Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1Cl)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:20][CH2:21][SH:22]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:22][CH2:21][CH2:20][C:19]([F:30])([F:18])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccncc1Cl
Reactant: Fc1ccc(C(F)(F)CCS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-chloro-pyridine-4-carboxylic acid methyl ester (0.28 g, 1.65 mmol) in DMF (10 ml) are added cesium carbonate (2.68 g, 8.25 mmol) and 3,3-difluoro-3-(4-fluorophenyl)-propane-1-thiol (synthesized according to the methods described in sections a) and b) of example 3) (0.34 g, 1.65 mmol) in a sealed tube. The reaction mixture is stirred at 90° C. for 1 h. After completion of the reaction, the mixture is diluted with water (15 ml) and extracted with EtOAc (3×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 10% acetone/hexane) to yield 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid methyl ester (0.19 g, 0.56 mmol, 34%).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:12][C:8]1[N:7]=[C:6]([C:4]2[N:23]=[C:24]([NH2:26])[S:25][C:3]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:11]=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(-c2nc(N)sc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C

Procedure:
A solution of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone hydrobromide (24.5 mg, 0.072 mmol), thiourea (7.5 mg, 0.094 mmol, 1.3 equiv), and potassium carbonate (0.11 mmol, 1.5 equiv) in ethanol (1 mL) is heated to 80° C. overnight. The resulting reaction mixture is cooled to ambient temperature and concentrated in vacuo. Reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provides 4-(6-Methyl-pyridin-2-yl)-5-quinolin-6-yl-thiazol-2-ylamine.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.S(C1C=CC(C)=CC=1)(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.Cl>CN1CCCC1=O.O>[F:21][C:20]([F:23])([F:22])[CH2:19][O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[C:5]=1[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCc1c(C)cc(C)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCc1c(C)cc(C)cc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
17 g of sodium hydroxide were metered into a mixture of 50 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenol (C) and 86 g of 2,2,2-trifluoroethyl tosylate in 450 ml of N-methylpyrrolidone at 120° C. Stirring was continued for 16 hours at 120° C., and the mixture was subsequently poured into 2 l of water. The pH was brought to 2 using 6N hydrochloric acid, and the mixture was extracted using dichloromethane. The combined organic phases were dried over sodium sulphate, the solvent was removed in vacuo, and the residue was distilled. This gave 32 g (43% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)phenyl 2,2,2-trifluoroethyl ether of a boiling point of 100° C. at 1 mbar.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>O1CCOCC1>[CH:24]1([CH2:23][NH:22][C:3]2[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[N:8]=2)[CH2:26][CH2:25]1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: NCC1CC1
Solvent: C1COCCO1
Product: N#Cc1nnc(NCC2CC2)nc1N1CCc2ccccc2CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 150 mg (0.50 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as prepared in example 1b and 74 mg (1.0 mmol) of aminomethyl-cyclopropane in 5 ml of dioxane was stirred at 120° C. overnight. The solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 98:2 v/v mixture of dichloromethane and methanol as the eluent. There were obtained 57 mg (35% of theory) of 3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white solid; MS: 321 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1>CN(C)C=O>[Cl:32][C:33]1[N:38]=[C:37]([N:21]2[CH:22]=[C:17]([CH:16]3[C:11]4[N:12]=[C:13]([CH3:15])[O:14][C:10]=4[CH:9]=[CH:8][C:7]4[CH:25]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]3=4)[C:18](=[O:24])[NH:19][C:20]2=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O

Procedure:
A solution of the product from step (vii) (4.50 g), cesium carbonate (4.37 g) and 2,4-dichloropyrimidine (3.00 g) in dry N,N-dimethylformamide (30 ml) was stirred for 25 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer dried (MgSO4). Evaporation of the solvent gave an oil which was purified by column chromatography eluting with 50-100% ethyl acetate in 40-60 petroleum ether.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>CO>[CH3:17][S:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:18]=[CH:19][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)(=[O:15])=[O:16]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)CCn1cnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (0.2 g, 7.09 mmol) in methanol was added LiOH (50 mg) followed by water (1 mL). The reaction mixture was allowed to stir at room temp for 2 h. it was then concentrated to remove methanol and the aqueous layer was acidified with citric acid. The precipitated product was filtered to give 1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid (90%). MS-ESI m/z 269 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 12.6 (br, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 4.8 (t, 2H), 3.8 (t, 2H), 3.0 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[C:19]1(C)[C:20](S(O)(=O)=O)=CC=C[CH:24]=1>C(O)CC>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:24][CH2:19][CH3:20])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Solvent: CCCO
Product: CCCOC1CCN(CCC)C(=O)N1c1nnc(SC)s1

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), propyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-propoxy-2(1H)-pyrimidinone.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][C@H:13]([CH3:18])[C:14]([O:16]C)=[O:15])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][C@H:13]([CH3:18])[C:14]([OH:16])=[O:15])[S:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)O
Yield: 33.7 %

Procedure:
The reaction was effected as described in Example 48, but using 1.74 g of methyl 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 70), 30 ml of methanol, 22 ml of tetrahydrofuran and 17.0 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0.56 g of the title compound as yellow crystals, melting at 131 to 134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].Br[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]2[CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: OC(CBr)CCBr
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(N2CCC(O)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
3-Methoxy-5-(trifluoromethyl)aniline (15.0 g) and 1,4-dibromobutan-2-ol (18.3 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (9.57 g, yield 47%) as an orange oil.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([CH2:29][NH:30][OH:31])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C1COCC1>[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([CH2:29][N:30]4[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:31]4)=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C=NC(=O)Cl
Reactant: O=c1c(CNO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(Cc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.14 ml of N-(chlorocarbonyl) isocyanate was added dropwise at −50° C. to a 4 ml THF solution of 110 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinolin-4(1H)-one, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 45 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [BH4-].[Na+].[I-].[OH:4][CH2:5][CH2:6][N+:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)=[CH:9][CH:8]=1>CO.O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH:9]=2)=[CH:14][C:15]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:21])=[O:20]
Reactant: CC(C)Oc1cc(-c2cc[n+](CCO)cc2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(C2=CCN(CCO)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A mixture of 100 mg of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine (see method 1) and 0.075 ml of 2-iodoethanol in 1.7 ml of acetonitrile is heated at 85° C. (bath) for 1 h. 75 μl of 2-iodoethanol are then added and the heating is continued for 15 h at 91° C. The mixture is then concentrated under vacuum, so as to obtain a solid which is taken up with 10 ml of ethyl ether. The resulting heterogeneous mixture is filtered and the solid is rinsed with ethyl ether and dried under reduced pressure, so as to obtain 147 mg of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in the form of a solid. 44 g of sodium borohydride are added, at a temperature of about 0° C. (ice/water bath) to a solution of 0.142 g of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 2.6 ml of methanol. After 30 minutes, a few drops of water are added and the mixture is left to return to ambient temperature. The mixture is concentrated to dryness under reduced pressure and then diluted with 150 ml of ethyl acetate. The organic phase is washed successively with 120 ml of a saturated sodium hydrogen carbonate solution and then 70 ml of a saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 90 mg of 2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanol.
Reaction SMILES: [CH2:1]([S:21][CH:22]([CH2:28][CH3:29])[C:23]([O:25]CC)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:21][CH:22]([CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)butanoate (209 mg, 0.50 mmol) was dissolved in ethanol (2.5 mL) and added to a solution of LiOH×H2O (168 mg, 4.0 mmol) in water (2.5 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 2 hours, cooled and added water (10 mL) and 1 M HCl (5 mL) to pH=1-2. The mixture was extracted with heptane (2×20 mL) and diethyl ether (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give 154 mg of the title compound as crude oil. Purification by flash chromatography on silica gel using gradient elution (starting with pure heptane and increasing stepwise to heptane:EtOAc (with 5% HOAc) 80:20) afforded 151 mg (77% yield) of the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:13]=[CH:14][N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][CH2:14][NH:15][CH:16]=1
Reactant: Clc1cccc2c1ccn2Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc2c1ccn2CC1=CNCN1
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of powdered KOH (7 mmol) in DMSO (12 mL) at room temperature (rt) under N2 was stirred for 0.5 h. 4-Chloro-1H-indole (Intermediate A1) (1.67 mmol) was added and the mixture was allowed to stir for 2 h at rt. The 4-chloromethyl-1-trityl-1H-imidazole (prepared according to the procedures in: James, L. K. et al; J. Med. Chem. 1997, 20, 721. and Cordi, A. A. et al Eur. J. Med. Chem. 1990, 25, 557, incorporated herein by reference) (Intermediate A2) (1.19 mmol) was added and the mixture was stirred at rt for 18 h. The solution was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4, filtered and evaporated to give the crude product. The residue was purified by chromatography on SiO2 with 1-2% MeOH in CH2Cl2 to give 4-chloro-1-(1-trityl-1H-imidazol-4-ylmethyl)-1H-indole (Intermediate A3). The protected imidazole compound (Intermediate A3) was mixed with H2O (3 mL) and acetic acid (6 mL) and heated to reflux for 1 to 2 h. The mixture was cooled to rt and made basic with 2M NaOH. The aqueous layer was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over Na2SO4. This mixture was filtered, freed of solvent and purified by chromatography with 5% NH3:MeOH in CH2Cl2 to give 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (˜20% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][S:23][C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[NH:26][CH:27]=[N:28]5)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(CSc3ncnc4nc[nH]c34)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 67 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 148°-151° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 6-mercaptopurine. The yield was 67% of theory.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:31]
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(N2CC3CN(C(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.156 g, 0.59 mmol) in pyridine (2 ml) was added 2-naphthalene carbonyl chloride (0.136 g, 0.71 mmol). The mixture was stirred for 3 h, then water (10 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to yield the title compound (0.217 g, 71%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])[CH3:14]>C(OCC)(=O)C>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1)=[O:26])[CH3:12]
Reactant: NC1COc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1COc2ccccc2C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 3,4-dihydro-3-amino-2H-benzopyran (0.9 g, 6 mmole) in 50 ml of ethyl acetate, there was added 1.22 g (6 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirred at room temperature for twenty hours. The solvent was removed under vacuum and the residue was suspended in 20% ethyl acetate/hexane. The precipitated solid was collected by filtration and dried to yield 1.25 g of N-[2,6-bis-(1-methylethyl)phenyl]-N'-(3,4-dihydro-2H-1-benzopyran-3-yl)urea, mp 186°-188° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([CH:7]([C:21]([O-:23])=O)[C:8]([C:18]([O-:20])=O)([OH:17])[C:9](CC)(CC)[C:10]([O-:12])=O)C>CO>[CH2:1]([NH:4][C:10](=[O:12])[CH2:9][C:8]([CH2:7][C:21]([NH:4][CH2:1][CH2:2][CH3:3])=[O:23])([C:18]([NH:4][CH2:1][CH2:2][CH3:3])=[O:20])[OH:17])[CH2:2][CH3:3]
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)CC(O)(CC(=O)NCCC)C(=O)NCCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
N,N′,N″-tri-n-propylcitramide was prepared by the reaction of n-propylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.245 g; 1 eq), n-propylamine (19.427 g; 3.16 eq) and methanol (40 mL). The clear light yellow solution stirred for 3 days at room temperature prior to the removal of methanol via rotary evaporation at 50° C. The resulting yellow liquid was dried in vacuo at 70° C. and a tacky white solid was obtained. The crude solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with a slight odor (19.19 g; 55% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.8 %

Procedure:
A mixture of tert-butyl 3-aminoazetidine-1-carboxylate (10.0 g, 58 mmol), ethyl 2-bromoacetate (10.7 g, 64 mmol) and potassium carbonate (24.0 g, 174 mmol) in MeCN (200 mL) was stirred at rt for 13 hrs. The reaction mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (gradient elution 0˜66% EtOAc/petroleum ether) to afford tert-butyl 3-(2-ethoxy-2-oxoethylamino)azetidine-1-carboxylate (12.1 g, 81%) as a white solid. ESI-MS (EI+, m/z): 259.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15]Br.[H-].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][O:9][CH2:15][CH2:14][O:13][CH3:12])[CH:7]=1
Reactant: COCCBr
Reactant: COc1ccc(Br)cc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cc(Br)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-2-methoxy-phenyl)-methanol (3.38 g, 14.8 mmol) and 2-bromoethyl methyl ether (2.06 g, 14.8 mmol) in DMF (30 mL) is added NaH (55% dispersion in oil; 1.36 g, 31.1 mmol) in three portions at room temperature, followed by stirring overnight. The mixture is poured into ice-cooled aqueous 2N HCl, the water phase is extracted with diethyl ether, the combined organic phase is washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexane/AcOEt 3:1) gives the title compound as liquid. TLC, Rf (hexane/AcOEt 1:1)=0.44. 1H-NMR (CDCl3): δ 3.45 (s, 3H), 3.64 (m, 2H), 3.71 (m, 2H), 3.83 (s, 3H), 4.60 (s, 2H), 6.76 (d, 1H), 7.37 (dd, 1H), 7.56 (d, 1H) ppm.