Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1)([O-])=O.C(Cl)(Cl)Cl>C(O)C.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccc([N+](=O)[O-])cc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-5-nitro-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.50 g) obtained in Example 404 is suspended in ethanol/tetrahydrofuran (1:1, 400 ml), and thereto is added Raney nickel, and the mixture is stirred at room temperature under atmospheric hydrogen pressure for 12 hours. To the resulting yellow suspension is poured chloroform (200 ml), and the mixture is stirred at room temperature for 0.5 hour. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform to chloroform/methanol=4/1), suspended in ethyl acetate/diethyl ether. The precipitates are collected by filtration, washed with diethyl ether, and dried to give trans-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.94 g). This product (150 mg) is suspended in methanol, and the mixture is treated with 4N hydrogen chloride in dioxane to give the title compound (158 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:26](O)(=[O:28])C>>[CH:26]([C:3]1[CH:4]=[C:5]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:2]=1[OH:1])=[O:28]
Reactant: O=S(=O)(O)c1ccc(O)c2ncccc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(S(=O)(=O)O)c2cccnc2c1O
Yield: 45 %

Procedure:
8-Hydroxyquinoline-5-sulfonic acid monohydriate (0.015 mol, 3.65 g), hexamethylenetetramine (0.225 mol, 21.0 g) and acetic acid (750 mL) were stirred and heated at 97°-100° C. for 6 hrs. After cooling, acetic acid was removed under reduced pressure, and the residue was treated with acetone (1 L) to give a precipitate which was filtered off and washed with additional acetone. Water (30 mL) and concentrated hydrochloric acid (15 mL) were then added to the solid. The resulting solution was refluxed for 2 hours. Then, the mixture was concentrated under reduced pressure and left for crystallization. The solid was filtered off, washed with water and dried to give pure 7-formyl-8-hydroxyquinoline-5-sulfonic acid in 45% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:22])[CH2:20][NH:21][C:23](=[O:25])[CH3:24])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C#Cc2ccc(C(C)CN)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCCOc1ccc(C#Cc2ccc(C(C)CNC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.12 g (0.41 mmol) 2-[4-(4-propoxy-phenylethynyl)-phenyl]-propylamine (I65) in 5.0 mL DCM are consecutively added 0.14 mL (1.02 mmol) TEA and 34.9 μL (0.49 mmol) acetyl chloride. The reaction mixture is stirred at r.t. for 3 h. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]([CH2:15][C:16]([O:18]CC)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.Cl>C(O)C.[OH-].[Na+]>[O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: CCOC(=O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetate (3.0 g, 8.64 mmol) was dissolved in 35 mL of ethanol and 2.9 mL of 6 N aqueous sodium hydroxide. The mixture was allowed to stir at ambient temperature overnight, and the pH was adjusted to 6 with 3 N aqueous hydrochloric acid. The mixture was filtered and dried to afford (4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetic acid as a pale yellow solid, mp decomposed at 350° C. MS (ESI) m/z 320 (M+H)+; Anal. calcd for C18H13N3O3: C, 64.23; H, 4.47; N, 12.48. Found: C, 64.48; H, 4.38; N, 12.60.
Reaction SMILES: C[O:2][CH:3]([O:28]C)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.OS(O)(=O)=O.[O-][Mn](=O)(=O)=O.[K+].O>C(O)(=O)C>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[C:3]([OH:28])=[O:2])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (23.0 g, 0.053 mole) in acetic acid is treated with 54 mol of 2.5 N H2SO4 and heated at 70° C. for 12 hours. A portion of the reaction solution is concentrated, diluted with acetone and treated portionwise, at 25°-30° C., with an aqueous solution of KMnO4 (23.7 g, 0.15 mole). Addition is continued until a persistent pink color is obtained at 27° C. The reaction mixture is filtered to remove MnO2 and the filtrate is concentrated in vacuo to give a residue. Addition of water to the thus-obtained residue precipitates the title compound as a pale yellow solid, 16.6 g. A sample is recrystallized twice from 75% aqueous ethanol to afford a crystalline solid, mp 174°-175.5° C., identified by elemental and NMR analyses.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(OCc4ccccc4)cc3n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(O)cc3n2)c1
Yield: 68.9 %

Procedure:
There was dissolved N-(2-benzyloxy-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidin-5-yl)-N′-(3-methyl-benzylidene)-hydrazine (50.7 mg, 0.115 mM) in a mixed solvent of methanol/methylene chloride (1:2) (3 mL), then 10% palladium on carbon (10.1 mg) was added to the solution and the mixture was stirred for 3 hours in a hydrogen gas atmosphere. The reaction liquid was filtered, the solvent was distilled off, and the resulting residue was purified by the reversed phase HPLC and then subjected to a desalting operation to thus give the title compound (27.8 mg, yield: 69%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1.[CH2:40]([O:42][C:43]([S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:76]=[CH:75][C:62]([C:63]([O:65][C:66]2[CH:74]=[CH:73][C:69]([C:70](O)=[O:71])=[CH:68][CH:67]=2)=[O:64])=[CH:61][CH:60]=1)=[S:44])[CH3:41].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:40]([O:42][C:43]([S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:76]=[CH:75][C:62]([C:63]([O:65][C:66]2[CH:74]=[CH:73][C:69]([C:70]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[C:18]5[CH:38]=[CH:39][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:16][CH:17]=5)=[CH:27][CH:26]=4)[CH:32]=3)=[O:71])=[CH:68][CH:67]=2)=[O:64])=[CH:61][CH:60]=1)=[S:44])[CH3:41]
Reactant: O=C(Oc1ccc(C(=O)Oc2cccc(O)c2)cc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Reactant: CCOC(=S)SCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=S)SCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCCBr)cc5)cc4)c3)cc2)cc1

Procedure:
Synthesized as described for the preparation of compound BC1. Quantities: 25 (0.22 g, 0.37 mmol), 22 (0.20 g, 0.37 mmol), DMAP (0.045 g, 0.37 mmol), DCC (0.15 g, 0.73 mmol). Yield 0.25 g (61%). EA: Found: C, 64.49; H, 6.81. C61H73BrO11S2 requires C, 65.05; H, 6.53%. 1H NMR: δH (CDCl3; 300 MHz): 1.22-1.62 (35 H, m, CH2/O—CH2—CH3), 1.71 (2 H, m, S—CH2—CH2), 1.87 (6 H, m, O—CH2—CH2/Br—CH2—CH2), 3.13 (2 H, t, 3J=7.4 Hz, SCH2), 3.42 (2 H, t, 3J=6.8 Hz, CH2Br), 4.07 (4 H, t, 3J=6.5 Hz, OCH2), 4.66 (2 H, q, 3J=7.1 Hz, O—CH2—CH3), 7.01 (2 H, d, 3J=8.7 Hz, Ar—H), 7.21 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.5 Hz, Ar—H), 7.51 (1 H, t, 3J=8.1 Hz, Ar—H), 8.17 (4 H, d, 3J=8.7 Hz, Ar—H), 8.30 (4 H, d, 3J=8.5 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 13.8, 26.0, 28.2, 28.3, 28.8, 28.9, 29.0, 29.3, 29.35, 29.4, 29.5, 31.7, 32.8, 34.0, 35.9, 53.8, 68.4, 69.5, 69.7, 114.4, 115.8, 119.3, 120.9, 122.1, 126.6, 129.9, 131.9, 132.4, 151.4, 155.5, 163.8, 164.1, 164.3, 210.8. m/z (MALDI) 1147.56 (100%) and 1149.59 (97%) [M+Na]+, C61H73BrNaO11S2 requires 1147.37 (100.0%) and 1149.37 (97%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C([O-])(O)=O.[Na+]>Cl>[OH:10][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:19]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)CCCCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: OCCCCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
1.6 g of methyl 7-hydroxyheptanoate and 1.08 g of o-phenylenediamine were refluxed for 7 hours in 15 ml of 2:1 hydrochloric acid aqueous solution. The reaction mixture was cooled to room temperature, then adjusted to pH 8 with addition of aqueous NaHCO3 and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.9 g of the title compound (yield: 41%).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:12]=2)[CH:6]=1)C.[OH-].[Na+]>CO>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][NH:17][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:27])=[O:3])[CH:16]=[CH:15][N:14]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 66 (2.4 g) was treated with 20 equivalents of sodium hydroxide in methanol. The mixture was heated at 50 C for 2 hours and the solvent removed by rotary evaporation. The residue was taken up in water and brought to pH 7 by addition of 1N HCl. The solvent was again removed by rotary evaporation. LC-MS showed the product had the expected M+H+ of 336. The crude product containing NaCl was used without purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.[OH-].[K+].Cl>CS(C)=O.O>[CH:11]1([CH2:14][O:15][C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCC2CC2)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
6-Chloropyridine-3-carboxylic acid (1.00 g, 6.347 mmol), cyclopropylmethanol (0.759 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.39 mmol) were dissolved in DMSO (25 mL) and heated at 100 C for 18 h. The reaction mixture was cooled to room temperature; water was added and acidified to pH 4-5 with 1M hydrochloric acid. The resultant precipitate was filtered off under vacuum to afford the title compound (1.079 g, 88%). Method B HPLC-MS: MH+ requires m/z=193 Found: m/z=194, Rt=1.95 min (96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1.[CH:19](OC)=[O:20].[H-].[Na+]>CN(C=O)C>[OH:20][CH:19]=[C:4]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC=O
Reactant: COC(=O)COc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)Oc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Methyl(3-phenylphenoxy)acetate (6.0 g) and methyl formate (30.2 ml) were dissolved in DMF and added dropwise with stirring to a suspension of sodium hydride (1.44 g, 50% dispersion in oil) in DMF at 0° C. (ice-bath). After 45 minutes, the ice-bath was removed and the reaction mixture was stirred for 2 hours at room temperature. Aqueous sodium carbonate was then added. The aqueous layer was washed with ether, acidified to pH 4-5 with concentrated hydrochloric acid and then re-extracted with ether. The combined organic layers were washed with brine, dried, filtered and evaporated to give methyl 3-hydroxy-2-(3'-phenylphenoxy)propenate as a pale yellow oil (6.05 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.Cl.[Zn]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
A solution of the product of part (ii) (10.0 g) in ethanol (400 ml) and 2N hydrochloric acid (200 ml) was heated to reflux with stirring. Zinc dust (8.80 g) was added at such a rate that the ensuing reaction was not too vigorous. The mixture was heated under reflux for 0.25 hour and then cooled and filtered. The filtrate was made basic with 0.88 ammonia solution and diluted with a large volume of water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel, eluting with dichloromethane. Earlier fractions contained impurity and the pure product was eluted in the later fractions. The product fractions were combined and evaporated to give an oil, (5.50 g). The product darkened rapidly and was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:26][CH3:27])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+]=[N-])[O:17][C:16]3=[O:24])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:25]>[Pd].C(OCC)(=O)C>[CH3:27][O:26][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH2:21])[O:17][C:16]3=[O:24])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:25]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2)CC1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 89 %

Procedure:
The suspension of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-azide (25.2 mmol) and 10% palladium on carbon (1.0 g) was in ethyl acetate (150 ml) was stirred at a room temperature under hydrogen atmosphere for 10 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified on silica gel column chromatography to provide title compound in 89% yield.
Reaction SMILES: [C:1]([CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>CN(C)C=O>[C:1]([CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:10][C:5]=2[CH2:4]1)#[N:2]
Reactant: CCOC(CBr)OCC
Reactant: N#CC1Cc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc2c(c1)CC2C#N)OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.5 g of 1-cyano-4-hydroxybenzocyclobutane in 205 ml of dimethylformamide is poured into a suspension of 67.8 mmol of sodium hydride in 160 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and then a solution of 10.2 ml of 1-bromo-2,2-diethoxyethane in 40 ml is added over the course of 15 minutes and the temperature is then maintained at 60° C. for 6 hours. The mixture is stirred for a further 12 hours, the dimethylformamide is removed by evaporation, and the residue is taken up in water, extracted with dichloromethane, dried and concentrated in vacuo. The residue is chromatographed over silica gel (CH2Cl2/AcOEt: 95/5), enabling the expected product to be isolated.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.O>[N:1]1([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a stirred solution of azetidine (2 g, 35.08 mmol) in DCM (25 mL) were added triethylamine (14.4 mL, 105.24 mmol), followed by phenyl chloroformate (5.5 mL, 42.10 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (30 mL) and extracted with DCM (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% MeOH/DCM as an eluent to get the desired compound as a white solid (4.5 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.35 (m, 2H), 7.22-7.18 (m, 1H), 7.12-7.08 (m, 2H), 4.20-4.08 (m, 2H), 4.04-3.92 (m, 2H), 2.29-2.21 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Reaction time: 0.33 h

Procedure:
Azetidine (0.110 mL, 1.6 mmol, Aldrich) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.78 g, 1.1 mmol, prepared as in Example 376, Step A) in DCM (11 mL). After stirring for 20 minutes, additional azetidine (0.10 mL, 1 mmol) was added. After 10 minutes, excess reagents and solvent were removed in vacuo. Flash chromatography, eluting with a gradient of 0-5% MeOH in DCM afforded purified product. Yield: 0.29 g (87%); LC-MS: 290.1 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 4.52 (q, 2H), 3.90 (s, 2H), 3.39 (t, 4H), 2.19 (quin, 2H), 1.45 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH2:19])=[O:5])[CH3:2].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH:19][S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:21])[CH:31]=2)=[CH:35][CH:36]=1)(=[O:41])=[O:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a mixture of 2.89 g (10.62 mmol) of 3-amino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester [WO 01/70673, Example 134] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (4.0 g, 11.8 mmol) in CH2Cl2 (40 mL) at 0° C. was added saturated aqueous NaHCO3 (40 mL). The solution was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (100 mL) and water (30 mL), the organic layer was washed with water (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40M chromatography, eluting with 1:2 ethyl acetate-hexanes, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester as a white solid (1.6 g, 25.8%). MS: 584 (M+H)+.
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](Br)[C@H:15]([OH:22])[C@H:14]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16]([N:24]=[N+:25]=[N-:26])[C@H:15]([OH:22])[C@H:14]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Br)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate (4) is reacted with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes followed by extraction in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate (6). The azide is hydrogenated at room temperature under pressure in dioxane-triethylamine solution using 10% palladium on carbon catalyst. The product is crystallized from dioxane-ethanol to provide 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester).