Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccncc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccc(Cl)cc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccc(Cl)cc3)n2)cc1
Yield: 47 %

Procedure:
In the same manner as in Example 74, 4-chlorothiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-chlorophenyl)-4-thiazolyl)benzoate. The product was recrystallized from ethanol. Yield: 47%. Pale yellow prisms. Melting point: 105 to 106° C.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
Benzyl 2,5-dihydropyrrole-1-carboxylate (25 g) was dissolved in chloroform (125 mL), and mCPBA (39 g) was slowly added with ice cooling. The mixture was stirred at room temperature for 1 day, then diluted with chloroform, and washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried with anhydrous sodium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=8:2-1:99) to obtain benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (18 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][CH:7]=1.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(-c2ccc(Cl)nn2)c1
Yield: 50.4 %

Procedure:
A mixture of 50.0 g of 3-chloro-6-(3-nitrophenyl)pyridazine, 160.8 g tin dichloride and 1000 ml ethanol was refluxed for 1.0 hr, then cooled and approximately 1/2 of the soluent removed by evaporation under reduced pressure. The reaction mixture was added to 2.5 liters saturated aqueous sodium bicarbonate solution. After adjusting the pH to ~8 with additional sodium bicarbonate, 1.2 liters of methylene chloride was added and stirring continued. The resulting mixture was filtered and the salts washed repeatedly with methylene chloride and ethyl acetate. All organic fractions were then combined, dried (MgSO4) and the solvent removed in vacuo, to give 22 g of solid product, mp 118°-121° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:12])[C@@H:5]2[N+:10]#[C-:11].C([Li])CCC.[CH3:19][C:20]([CH3:22])=[O:21].C(O)(=O)C>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:13])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:12])[C@@:5]2([C:20]([OH:21])([CH3:22])[CH3:19])[N+:10]#[C-:11]
Reactant: CC(C)=O
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N2[C@@H]1CCOC2(C)C
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (500 mg) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in hexane (2.33 ml of 1.55M solution) at -70° C. and the mixture was stirred at -70° C. for 15 minutes. A solution of acetone (0.265 ml) in tetrahydrofuran (2.4 ml) was added to the reaction mixture at -70° C. and the mixture was stirred at -70° C. for 25 minutes. Acetic acid (0.477 ml) was added to the mixture at -70° C. After stirring at -70° C. for 20 minutes, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with isopropyl ether and filtered to give (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (460 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH:32]([F:38])[F:37])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3 (2H)-one (Intermediate 3B; 368 mg, 0.893 mmol) and methyl 2-chloro-2,2-difluoroacetate (0.5 mL, 4.74 mmol) in DMF (2 mL) was charged with K2CO3 (2.5 g, 18.09 mmol) at room temperature. The reaction was stirred at 80° C. for 30 min. The reaction mixture was diluted with H2O and filtered to give 6-chloro-3-(difluoro-methoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C26H18ClF2N3O [M+1]+ 462. found 462.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-])=O)=[N:7][CH:8]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Fe].O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: CSc1ccc([N+](=O)[O-])nc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(N)nc1
Yield: 83.2 %

Procedure:
5-(methylthio)-2-nitropyridine (270 g), iron powder (600 g), acetic acid (500 mL) and water (2 L) were heated to reflux for 4 hours. Then saturated sodium bicarbonate solution (6 L) was added into the reaction mixture. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration, the residual solution was removed under reduced pressure to obtain the target compound (185 g). 1H-NMR (300 MHz, CDCl3): δ 2.39 (3H, s), 4.49 (2H, brs), 6.47 (1H, d), 7.50 (1H, dd), 8.11 (1H, d). LC-MS m/z: 141 [M++1].
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:14]2[C@H:23]([C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)[O:11]C(=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S([O-])(=O)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:12]([OH:11])[CH2:13][N:14]1[C@H:23]([C:24]([NH:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@H:21]2[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
34.7 g of (3S,4aS,8aS)-2-[(4S,5R)-4-benzyl-2-oxo -oxazolidin-5-yl methyl]-N-tert.-butyl-decahydro -isoquinoline-3-carboxamide-p-nitrobenzenesulphonate were divided between 110 ml of ethyl acetate and 110 ml of saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the ethyl acetate extracts washed with 110 ml of saturated sodium bicarbonate and with water. The organic extracts were evaporated and the residue diluted with 55 ml of ethanol and combined with stirring with a solution of 11.0 g of sodium hydroxide in 55 ml of water. The mixture was refluxed for 5 hours, diluted with 55 ml of water and cooled to room temperature. The suspension was filtered and the residue washed with water until the filtrate was neutral. The residue was evaporated and yielded 20.7 g (93%) 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert. -butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, melting point 175-176°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[F:10][CH2:11][C:12]1([C:15]2[CH:16]=[C:17]([NH2:27])[N:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=2)[CH2:14][CH2:13]1.N1C=CC=CC=1.CCOC(C)=O>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:27][C:17]1[N:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:19]=[C:15]([C:12]2([CH2:11][F:10])[CH2:13][CH2:14]2)[CH:16]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C3(CF)CC3)cc2N)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C3(CF)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Slowly add ClCO2CH2CCl3 (1.00 equiv; 717.49 μmoles; 152.01 mg) to a solution of 5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (176 mg, 0.71 mmoles) and pyridine in 4 mL of THF under nitrogen at 0° C. Stir the mixture from 0° C. to room temperature for 5 hours. Filter the insoluble and remove solvent from filtrate under reduced pressure give an oil. Subject oil to chromatorgraphy (hex/AcOEt 20-80%) to give 110 mg of title compound as a yellow oil. MS (ES+): m/z=420.0 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1>CC(N(C)C)=O>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=1)[O:1][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc(OCCBr)cc1
Reactant: OCc1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(OCCOc2cc(CO)cc(CO)c2)cc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a stirred solution of (5-hydroxy-1,3-phenylene)dimethanol (3.0, 20.0 mmol), sodium carbonate (2.5 g, 29.0 mmol) and sodium iodide (0.45 g, 2.9 mmol) in 60 ml of DMA was added 1-(4-(2-bromoethoxy)phenyl)ethanone (5.0, 20.57 mmol). The mixture was stirred overnight, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (4:1 to 5:1) to afford 5.41 g (86%) of the title compound. 1H NMR (CD3OD) 7.99 (ddd, 2H, J=2.8, 4.8, 9.8 Hz), 7.07 (ddd, 2H, J=2.8, 4.7, 9.8 Hz), 6.94 (s, 1H), 6.89 (s, 2H), 4.58 (s, 4H), 4.42 (dd, 2H), J=2.2, 6.1 Hz), 4.37 (m, 2H), 2.55 (s, 3H); 13C NMR 199.55, 164.66, 160.59, 144.72, 132.03, 131.74, 119.16, 115.64, 113.11, 68.36, 67.87, 65.20, 26.53; MS m/z+ 339.2 (M+Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(S(=O)(=O)c2cccc3ccccc23)C1=O
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalene sulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, 150 mL of ethyl acetate was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 369 mg of white crystals.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C@H:23]2[O:55][C@H:54]([CH2:56][O:57][C:58](=[O:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:34]([O:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:24]2[O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:20]([O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@@H:19]([CH2:75][O:76]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C@H:23]2[O:55][C@H:54]([CH2:56][O:57][C:58](=[O:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@H:34]([O:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:24]2[O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:20]([O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@@H:19]([CH2:75][OH:76])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 mL round bottom flask was added 2-azidoethyl 2,4-di-O-benzoyl-3-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-6-O-trityl-α-D-mannopyranoside (450 mg, 0.352 mmol) and CH2Cl2 (3 mL). To the above solution was added TFA (3 mL, 38.9 mmol). After stirring at 25° C. for 1 hr, the reaction mixture was diluted with CH2Cl2 (10 mL), washed with water (3×15 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (40 g), eluting with 0-100% EtOAc in hexanes, to give the title product. LC-MS Method A: m/e=1053.57 [M+18]; Rt=2.73 min. 1H NMR (CDCl3) δ 7.0-8.5 (m, 45H), 6.1 (t, 1H), 6.0 (t, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.3 (s, 1H), 5.25 (s, 1H), 4.6 (m, 2H), 4.5 (m, 1H), 4.3 (m, 1H), 4.0-4.2 (m, 3h), 3.8 (m, 1H), 3.3-3.5 (m, 3H).
Reaction SMILES: C(Cl)(=O)C.[NH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH:31]=O)=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH2:31][NH:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8])=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Reactant: NC(CO)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1ncnc2c(CNC(CO)CO)cn(COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Acetyl chloride (0.117 ml, 1.65 mmol) was added to a stirred solution of 2-aminopropane-1,3-diol (0.3 g, 3.29 mmol) and 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.196 g, 0.659 mmol, prepared as in G. B. Evans, R. H. Furneaux, A, Lewandowicz, V. L. Schramm and P. C. Tyler, J. Med. Chem., 2003, 46, 3412) in MeOH (5 ml). Sodium cyanoborohydride (0.062 g, 0.988 mmol) was added and the mixture was stirred at rt overnight. The solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-MeOH-28% NH4OH, 95:5:0.5 then 9:1:0.05) to give 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-propane-1,3-diol (0.188 g, 77%) as a colourless solid. 1H NMR (CD3OD) δ 8.42, (s, 1H), 7.65 (s, 1H), 7.25-7.16 (m, 5H), 5.75 (s, 2H), 4.50 (s, 2H), 4.10 (s, 3H), 4.03 (s, 2H), 3.68 (dd, J=11.2, 5.9 Hz, 2H), 3.58 (dd, J=11.2, 5.9 Hz, 2H), 2.81 (pentet, J=5.6 Hz, 1H). 13C NMR (CD3OD, 75.5 MHz, referenced to centre line of CD3OD at δ 49.0) δ 157.9, 150.8, 150.6, 138.7, 134.1, 129.3, 128.8, 128.6, 117.0, 116.2, 78.5, 71.5, 62.5 (CH2X2), 61.3, 54.3, 41.4. +ESMS Found 373.1865 (M+H)+ C19H25N4O4 requires 373.1876.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C=O.[C:36]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]([CH3:36])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (150.7 mg) obtained in Example 25-5 was dissolved in methanol (3.0 ml). Then, a 36% formaldehyde aqueous solution (manufactured by Kanto Kagaku) (50 μl) and sodium cyanoborohydride (36.2 mg) were added to the solution in this order. After the reaction solution was adjusted to pH 5 with acetic acid, the solution was stirred at room temperature for 17 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Subsequently, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (126.2 mg) of the subjected compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1(N)[CH2:26][CH2:25]1>C(O)C>[C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH:24]3[CH2:26][CH2:25]3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CC1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Solvent: CCO
Product: O=C1C(c2cccc(C(F)(F)F)c2)=C(NC2CC2)OC1c1ccccc1
Yield: 36.8 %

Procedure:
In this example, a mixture containing 5.0 g (0.0157 g mole) of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran and 8.96 g of cyclopropylamine in 50 ml of ethanol containing 5% water was refluxed for six days. At the end of this time, a sample of the reaction mixture was checked by thin layer chromatography and then an additional 8.96 g of cyclopropylamine was added. The mixture was refluxed for an additional 24 hours and then allowed to stand at room temperature over night. The mixture was then concentrated by evaporation under vacuum, affording a crude product oil. The crude product was chromatographed over silica gel eluting with 80:20 (V/V) petroleum ether and ethyl acetate. The product fractions were combined and evaporated in vacuo affording 2.07 g of the title compound Elemental Analysis Carbon calc.: 66.8%, found 67.4%; hydrogen calc.: 4.5%, found 4.7%; nitrogen calc.: 3.9%, found 4.6%; melting point 160°-164° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=O)=O)[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([S:3][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1
Solvent: O=C(O)C(F)(F)F
Product: CCSc1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized using an analogous procedure to that outlined in the preparation of Compound 176. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.20 Hz, 3 H) 1.48-1.56 (m, 2 H) 2.09-2.20 (m, 1 H) 2.25 (br. s., 2 H) 2.27 (s, 3 H) 2.80 (d, J=4.55 Hz, 3 H) 3.03 (q, J=7.16 Hz, 4 H) 3.53 (d, J=11.37 Hz, 2 H) 4.08 (d, J=6.82 Hz, 2 H) 7.00 (d, J=8.08 Hz, 1 H) 7.10 (d, J=8.34 Hz, 1 H) 7.36-7.52 (m, 4 H) 7.59 (s, 1 H) 8.27 (s, 1 H) 9.41 (br. s., 1 H) 11.95 (s, 1 H); [M+H] calc'd for C27H32N3OS, 446.2; found, 446.4; [M+H+TFA] calc'd for C29H33N3O3F3S, 560.2; found, 560.4.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]4[S:20][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:17]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1N=C(NC2C=C(C3CC3)NN=2)C(C)=CN=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([CH3:26])=[CH:14][N:13]=[C:12]([C:16]4[S:20][C:19]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:18][CH:17]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Product: Cc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Yield: 24.8 %

Procedure:
5-(4-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-methylpyrimidin-2-yl)thiophene-2-sulfonamide (Compound 40) (43 mg, 24.8%) was prepared following same procedure as described in Compound 50 by starting with 2-bromo-5-methyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine. LC-MS (m/z)=377.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.75-0.76 (m, 2H), 0.97-0.99 (m, 2H), 1.93-1.95 (m, 1H), 2.18 (s, 3H), 6.51 (s, 1H), 7.57 (d, J=3.6 Hz, 1H), 7.73 (d, J=3.2 Hz, 1H), 7.78 (s, 2H), 8.14 (s, 1H), 9.13 (s, 1H), 12.17 (s, 1H).