Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:12]2)=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(C2CSc3ccccc3NC2=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2CSc3ccccc3NC2=O)cc1Br
Temperature: 25 °C
Reaction time: 22 h

Procedure:
24 ml of a N solution of bromine in acetic acid were added to a solution of 2.28 g of 2,3-dihydro-3-(4-methoxy phenyl)-1,5-benzothiazepin-4(5H)-one of Step D of Example 1 in 16 ml of acetic acid. After 22 hours of stirring at ambient temperature, 100 ml of essence G were added and the gummy precipitate obtained was separated off by decanting the solution. Then, it was crystallized from 20 ml of ethanol and stirred for 30 minutes, followed by separation to obtain 2.22 g of the desired product melting at 200° C., then 220° C. The product was used as is for the following step. An analytical sample was prepared by dissolving 540 mg of the above product in 20 ml of methylene chloride and the solution was treated with activated charcoal and filtered. 50 ml of ethanol were added followed by concentration to 25 ml. After separating, 450 mg of product melting at 206° C., then 220° C. were obtained. The product was re-dissolved in 60 ml of ethanol at reflux, concentrated to 40 ml and separated after one night at ambient temperature to obtain 350 mg of the desired product melting at 210° C., then 220° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C)c4)cc3)c2cc1OC
Yield: 45.3 %

Procedure:
(4-Hydroxyphenyl)(3-methylphenyl)methanone (307 mg) was dissolved in xylene to prepare a solution. 4-Dimethylaminopyridine (194 mg) and 4-chloro-6,7-dimethoxyquinoline (342 mg) were added to the solution, and the mixture was heated under reflux for 23 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-ethyl acetate, chloroform, and hexane-acetone as solvents to give the title compound (262 mg, yield 45%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[S:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccc(Cl)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 6.35 g of p-chlorophenyl isothiocyanate and 30 ml of hexamethylphosphoric triamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:12]>>[CH2:1]([N:8]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1nnnn1Cc1ccccc1
Temperature: 150 °C

Procedure:
An equimolar mixture of benzyl azide and ethyl cyanoformate is heated in a bomb under antogenous pressure at 150° C. for 4 hours. The resulting yellow oil is crystallized from hexane to give the title compound, m.p. 58°-61° C.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([Cl:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(Cl)cc2c(=O)c3ccccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2c(c(Cl)cc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-9-oxo-9H-xanthene (2.9 g), m-chloroperbenzoic acid (3.5 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The obtained 4-chloro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene was dissolved in acetone (300 ml) and, to the stirred solution, a mixture of chromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid (5 g) was added dropwise at room temperature. After standing overnight, to the mixture was added isopropanol (10 ml) and the resulting mixture was filtered and the filtrate was evaporated to dryness under vacuum. After adding water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.7 g of 4-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound showed a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)=[N+]=[N-].[H][H]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1
Reactant: [H][H]
Reactant: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nc(CN)n(C)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 68.4 %

Procedure:
In 8 ml of ethanol was dissolved 150 mg (0.44 mmol) of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60), and 50 mg of 10% palladium carbon was added at -20° C. The mixture was stirred at room temperature under a stream of hydrogen. After 4 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated to give 94 mg of Compound I-101 (yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][N:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[S:17]([CH3:20])(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:16]([CH3:15])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN(c1ccc(C(=O)O)cc1)S(C)(=O)=O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)S(C)(=O)=O

Procedure:
500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with 270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl 4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 416.3 (M)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])=[N:5][NH:6]2.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])=[N:5][N:6]2[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1nn(CCN2CCOCC2)c2cccc(I)c12
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of Example 162A (100 mg), 4-(2-chloroethyl)morpholine (48 mg), and Na2CO3 (82 mg) in DMF (5 mL) was heated overnight at 80° C., cooled to room temperature, and partitioned between 1N HCl and ethyl acetate. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide 45 mg of the desired product. MS (ESI(+)) m/e 503 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reaction time: 16 h
Yield: 103.3 %

Procedure:
To a dry flask purged with N2 was added platinum(IV) oxide (127 mg, 0.56 mmol) followed by tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (587 mg, 1.86 mmol) as a solution in acetic acid (19 mL). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid and ethanol. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic was washed with saturated aqueous NaHCO3 (2×75 mL) and the aqueous mixture was back extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness to afford 610 mg (100%) of the desired product as a gray solid. 1H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 1 H), 7.57 (br s, 2 H), 6.78 (d, 1 H), 6.42 (d, 1 H), 4.08-3.97 (m, 2H), 3.28-3.18 (m, 1 H), 1.94 (d, 2 H), 1.55-1.42 (m, 2 H), 1.41 (s, 9 H); ES-MS m/z 318.1 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[CH2:10]1[CH2:20][C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>O.C(Cl)(Cl)Cl>[NH:1]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:20][C:18]1=[O:19]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCCc2ccccc2N1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A solution of sodium azide (25 g, 370 mmol) in water (13 mL) and chloroform (160 mL) is cooled to 0° C. and treated dropwise with concentrated sulfuric acid (11 mL). Stirring is continued for 30 min and the layers separated. The organic layer is dried over anhydrous sodium sulfate, filtered, and α-tetralone (20 g, 137 mmol) is added in one protion with stirring. The resulting solution is heated at 40° C. and concentrated sulfuric acid (38 mL) is added dropwise to maintain the internal temperature at 40-45° C. and stirring continued for 1 h, then cooled to 20° C. and poured into a sepratory funnel. The bottom layer is added dropwise with stirring to ise water (900 mL). The resulting solids are collected by filtration, and dried in vacuo at 40° C. to give 19.7 g of an off-white solid (89%), mp 139-140° C.; MS (ESI+) m/z 162 (M+H).
Reaction SMILES: IC.[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[C:3]([O:7][C:8](=[O:19])[N:9]([C:10]1[CH:11]=[C:12]([CH3:18])[C:13]([Br:17])=[C:14]([CH3:16])[CH:15]=1)[CH3:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(C)c1Br
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1Br
Reaction time: 27 h
Yield: 18.8 %

Procedure:
Iodomethane (20.5 ml, 329 mmol) was added to a solution of (4-bromo-3,5-dimethyl-phenyl)-carbamic acid tert-butyl ester (47.5 g, 158 mmol) and cesium carbonate (80.6 g, 247 mmol) in DMF (165 ml) at room temperature, and the mixture was stirred for 27 hours. Further, cesium carbonate (26.9 g, 82.6 mmol) and iodomethane (20.5 ml, 329 mmol) were added at room temperature, and the mixture was further stirred for three days. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (9.34 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[OH2:22]>Cl>[OH:15][CH2:14][CH:13]([CH2:18][OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 49 %

Procedure:
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.59 g, 1.9 mmol) in hydrochloric acid (1.0M, 4 ml) was stirred at 60° C. for 24 hours. The solution was diluted with water and neutralised with Amberlite IR 45 (OH− form). The mixture was filtered, the resin washed with water and the solvent evaporated under reduced pressure. The residue was recrystallised from water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (238 mg, 49%), m.p. 275-277° C.; λmax (H2O) 253 (ε 11,500) and 270 (shoulder, ε 8,630) nm; νmax (KBr) 3420, 3140, 1690, 1645, and 1605 cm−1; δH [(CD3)2SO] 1.3-1.5 (3H, m, CHCH2CH2), 3.42 (4H, d, J 5 Hz, 2×CH2O), 3.99 (2H, t, J 7 Hz, CH2N), 4.41 (2H, br, D2O exchangeable, 2×OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 7.71 (1H, s, 8-H), and 10.55 (1H, br, D2O exchangeable, 1-H); (M+ found 253.1176. C10H15N5O3 requires M+ 253.1175).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1.[Br:19]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][Br:19])[CH:8]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1

Procedure:
A mixture of 22.6 g (0.07 mole) of 2-bromo-5-chloro-3-(3-methylphenyl)benzofuran, 12.5 g (0.07 mole) of N-bromosuccinamide in 500 ml of carbon tetrachloride is irradiated and heated with a sun lamp for about 20 hours. The reaction mixture is filtered hot and the filtrate is allowed to cool. A solid forms which is collected, washed with carbon tetrachloride, and dried, then recrystallized from ethyl acetate to provide white product, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran, which is used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCN1
Reactant: Ic1ccccc1
Product: O=C1CCCN1c1ccccc1

Procedure:
Example 2.1 was repeated, replacing the oxazolidin-2-one with 152 μl of pyrrolidin-2-one (2 mmoles) and operating with 336 μl of iodobenzene (3 mmoles), the latter being added at the same time as the pyrrolidin-2-one.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15](OC)=[O:16])[N+:11]([O-:19])=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:9]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[OH-].[Na+]>O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[N:11]3[O:19][C:15](=[O:16])[N:14]=[C:12]3[N:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Nc1cc(N2CCC(O)CC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(N2CCC(O)CC2)nc2nc(=O)on12
Reaction time: 3.5 h

Procedure:
3.1 G. of dimethyl racemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 100 ml. of methylene chloride and 100 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.6 and stirred at this pH for 3.5 hours. The two phases are then separated and the aqueous phase is adjusted to pH 3.2 with concentrated hydrochloric acid solution. The separated white precipitate is filtered off, pre-dried and recrystallized from methylene chloride and methanol, there being obtained pure methyl racemic-5-(4-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 250°-260° C. (decomposition).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCCC2)cc1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (15 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 1.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 4-methoxybenzenesulphonyl chloride (2.95 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the organic phase was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (2.771 g, 79%) as an oil. H1-NMR (chloroform-D3): 1.61 (m, 8H), 3.87 (s, 3H), 4.57 (m, 1H), 6.67 (s, 1H), 6.99 (m, 2H), 7.83 (m, 2H). MS(ESI): 294 (M+Na).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=S)[NH2:14])(=[O:3])[CH3:2].[C:16]([NH:21][NH2:22])(=O)[CH2:17][CH2:18][CH3:19]>C(O)CCC>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:14]=[C:16]([CH2:17][CH2:18][CH3:19])[NH:21][N:22]=1)(=[O:3])[CH3:2]
Reactant: CCCC(=O)NN
Reactant: CC(=O)N1c2ccccc2CC1C(N)=S
Solvent: CCCCO
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)n[nH]1
Reaction time: 0.17 h

Procedure:
A suspension of intermediate (13) (0.0102 mole) in n-butanol (200 ml) was treated with butanoic acid hydrazide (0.0254 mole), stirred for 10 minutes, and then heated to reflux for 10 days. The reaction was cooled, concentrated in vacuo, distributed between DCM and distilled water. The concentrated organic phase was subjected to reverse phase preparatory column chromatography to give 1-acetyl-2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole (compound 91).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:28][CH2:25][CH2:26][CH3:27])=[O:22])[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCN
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 125 °C
Yield: 69.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (107 mg, 0.31 mmol) in toluene (2 ml) was treated with n-propylamine (250 μl, 3.10 mmol) and the mixture was heated at 125° C. in a sealed vessel for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with aqueous citric acid solution (5%w/v), water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (80:20) gradually changing to dichloromethane:ethyl acetate (60:40) then to dichloromethane:methanol (90:10) to afford the title compound as an oil (76 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:1][C:2]1[C:10]2[S:9][C:8]([N:13]([CH3:14])[CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2cccc(Br)c2s1
Reactant: CNC
Product: CN(C)c1nc2cccc(Br)c2s1
Temperature: 70 °C
Yield: 98.2 %

Procedure:
7-Bromo-2-chlorobenzothiazole (100 mg, 0.40 mmol) was added to dimethylamine (2.0 M in MeOH, 1 mL, 2 mmol) and the solution was heated at 70° C. for 1 h. The crude mixture was purified by ISCO chromatography (100% DCM) to afford 101 mg (98%) of the title compound as white solid. MS (ESI): 257.33, 259.36 [M+H]+; HPLC tR=1.40 min (HPLC: Anayltical—2 min).
Reaction SMILES: [C:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:4][OH:5])#[N:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:20][S:21]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(CO)(c1ccc(Cl)cc1)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)OCC(C#N)(c1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethanol (18 g., 0.06 mole) and methane sulfonyl chloride (7.8 g., 0.07 mole) in 200 ml. of benzene is added dropwise at 10° C., 7.5 g. (0.08 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 22 g. of product; mp 124°-7° C., which is identified by nmr.