Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3]>C(O)C.[Pt]=O>[CH3:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH2:10][OH:11]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)CCCC(C)CCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
Geraniol (100 g) was dissolved in ethanol (500 ml), added with platinum oxide (500 mg) and stirred for 24 hours at room temperature under hydrogen atmosphere. After the completion of the reaction, insoluble material was removed by filtration through a Celite layer and the filtrate was concentrated under reduced pressure to obtain 3,7-dimethyloctanol (100 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24]3)[CH3:22])=[CH:15][CH:14]=1)[CH2:7][C:6]2=[O:29].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)(O)[O-].[K+].Br[C:54]1[CH:66]=[CH:65][C:57]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)=[CH:56][CH:55]=1>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C@@H:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24]3)[CH3:22])=[CH:17][CH:18]=1)[CH:7]([C:54]1[CH:66]=[CH:65][C:57]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[CH:56][CH:55]=1)[C:6]2=[O:29]
Reactant: COc1ccc2c(c1)C(=O)CC(c1ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc1)O2
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)C(c1ccc(OC3CCCCO3)cc1)C(c1ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc1)O2
Temperature: 110 °C

Procedure:
6-Methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)chroman-4-one (420 mg, 1.06 mmol) was dissolved in 1,4-dioxane/water (4:1, 10 mL) and degassed twice. Pd2(dba)3 (11 mg, 0.011 mmol), tri-tert-butylphosphonium tetrafluoroborate (14 mg, 0.05 mmol), and potassium bicarbonate (85 mg, 0.8 mmol) were added and the reaction mixture was degassed twice. 2-(4-bromophenoxy)tetrahydro-2H-pyran (355 mg, 1.38 mmol) was then added and the reaction mixture was heated to 110° C. for 7 h. After cooling, ethyl acetate and brine were added to the reaction mixture and the two layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by purified by silica gel chromatography to afford 6-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one. LCMS: 572.1 (M+H)+.
Reaction SMILES: C(N([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.[Cl:49]C(OC(Cl)C)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:49][CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CCl)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reaction time: 2.5 h

Procedure:
Into a solution of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (7.7 g, 11.53 mmol) in THF (200 ml) which was cooled with a dry ice-acetone bath was added α-chloroethyl chloroformate (1.7 ml, 11.64 mmol). The temperature of the mixture was elevated up to room temperature, and the mixture was stirred for 2.5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1)=[O:8])([O-:3])=[O:2].CN(C=O)C.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[N:11]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1cccc([N+](=O)[O-])c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccccc2n1CCN1CCOCC1)c1cccc([N+](=O)[O-])c1
Temperature: 54 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-nitro-N-(1H-benzoimidazol-2-yl)-benzamide prepared above in Example 1 (150 mg, 0.532 mmol, 1.0 equiv) in 3 mL of 5:1 acetone:DMF was added 109 mg of 4-(2-chloroethyl)morpholine hydrochloride (0.585 mmol, 1.1 equiv) and 221 mg K2CO3 (1.60 mmol, 3.0 equiv). The resulting suspension was heated to 54° C. with stirring for 3 h. The suspension was then diluted with 10 mL sat. NaHCO3, and the acetone was removed under reduced pressure. The resulting suspension was then diluted with 20 mL CH2Cl2, shaken until no solids remained, and passed through a 20 mm (40 mL) 3M Empore octadecyl (C18) cartridge to remove water. The collected organics were then concentrated under reduced pressure. Purification by flash chromatography (SiO2, 2-4% MeOH/CH2Cl2) gave 124 mg of the product as a tan solid (0.314 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 12.85 (s, 1H), 8.97 (s, 1H), 8.61 (d, J=7.6 Hz, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.26 (m, 2H), 4.42 (t, J=5.9 Hz, 2H), 3.49 (m, 4H), 2.75 (t, J=5.9 Hz, 2H), 2.55 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CCCCN3C(=O)c4ccccc4C3=O)ccnc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(CCCCN)ccnc2c1
Yield: 99.1 %

Procedure:
3.46 g of the product of Stage C were dissolved in 70 ml of hot ethanol and 1.86 ml of hydrazine hydrate were added. The reaction medium was refluxed for 17 hours and the precipitate was eliminated by filtration. The solvent was evaporated and the residue was taken up in 70 ml of dichloromethane. Filtration was carried out and the solvent was evaporated to obtain 2.19 g of the expected product.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[N:16]([O-])=[O:17].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([N:16]=[O:17])=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(N=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15.5 g (80 mmol) of ethyl N-methyl-N-phenylglycinate in 80 g of ice and 40 mL of conc.HCl was stirred at 0-5° while a solution of 6 g (87 mmol) of NaNO2 in 40 mL of water was added dropwise over 30 min. After stirring at this temp. for 1 hr, a solution of 27 g (250 mmol) of Na2CO3 in 150 mL of water was added dropwise with cooling. The green solid was collected, washed with cold water, extracted into CH2Cl2, passed thorugh silica with CH2Cl2 to remove an impurity, and the product eluded with 10% ethyl acetate/CH2Cl2 to give 14.7 g (66 mmol, 83%) mp 55-56° after washing with 10% ethyl acetate/hexane. Anal. C11H14N2O3 (222): Calcd.: C,59.45; H,6,35; N,12.60. Found: C,59.46; H,6.14; N,12.49. MS(FD) m/z 222. 1H NMR(CDCl3)δ: 7.8,broad s,2H,ArH; 6.69,d,2H,ArH; 4.22,q,2H,CH2—O; 4.20,s,2H,CH2—N; 3.23,s,3H,CH3—N; 1.27,t,3H,CH3—C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.OC1[C:19]2([CH2:21][CH2:20]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])C1>C(OCC)(=O)C>[C:5]([O:4][CH:1]1[C:19]2([CH2:20][CH2:21]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CN([C@H](C)c2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzoyl chloride (0.31 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2C12 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAC 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}benzamide (0.55 g, 76%) as a white solid: mp 227–229° C.; 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 9.16 (t, J=5.7 Hz, 1H), 7.95–7.72 (m, 5H), 7.60–7.46 (m, 3H), 5.22–5.12 (dd, J=5.4 and 12.8 Hz, 1H), 4.96 (d, J=5.7 Hz, 2H), 2.98–2.85 (m, 1H), 2.65–2.50 (m, 2H), 2.11–2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.80, 167.54, 166.96, 166.60, 139.34, 134.77, 133.92, 133.02, 131.52, 131.42, 128.34, 127.28, 127.12, 121.83, 48.88, 38.32, 30.93, 21.98; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.47; H, 4.50; N, 10.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)([CH3:30])[CH3:31])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 48.6 mg (0.238 mmol) of 2-(3,5-dichlorophenyl)propan-2-amine are placed in 2 ml of dimethylformamide and treated with 38.6 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. Without further workup, the mixture is purified directly by preparative HPLC [Method 10]. 70 mg (61% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4].[CH3:15][C:16]([CH3:27])([CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]1)[CH2:17][NH:18][CH3:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:18]([CH2:17][C:16]([CH3:15])([CH3:27])[CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)[CH3:19])=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CNCC(C)(C)C1OCCC(C)O1
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Solvent: CCOC(C)=O
Product: CC1CCOC(C(C)(C)CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1

Procedure:
5-(N,N-Dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams) N-[2,2-dimethyl-2-(4-methyl-1,3-dioxan-2-yl)ethyl]methylamine (6 grams) and ethyl acetate (20 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer. The reaction mixture is heated on a steam bath for a period of about 2 hours. Solvent is then stripped off using a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N-[2,2-dimethyl-2-(4-methyl-1,3-dioxan-2-yl)ethyl]-N-methylurea as the residue.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:7])(C)(C)C.Cl.C(O)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:62][CH:63]1[NH:68][CH2:67][C:66]2[S:69][C:70](C([O-])=O)=[N:71][C:65]=2[CH2:64]1.[Li+].CN1CCOCC1>C(O)C.C(OCC)C>[ClH:26].[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([C:70]3[S:69][C:66]4[CH2:67][NH:68][CH:63]([CH3:62])[CH2:64][C:65]=4[N:71]=3)=[O:7])[CH:9]([CH2:27][C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:10]1)(=[O:16])=[O:15])=[CH:25]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To an ethanol solution (50 ml) of 1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine (710 mg) was added a saturated ethanol hydrochloride solution (20 ml) at room temperature. The resulting mixture was stirred for 3 hours. After concentration of the reaction mixture under reduced pressure, diethyl ether and ethanol were added to precipitate crystals. The resulting crystals were collected by filtration, washed with ethanol and then dried under reduced pressure. The crystals were dissolved in N,N-dimethylformamide to form an N,N-dimethylformamide solution (50 ml), followed by the addition of 1-hydroxybenzotriazole (68.8 mg), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (115.4 mg), lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (189.0 mg) and N-methylmorpholine (140.5 mg) at room temperature. The resulting mixture was stirred at room temperature for 19 hours. The reaction solvent was distilled off under reduced pressure. Distilled water and ethyl acetate were added to the residue and the water layer was extracted three times. The organic layers were combined, washed four times with distilled water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol : ethyl acetate=1:50). Diethyl ether and methylene chloride were added to the purified product to precipitate crystals. The resulting crystals were collected by filtration, followed by washing with diethyl ether. A 1N aqueous hydrochloric acid in ethanol (0.5 ml) and a small amount of distilled water were added. The solvent was then distilled off under reduced pressure. The residue was dried under heat at 60° C. under reduced pressure, whereby the title compound (187 mg) was obtained as a yellow amorphous solid. MS (FAB+) m/z: 607 [(M+H)+, Cl35], 609 [(M+H)+, Cl37].
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH2:11])=[S:1])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(CC#N)c1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cccc(CC(N)=S)c1
Reaction time: 8 h

Procedure:
Hydrogen sulphide gas was passed through a solution of 3-methylphenylacetonitrile (26.2 g.) in dry pyridine (30 ml.) and triethylamine (20.2 g.) during 5 hours. The solution was allowed to stand at room temperature overnight and then evaporated under reduced pressure. The residue was dissolved in benzene and precipitated with light petroleum (b.p. 60°-80°). The product, m.p. 66°-69°, was recrystallised from a mixture of ethanol and water to give pure 3-methylphenyl(thioacetamide), m.p. 76°-78°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](O)(=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N+:19]([O-:23])[CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:24])[C:17]4[CH:22]=[CH:21][CH:20]=[N+:19]([O-:23])[CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc[n+]([O-])c1

Procedure:
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and nicotinic acid N-oxide (83 mg, 0.6 mmol, 1.2 eq.) as a light yellow solid (37.2 mg, 23%). HPLC, Rt: 1.98 min. (purity 98.8%). LC/MS, M+(ESI): 322.1, M−(ESI): 320.1.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:54])([CH3:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:51]([OH:54])([CH3:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 20d (0.46 g, 0.61 mmol) in a methanol/tetrahydrofuran mixture (v/v=6/1, 7 mL) were added o-dichlorobenzene (0.45 g, 3.05 mmol) and 10% Pd/C (64 mg, 0.06 mmol) at room temperature. The mixture was stirred at room temperature for 30 min under H2 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/2 to give the title compound 20 as a white solid (0.26 g, 88.1%, HPLC: 97.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 505.2 [M+Na]+; and 1H NMR (400 MHz, CD3OD) δ(ppm): 7.45 (d, 1H), 7.39 (m, 2H), 6.95 (d, 1H), 6.90 (m, 2H), 4.20 (d, 1H), 4.06 (dd, 5.9 Hz, 4H), 3.97 (dd, 1.4 Hz, 1H), 3.90 (dd, 1H), 3.66 (t, 1H), 3.53 (d, 1H), 1.38 (t, 3H), 1.33 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:13]=1[CH2:14][NH2:15].CCN(C(C)C)C(C)C.CCCCO>O>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:14][NH:15][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(OC)c(CN)c(OC)c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(CNc2cc(Cl)ncn2)c(OC)c1
Temperature: 100 °C
Yield: 90.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 1.48 g, 10.0 mmol), 2,4,6-trimethoxybenzylamine hydrochloride (2.33 g, 10.0 mmol), DIPEA (4.8 mL, 27.7 mmol), and n-BuOH (50 mL) was heated at 100° C. for 2 h. The mixture was cooled, diluted with water (200 mL) and the precipitated product was collected by vacuum filtration on a Büchner funnel. The product was washed with cold water, ether, and vacuum dried to give an off-white solid (2.8 g, 90%). 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.38 (s, 1H), 6.49 (s, 1H), 6.25 (s, 2H), 4.34 (s, 2H), 3.77 (s, 9H).