4.26 (m, 1H), 4.59 (d, J=4.8 Hz, 1H), 4.74-4.85 (m, 2H), 5.49-5.52 (m, 1H), 5.51 (d, J=5.1 Hz, 1H), 5.84 (d, J=5.1 Hz, 1H), 7.85 (s, 2H), 8.33 (s, 1H). MS t/z 347.11 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([O:33][CH3:34])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH2:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:26]([O:33][CH3:34])[CH:25]=1
Reactant: Cc1cc(CN(C(=O)OC(C)(C)C)c2cnccc2I)no1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1cc(C)on1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from tert-butyl 4-iodopyridin-3-yl((5-methylisoxazol-3-yl)methyl)carbamate and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (88%). MS (ESI): m/z=414.182 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:19]=[CH:18][NH:17][C:10]=3[N:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>CCO>[CH:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1NC1CCCCC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 55 °C
Yield: 81.5 %

Procedure:
To a solution of N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.15 g, 0.57 mmol) in EtOH (10 mL) was added tin (II) chloride dihydrate (0.65 g, 2.9 mmol). The reaction mixture was heated at about 55° C. for about 1 h. The solvent was removed under reduced pressure and EtOAc (75 mL) and saturated aqueous NaHCO3 (25 mL) were added. The solid that formed was collected by vacuum filtration, washed with EtOAc (25 mL), and discarded. The filtrate was washed with saturated aqueous NaHCO3 (3×20 mL), dried over anhydrous MgSO4, filtered, and concd to give N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.107 g, 87%) as a brown residue: LC/MS (Table 1, Method c) Rt=1.21 min; MS m/z 231 (M+H)+.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:16])[CH:15]=[C:10]([Cl:9])[C:11](=[O:18])[CH:12]=[C:13]1[Cl:17])[CH3:8]
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C=C1Cl
Yield: 92 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.59 g (3.33 mmol) of 2,5-dichloro-p-benzoquinone in 6.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate, and the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.81 g of the desired product (yield 92%).
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>C1COCC1>[C:11]1([C:8]2[O:7][C:6]([C:4]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:5])=[CH:10][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(-c3ccccc3)o2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 38d (0.231 g, 1 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1d as white crystals (35.5%). 1H NMR (CDCl3) δ 7.85-7.82 (m, 1H), 7.48-7.36 (m, 4H), 7.35 (s, 2H), 7.25 (d, 1H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz), 3.96 (s, 3H), 3.95 (s, 6H); MS (ESI) m/z 339.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium carbonate (773 mg, 5.59 mmol) in dichloromethane (25 mL) was added m-toluidine (0.5 mL, 4.66 mmol) followed by dropwise addition of chloroacetyl chloride (0.44 mL, 5.59 mmol) and the mixture was stirred at ambient temperature overnight. The reaction was quenched by addition of water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide 2-chloro-N-m-tolyl-acetamide. MS (DCI-NH3): m/z 201 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: NC1CCCC1
Product: N#Cc1c(NC2CCCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 292 mg (3.43 mmol) of cyclopentylamine to give 10 mg (9% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and pyrrolidine to give a yellow solid. MS m/z: 389.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][CH2:12][CH:11]=[CH2:10]
Reactant: C=CC[Mg]Br
Reactant: BrCc1ccccc1Br
Solvent: C1CCOC1
Product: C=CCCc1ccccc1Br
Temperature: 0 °C

Procedure:
To an ice cold solution of 2-bromobenzyl bromide (5.00 g, 0.020 mol) in THF (25 mL) was added 1M allyl magnesium bromide (100 mL, 0.100 mol) slowly via cannula. The reaction mixture was stirred at reflux for 1.5 h, cooled in an ice bath and quenched with 50 mL of aqueous 2M H2SO4. Water (50 mL) was added to dissolve any remaining solid and the layers were separated. The aqueous layer was extracted with Et2O (2×150 mL). The combined organic extracts Were dried over Na2SO4, filtered and concentrated to yield 1-bromo-2-but-3-enyl-benzene as a light yellow oil. The isolated crude product was carried forward without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([C:18]2[S:22][C:21](=[S:23])[NH:20][N:19]=2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].Br[CH2:25][C:26]([OH:28])=[O:27]>CO>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([C:18]2[S:22][C:21]([S:23][CH2:25][C:26]([OH:28])=[O:27])=[N:20][N:19]=2)[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(-c2nnc(SCC(=O)O)s2)cc(C(C)(C)C)c1O
Reaction time: 4 h

Procedure:
Aqueous 1M NaOH (12.4 ml, 0.0124 mole) is added to 0° C. solution of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione (2.0 g, 0.0062 mole) in methanol (20 ml). This is followed by addition of 2-bromoacetic acid (0.95 g, 0.0068 mole) in one portion. The resulting mixture is allowed to stir four hours with periodic warming. The solution is concentrated in vacuo and the residue is partitioned between ether and water. The layers are separated and the aqueous phase is made acidic with aqueous 6M HCl. The aqueous layer is extracted with 1:1 ethyl acetate/ether (2×). The combined organic layers are washed with saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo provides a solid which is recrystallized from ethyl acetate/hexane to give 1.6 g (2.4 g theor., 68%) of [[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl[thio]acetic acid, mp 187.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[NH:13][C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OCc3ccccc3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Yield: 92.2 %

Procedure:
The product of Example 352B (277 mg, 0.7398 mmol) in ethanol (20 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) with 10% palladium on carbon (28 mg, 10 weight %) for 1.25 hour. The reaction was filtered through a PTFE membrane filter (0.45 μm) and the catalyst thoroughly washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure and the resulting oil triturated with dichloromethane/hexanes (1:1 v/v) to give the title compound as a crystalline white solid (194 mg, 92%). MS (ESI−) m/z 283 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.17 Hz, 3 H) 3.64 (s, 2 H) 4.15 (q, J=7.23 Hz, 2 H) 7.06 (d, J=2.57 Hz, 1 H) 7.11 (dd, J=8.83, 2.57 Hz, 1 H) 7.20 (d, J=8.83 Hz, 1 H) 10.21 (s, 1 H) 12.11 (s, 1 H).