Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.N1CCOCC1>O1CCCC1>[OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:14]
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and HBTU (25.1 g, 66.3 mmol, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in tetrahydrofuran was added 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 h, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 h, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the crude was purified by silica gel column chromatography to provide the title compound (5.8 g, 48%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(Cl)Cl.[OH2:18].CC#N>O>[C:10]([O:9][C:8]([NH:7][C:4]1([CH2:3][C:2]([OH:18])=[O:1])[CH2:5][CH2:6]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:3].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:1])=[O:13])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(C(=O)Cl)cc1

Procedure:
4-(2-Diethylaminoethoxy)benzoic acid hydrochloride is suspended in methylene chloride and a five-fold excess of thionyl chloride is added. The mixture is refluxed until the solid dissolves, then concentrated under reduced pressure to give 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:34])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:24][C:22]=2[N:23]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:34])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])=[CH:24][C:22]=2[N+:23]=1[O-:6])[CH3:17]
Reactant: CCc1nc2cc(OCCN(C)C)ccc2[n+]([O-])n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2ccc(OCCN(C)C)cc2[n+]1[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
Hydrogen peroxide (70%; 0.30 mL, ca. 6.1 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (0.85 mL, 6.1 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 20° C. for 10 min, then cooled to 5° C., added to a solution of 1-oxide 29 (160 mg, 0.61 mmol) and trifluoroactic acid (0.10 mL, 1.31 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with CHCl3 (4×40 mL). The combined organic fraction was dried (Na2SO4) and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-8%) MeOH/CH2Cl2 to give 1,4-dioxide 30 (55 mg, 32%) as a bright yellow solid, mp (MeOH, EtOAc) 146-149° C.; 1H NMR δ 8.33 (d, J=9.6 Hz, 1 H, H-8), 7.78 (d, J=2.6 Hz, 1 H, H-5), 7.42 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.30 (t, J=5.4 Hz, 2 H, OCH2), 3.21 (q, J=7.5 Hz, 2 H, CH2), 2.83 (t, J=5.4 Hz, 2 H, NCH2), 2.37 [s, 6 H N(CH3)2], 1.43 (t, J=7.4 Hz, 3 H, CH3); 13C δ 164.9, 157.1, 141.5, 129.7, 124.7, 123.4, 98.0, 67.9, 57.7, 45.8 (2), 24.1, 9.3. Anal. Calcd for C13H18N4O3.¼MeOH: C, 55.6; H, 6.7; N, 19.6. Found: C, 55.5; H, 6.4; N, 19.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.CS(O[CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:13][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: CC(OS(C)(=O)=O)C(F)(F)F
Reactant: O=C1NCCc2ccc(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc2c(c1Cl)C(=O)NCC2)C(F)(F)F
Temperature: 140 °C
Reaction time: 48 h
Yield: 15.1 %

Procedure:
A mixture of 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 120 mg, 0.610 mmol), 1,1,1-trifluoropropan-2-yl methanesulfonate (526 mg, 2.74 mmol), and K2CO3 (420 mg, 3.05 mmol) in dry DMF (8 mL) was stirred in a sealed-tube at 140° C. for 48 hours. To the reaction mixture was added H2O (40 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparatory TLC (EtOAc, Rf ˜0.65) to give 8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58a, 27 mg, 15%) as a yellow oil.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[CH3:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[CH3:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: Cc1cccc(N)c1
Reactant: C/C(N)=C\C#N
Solvent: CC(=O)O
Solvent: O
Product: CC(=CC#N)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-methylaniline (7.18 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34]S[CH2:32][CH2:31]4)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.O[O:38][S:39]([O-:41])=O.[K+]>CO.O>[O:38]=[S:39]1(=[O:41])[CH2:34][CH2:35][CH:30]([NH:29][C:27]([C:14]2[C:15](=[O:26])[N:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:17]3[C:12]([C:13]=2[OH:36])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=3)=[O:28])[CH2:31][CH2:32]1
Reactant: O=C(NC1CCSCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(NC1CCS(=O)(=O)CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Yield: 37.3 %

Procedure:
To a solution of 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(3-pyridinylmethyl)-N-(tetrahydro-2H-thiopyran-4-yl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 0.05 mmol) in methanol (4 mL) was added Oxone (59.3 mg, 0.10 mmol) as a solution in water (1 mL). The resultant mixture was stirred overnight and then concentrated in vacuo. Ethyl acetate was added followed by water. The organics were washed with brine and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give the title compound (10 mg, 38%) as a white solid as a format salt. 1H NMR (400 MHz, CDCl3) δ 10.41 (d, J=6.5 Hz, H), 8.58 (s, 1 H), 8.53 (d, J=4.3 Hz, 1 H), 8.41 (s, 1 H), 8.10 (s, 1 H), 7.36 (d, J=8.0 Hz, 1 H), 7.23 (m, 1 H), 7.16 (s, 1 H), 7.01-6.97 (m, 4 H), 5.37 (s, 2 H), 4.26 (m, 1 H), 4.04 (s, 2 H), 3.14 (m, 4 H), 2.49-2.29 (m, 4 H); HRMS m/z calcd for C27H26N4O5FS (M+H)+ 537.1608, found 537.1601.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]Br)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromomethyl)-4(1H)-quinazolinone in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH:29]1([NH:32][CH2:33][C:34]2[N:35]=[CH:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)[CH2:31][CH2:30]1>>[CH:29]1([N:32]([CH2:33][C:34]2[N:35]=[CH:36][NH:37][CH:38]=2)[S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:31][CH2:30]1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CC(C)(C)OC(=O)n1cnc(CNC2CC2)c1
Solvent: CCN(CC)CC
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)N(Cc4c[nH]cn4)C4CC4)cc3c12

Procedure:
8-[Cyclopropyl-(1H-imidazol-4-ylmethyl)-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 284 mg (0.87 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 605 μL (4.35 mmol) of triethylamine and 309 mg (1.3 mmol) of cyclopropyl-(1-tert-butoxycarbonyl-1H-imidazol-4-ylmethyl)-amine to give, after purification by precipitation and trituration in water, 350 mg (76%) of 8-[cyclopropyl-(1H-imidazol-4-ylmethyl)-sulfamoyl]-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:23][CH:24]=2)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:22]4[N:23]=[CH:24][C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)=[CH:20][N:21]=4)[CH:26]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C)CC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
67 mg (0.44 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one and 125 mg (0.44 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}methanol are suspended in 5 ml of DMF with 222 mg (0.67 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. 156 mg (0.67 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 15 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by column chromatography on silica gel, giving 67 mg of “A125”; HPLC: Rt=2.26 min (method B); ESI: 418 (M+H);
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][O:1][C:5]=3[CH:6]=2)[CH2:15][CH2:14]1
Reactant: Oc1ccc2ncoc2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1nc2ccc(OCC3CC3)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 1,3-benzoxazol-6-ol (2.31 g), (bromomethyl)cyclopropane (3.46 g), potassium carbonate (3.54 g) and DMF (25 mL) was stirred at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.88 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[NH:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O-:3])=[O:2].[O:27]1CCC[CH2:28]1.[H-].[Na+].ClC1C=C(NC(N2C=CN=C2)=O)C=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10](=[O:11])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:28]2=[O:27])[CH:24]=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(NCc1ccccc1)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: O=C(Nc1cccc(Cl)c1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3.5 g of 2-(m-nitroanilino)-N-benzylbenzamide and 30 ml of dry tetrahydrofuran was added 1.0 g of about 55 % sodium hydride, and stirring was performed for 30 minutes at room temperature. To this was added dropwise a solution of 4.9 g of 1-[N-(m-chlorophenyl)carbamoyl]imidazole and 30 ml of dry tetrahydrofuran. The mixture was allowed to stand for 30 minutes at room temperature and then refluxed for 2 hours. After the reaction was complete, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.0 g of 1-(m-nitrophenyl)-3-benzylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 206°-207° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:32]>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N:14]([CH3:32])[C:15](=[O:17])[CH3:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH2:3][CH2:2]1
Reactant: CI
Reactant: CCOc1ccc(C(C)c2nc3cc(NC(C)=O)ccc3n2CC2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)c2nc3cc(N(C)C(C)=O)ccc3n2CC2CC2)cc1
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of N-[1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-1H-benzimidazol-5-yl]-acetamide (2.13 g, 5.64 mmol) in THF (100 mL) was added NaH (0.45 g, 11.28 mmol) at 0° C. After stirring for 2 h, iodomethane (1.60 g, 11.28 mmol) was added at room temperature. The mixture was stirred overnight, quenched with MeOH (2 mL) and diluted with ether (200 mL) which was washed with saturated solution of ammonium chloride (100 mL) and dried with Na2SO4. After filtration and evaporation, the title compound (2.43 g, 100%) as a crude product was obtained. MS (ES) (M+H)+=392.40.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In THF (250 ml) was dissolved 3-nitrobenzyl chloride (25.0 g), and to the mixture was added piperidine (36 ml). The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(3-nitrobenzyl)piperidine (32.2 g) as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:12])=[O:11])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:12])=[O:11]
Reactant: C[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NS(=O)(=O)c1ccccc1N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 53.6 %

Procedure:
N-o-nitrobenzenesulfonyl-L-alanyl-L-proline (1.51 g, 4.1 mmole) was dissolved in ethanol (10 ml) and hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate, diethyl ether and petroleum ether to give N-o-aminobenzenesulfonyl-L-alanyl-L-proline (yield: 0.75 g, 56.9%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4([CH:36]=O)[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[CH3:50][O:51][N:52]=[CH:36][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:21]3[CH:20]=[C:19]([C@H:8]4[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]4)[CH:24]=[CH:23][C:22]=3[Cl:25])=[CH:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4(C=O)CC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CC1(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Temperature: 80 °C
Yield: 118.1 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-formylcyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (300.0 mg, 0.44 mmol), in ethanol (5 mL) under nitrogen atmosphere, was added pyridine (0.17 mL, 2.20 mmol) and O-methylhydroxylamine hydrochloride (73.0 mg, 0.88 mmol). The reaction mixture was heated at 80° C. for 4 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford the title compound (240 mg, 77%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:24]3[CH:29]=[CH:28][N+:27]([O-])=[CH:26][CH:25]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.O.[PH2]([O-])=O.[Na+]>[Pd].C(O)(=O)C>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1cc[n+]([O-])cc1
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccncc1
Reaction time: 2 h
Yield: 20 %

Procedure:
A suspension of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.100 g, 0.00025 mol) and 10% palladium on carbon (0.016 g, 0.00002 mol) in acetic acid (3 mL) was reacted with sodium hypophosphite monohydrate (0.033 g, 0.00038 mol) at 60° C. After 2 hours, an additional 10% palladium on carbon (0.016 g, 0.00002 mol) was added. The mixture was stirred 18 hours after which time additional 10% palladium on carbon (0.016 g, 0.00002 mol) and sodium hypophosphite monohydrate (0.033 g, 0.00038 mol) was added. The mixture was stirred for an additional 24 hours. The mixture was filtered through Celite® 521, washing with acetic acid. The solvent was removed in vacuo, and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40% isocratic for five minutes, then 40%-100% acetonitrile—0.1M ammonium acetate over 30 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 3-(4-phenoxyphenyl)-1-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.00005 mol) as a white solid:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[F:17].CCCCCC.CN([CH:27]=[O:28])C>C1COCC1>[F:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: Fc1c(Br)ccc2c1ncn2C1CCCCO1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 91.2 %

Procedure:
To a solution of 146 (10 g, 0.034 mol) in dry THF (100 mL) at −78° C. was added dropwise 1.6 M N-butyl lithium solution in hexane (23 mL, 0.0374 mol). After stirring for 45 min at −78° C., a solution of DMF (5 g, 0.068 mol) in THF (20 mL) was added dropwise. After 1 h at −78° C. the reaction mixture was quenched slowly by adding water. The aqueous phase separated was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 15% EtOAc/petroleum ether to afford 7.7 g (93%) of 4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (148) as a yellow solid.