Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=C)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=[O:27])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methyl-5-vinylisoxazole-3-carboxamide (53 mg, 0.154 mmol) in THF (1 mL) and water (0.5 mL) was added sodium periodate (99 mg, 0.462 mmol) and Os EnCat™ (Microencapsulated OsO4) (10.26 mg, 3.08 μmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered through a cotton wool plug and the eluent was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:5](=[O:12])[O:4][CH2:3][CH2:2]1.Cl.[CH3:14][NH:15][CH3:16]>>[OH:4][CH2:3][CH2:2][O:1][C:6]1([C:5]([N:15]([CH3:16])[CH3:14])=[O:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C1OCCOC12CCOCC2
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)C1(OCCO)CCOCC1
Yield: 99 %

Procedure:
Using 1,4,9-trioxaspiro[5.5]undecane-5-one produced in Reference Example 15 (15a) and dimethylamine hydrochloride (659 mg, 8.14 mmol), the desired title compound (630 mg, yield 99%) was obtained by the same method as in Example 5.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]=[CH:7][C:8]#[N:9]>C1COCC1.[Ni]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CC=CC1CCCO1
Agent: [Ni]
Solvent: C1CCOC1
Product: NCCCC1CCCO1
Reaction time: 8 h
Yield: 51 %

Procedure:
Raney Ni (approx 1 mL) was added to 3-(tetrahydro-furan-2-yl)-acrylonitrile (0.43 g, 3.5 mmol) in THF (6 mL), the mixture was evacuated then charged with 1 atm H2 (balloon) then stirred overnight. The mixture was recharged with Raney Ni (1 mL) and H2 and stirring was continued an additional 24 hour, until no starting material was evident via TLC. The reaction contents were filtered through a celite plug, that was thoroughly rinsed with MeOH, solvents removed to yield 3-(Tetrahydro-furan-2-yl)-propylamine (51% yield). ESI-MS (m/z) 130 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOCC.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:45][CH2:46]3)[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCN1CCC(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
A mixture of 0.55 g of the compound obtained in step C of EXAMPLE 30, 0.47 g of 4-phenylpiperidine and 0.5 g of K2CO3 in 4 ml of DMF is heated at 80° C. for 5 hours. After cooling, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in ether, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.25 g of the expected product.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CS(C)=O.CCCCCC>[C:3]1([C:13]2([C:14]#[N:15])[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC1(c2cccc3ccccc23)CCCC1
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 5.24 g, 131.6 mmol) in dimethyl sulfoxide (50 mL) was added dropwise a mixture of naphthalen-1-yl-acetonitrile (337) (10.0 g, 59.8 mmol) and 1,4-dibromobutane (12.91 g, 59.8 mmol) dissolved in dimethyl sulfoxide-ether (1:1; 120 mL) at 0° C. and stirred for 30 min at the same temperature and then stirred at room temperature for 4 h (silica TLC, 10% ethyl acetate in hexane, Rf=0.65). The reaction mixture was quenched with HCl [1N; 20 mL] at 0° C. Ethyl acetate (400 mL) was added and the mixture was washed with water (500 mL) and brine (2×200 ml) and dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using a gradient eluent; mixture of ethyl acetate and hexane to get pure 1-naphthalen-1-yl-cyclopentanecarbonitrile (338) (8.4 g, 63%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH:19]([C:22]1[N:26]=[C:25]([C:27](O)=[O:28])[O:24][N:23]=1)([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[O:24][N:23]=[C:22]([CH:19]([CH3:21])[CH3:20])[N:26]=3)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)c1noc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.33 g, 1.28 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.28 mmol), HOBt (0.26 g, 1.92 mmol), DIPEA (0.7 mL, 3.84 mmol) and EDCI (0.37 g, 1.92 mmol) using DMF (10 mL) as solvent. Yield 0.197 g. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 1.33 (d, 6H), 3.15 (m, 1H), 4.38 (m, 2H), 4.57 (m, 1H), 6.78 (d, 1H), 7.71 (d, 1H), 7.77 (m, 1H), 7.87 (dd, 1H), 8.02 (dd, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CN2C(=NCCC2)C1.C([O:41][C:42](=[O:45])[CH2:43]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:43][C:42]([OH:45])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: c1ccccc1
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetylglucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350 ml of benzene is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto, and it is hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:13]([NH:15][CH2:16][C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18])[CH3:14]>>[CH2:13]([NH:15][CH2:16][C@@H:17]1[O:18][C@:23]([OH:24])([CH2:25][OH:26])[C@@H:21]([OH:22])[C@@H:19]1[OH:20])[CH3:14]
Reactant: CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O

Procedure:
The process of claim 1 in which D-glucose is aminated to N-ethyl glucamine which in turn is oxidized to produce 6-ethylamino-6-deoxy-α-L-sorbofuranose which is reduced to produce N-ethyl-1-deoxynojirimycin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+]>O1CCCC1>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)#[N:11]
Reactant: COc1ccc(CC#N)cc1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
p-Methoxyphenylacetonitrile (50 gm, 0.3 mole) was added to dry tetrahydrofuran (250 ml) and the solution cooled to -70° C. under nitrogen. n-Butyl lithium in hexane (210 ml, 0.3 mole) was added dropwise, with stirring. The temperature was maintained below -50° C. and a yellow precipitate appeared. After the addition was complete, the reaction mixture was maintained below -50° C. for 30 minutes and cyclohexanone (35 ml, 0.3 mole) was added. After a further 45 minutes below -50° C. the temperature was allowed to rise to 0° C. and a saturated ammonium chloride solution was added. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulphate and evaporated. The product crystallized (25.2 gm, m.p. 125°-127° C.).
Reaction SMILES: [N+](C1N(C)C(C2N3N=C(N=C[O:21][CH2:22][CH3:23])C=CC3=NN=2)=NC=1)([O-])=O.C(CN)O.[N+:28]([C:31]1[N:35]([CH3:36])[C:34]([C:37]2[N:41]3[N:42]=[C:43]([N:46]=[CH:47][NH:48]CCO)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)=[N:33][CH:32]=1)([O-:30])=[O:29]>C(O)(C)C.O1CCOCC1>[N+:28]([C:31]1[N:35]([CH3:36])[C:34]([C:37]2[N:41]3[N:42]=[C:43]([N:46]=[C:47]([CH2:23][CH2:22][OH:21])[NH2:48])[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)=[N:33][CH:32]=1)([O-:30])=[O:29]
Reactant: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CNCCO)nn12
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: NCCO
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)CCO)nn12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1.2 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[4,3-b]pyridazine was dissolved in 13 ml. isopropanol-dioxan mixture (7:3), 1 ml. ethanolamine was added thereto at 20° C., while stirring, and stirring was then continued for 30 minutes. The precipitated crystals were filtered off with suction, washed with isopropanol and water and dried for 2 hours at 120° C. in a vacuum. There was obtained 1.07 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(β-hydroxyethylaminomethyleneamino)-s-triazolo[4,3-b]pyridazine, which has a melting point of 191° - 192° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH:13]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22].C1COCC1.[C-]#N.[Na+]>CN(C=O)C.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: OCc1cc2cnc(Cl)nc2n1C1CCCCCC1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 85 %

Procedure:
To a solution of (2-chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (6.24 g, 22.3 mmol) in DMF (100 mL) were added a solution of dimethylamine in THF (2 M, 46 mL, 4.1 equiv) and sodium cyanide (1.04 g, 0.95 equiv) and the resulting mixture was stirred at room temperature for 4 min. The reaction mixture was treated with manganese dioxide (100.4 g, 45 equiv) in four portions over 1 h and stirred for additional 1 h. The reaction mixture was filtered through a pad of Celite (rinsed with EtOAc 600 mL). The filtrate was washed with water (200 mL). The aqueous phase was extracted with EtOAc (2×150 mL). Combined organics were washed with 4% aqueous solution of NaCl (2×250 mL), dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue in MeCN followed by column chromatography of the mother liquor (EtOAc/Heptane 30 to 100%) provided 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (6.07 g) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 6.52 (s, 1H), 4.63 (tt, J=11, 4.0 Hz, 1H), 3.20 (s, 3H), 3.11 (s, 3H), 2.52 (m, 2H), 1.99 (m, 2H), 1.88 (m, 2H), 1.70 (m, 4H), 1.58 (m, 2H) MS m/z 321.5 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[C:15]3[C:19]=2[N:18]=[C:17]2[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=32)=[CH:8][CH:9]=1)=[O:4].O[Li].O.Cl>O1CCCC1.O>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:14]2[C:15]3=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[N:18][C:19]3=[C:11]([O:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[CH:12]=[CH:13]2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(OC2=C3N=C4CCCCC4=C3C(Cc3ccc(Br)cc3)C=C2)o1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2=C3N=C4CCCCC4=C3C(Cc3ccc(Br)cc3)C=C2)o1
Temperature: 25 °C
Reaction time: 28 h
Yield: 40.1 %

Procedure:
A solution of the methyl ester (0.9 g) from Example 114 in 10 mL of tetrahydrofuran was treated with a solution of 0.8 g of LiOH.H2O in 10 mL water. The reaction mixture was stirred at room temperature for 28 h, diluted with water, acidified with 2N-HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 5-[[1,2,3,4-tetrahydro-9-(4-bromophenyl)methyl-9H-dibenzo[b,d]pyrrol-6-yl]oxy]-2-furancarboxylic acid (0.35 g; 40.0%) as a white solid after repeated crystallizations from ethyl acetate, mp 155.5°-157.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21])(=[O:10])=[O:11]
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc(OC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
1,2-Bis(methylsulfonyl)-2-[(4-methoxyphenoxy)carbonyl]-1-methylhydrazine (compound 9) was synthesized as follows: Triethylamine (0.269 g, 0.0029 mol) was added to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (0.50 g, 0.0025 mol) and 4-methoxyphenyl chloroformate (0.63 g, 0.0033 mol) in acetone (30 ml) and the mixture stirred for 1 hr. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether (5 ml) and the petroleum ether layer decanted. Column chromatography of the residue on silica gel (70-270 mesh, 60 Angstroms, CHCl3), followed by crystallization from ethanol gave 0.14 g (16.1%) of the desired compound. Mp was approximately 101-102° C. 1H NMR (acetone-d6) : δ 7.3 and 7.0 (4H, 2d, aromatic H), 3.9 (3H, s, OCH3), 3.6, 3.4 and 3.2 (9H, 3s, 2 CH3SO2 and NCH3).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[Cl:12])[N:5]([CH3:13])[N:4]=1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[Cl:12])[N:5]([CH3:13])[N:4]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(COc2cccc(OCc3ccccc3)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.2 mg, 0.28 mmol, Example 5), 3-benzyloxy-phenol (75.2 mg, 0.36 mmol, TCl) and potassium carbonate (59.6 mg, 0.43 mmol) in dimethylformamide was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with water and brine, and dried and concentrated. The crude product was either used directly in the next step (described in Example 7) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-(3-benzyloxy-phenoxymethyl)-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine. (Yield 33 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCCl>[CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH+:3]1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)C=CC(C)(C)N2
Solvent: ClCCCl
Product: Cc1ccc2c(c1)C=CC(C)(C)[NH+]2[O-]
Temperature: 40 °C

Procedure:
To a stirring solution of 2,6-Dimethylquinaldine (1) (5 g, 0.0318 mol) in 1,2 dichloroethane (130 ml) was added 3-CPBA (3-chloro-peroxybenzoic acid) (7.43 g of 72% activity, 0.0310 mol). The reaction was then heated to 40° C. for 24 hours. The completed reaction mixture was allowed to cool to room temperature, concentrated, and 10% K2CO3 and a minimal amount of ethyl acetate was to produce a two phase mixture. A precipitate then formed in both layers and was filtered, washed with water to remove traces of K2CO3 and dried to afford 4.67 g (85%). H1 NMR (CDCl3): δ 2.52_(s, 3H), 2.66 (s, 3H), 7.28-7.56 (m, 4H), 8.70-8.79 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][CH2:18][CH3:19])[C:4](=[O:16])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1.[H][H]>[Pd].CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[C:4](=[O:16])[N:3]([CH2:17][CH2:18][CH3:19])[C:2]([CH3:1])=[N:6]2)=[CH:12][CH:11]=1
Reactant: CCCn1c(C)nn(-c2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCn1c(C)nn(-c2ccc(N)cc2)c1=O
Yield: 91 %

Procedure:
A mixture of 57 parts of 2,4-dihydro-5-methyl-2-(4-nitrophenyl)-4-propyl-3H-1,2,4-triazol-3-one and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 20%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 46 parts (91%) of 2-(4-aminophenyl)-2,4-dihydro-5-methyl-4-propyl-3H-1,2,4-triazol-3-one, mp. 138.8° C. (int. 21).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:34]3[CH2:45][CH2:44][C:43]4[C:42]5[CH2:41][C:40]([CH3:47])([CH3:46])[CH2:39][C:38]=5[S:37][C:36]=4[C:35]3=[O:48])[C:31]=2[CH:32]=[O:33])=[CH:3]1.[BH4-].[Na+].[CH3:51][OH:52]>>[OH:33][CH2:32][C:31]1([CH:51]=[O:52])[C:30]([N:34]2[CH2:45][CH2:44][C:43]3[C:42]4[CH2:41][C:40]([CH3:46])([CH3:47])[CH2:39][C:38]=4[S:37][C:36]=3[C:35]2=[O:48])=[CH:29][N:28]=[CH:27][CH:26]1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2cncc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cn1cc(C2C=NC=C(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)C2(C=O)CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 106j (130 mg, 0.20 mmol) in methanol (5 mL) at 0° C. was added sodium borohydride (22 mg, 0.6 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 106 (60 mg, 45%) as a yellow solid. LCMS: [M+H]+ : 668. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=2.0, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 7.87 (d, J=2.5, 1H), 7.38-7.36 (m, 2H), 7.24-7.22 (m, 1H), 5.15 (t, J=5.0, 1H), 4.56-4.42 (m, 6H), 4.08-4.04 (m, 2H), 3.60 (s, 3H), 3.43-3.42 (m, 1H), 3.07-2.94 (m, 6H), 2.55-2.53 (m, 4H), 2.39-2.38 (m, 4H), 1.23 (s, 6H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[C:18](O)(=[O:21])[CH2:19][OH:20].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[OH:21][CH2:18][C:19]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:20]
Reactant: O=C(O)CO
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CO)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 60 °C
Yield: 19.8 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mol) and glycolic acid (83 mg, 1.085 mmol) in dry DMF (6 mL), EDC (191 mg, 1 mmol) and HOBt hydrate (154 mg, 1 mmol) were added and the reaction mixture was heated at 60° C. for 18 hrs. The solvent was evaporated in vacuo (45° C., 0.1 mbar) and the residue was dissolved in ethyl acetate (50 mL) and washed with water (2×25 mL). The organic phase was washed dried over sodium sulphate, filtered, the solvent evaporated in vacuo, the residue was triturated with DCM and further purified by preparative LCMS to afford 2-hydroxy-N-(3-(quinoxalin-2-yl)phenyl)acetamide (60 mg, 23% yield). LCMS calculated for C16H13N3O2 (M+H): 280.29. found 280. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.38 (1H, br.), 9.52 (1H, s), 8.62 (1H, m), 8.14-8.20 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 5.64 (1H, br), 4.08 (2H, s).