Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[NH:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C(C)=O

Procedure:
0.54 g of methyl 4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate are suspended in 16 ml of acetic anhydride and heated to about 100° for 3 hours. The reaction solution is evaporated in vacuo and the residue is taken up in 32 ml of water and stirred up. The mixture is extracted twice with 30 ml of dichloromethane each time and once with 15 ml of dichloromethane. After drying over sodium sulfate, it is filtered and evaporated in vacuo. The residue is chromatographed on silica gel with dichloromethane/acetone (9:1). By recrystallization from ether there is obtained methyl 5-acetyl-4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate of m.p. 132°-134°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Cl:23][C:24]1[C:29]([CH:30]([OH:32])[CH3:31])=[C:28]([Cl:33])[N:27]=[CH:26][N:25]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:33][C:28]1[C:29]([C:30](=[O:32])[CH3:31])=[C:24]([Cl:23])[N:25]=[CH:26][N:27]=1
Reactant: CC(O)c1c(Cl)ncnc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane; 1.3 g, 3.1 mmol) was added to a solution of 1-(4,6-dichloro-pyrimidin-5-yl)-ethanol (from Step 1; 540 mg, 2.8 mmol) in dichloromethane at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 5 min and then at room temperature for 90 min. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×50 mL). The organic layers were washed with water and brine, dried (sodium sulfate), filtered, and evaporated. The residue was triturated twice with ether/petroleum ether (2:1), the solvent was decanted and the solvent was evaporated to give 1-(4,6-dichloro-pyrimidin-5-yl)-ethanone (500 mg, 93%) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.64 (s, 3H), 8.83 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]([O:7]C)=[CH:5][C:4]=1[CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:15].C(O)(=O)C.Br>O>[CH:14]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:3]=1[OH:2])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:15]
Reactant: CCCCCCCCCCCCCCCCC(C)c1cc(OC)c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCC(C)c1cc(O)c([N+](=O)[O-])cc1O

Procedure:
To 5.0 g of 2-sec-octadecyl-5-nitrohydroquinone dimethyl ether and 135 ml of glacial acetic acid were added 15 ml of 47% hydrobromic acid and the mixture was heated with reflux for 10 hours. After being allowed to cool, the mixture was added to water and then extracted with ether. After washing with water and drying, the solvent was distilled off under reduced pressure and the residue was purified through silica gel column chromatography. As the developing solvent,benzene/n-hexane (1:1) was used. The end product was obtained in 1.7 g as yellowish brown semisolid. The structure was determined by means of IR, NMR and elemental analysis data. Elemental analysis:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[OH-].[Na+]>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-n2cc(C(=O)O)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
Compound 12 (0.05 mg, 0.12 mmol) was dissolved one equivalent of 1N NaOH. The solution was allowed to stir at Rt for 2 h, then acidified to pH 4. The resulting precipitate was filtered and washed with water and ether. 1HNMR (CD3OD) δ 3.75 (m, 1 H), 3.90 (m, 1 H), 4.13 (d, 1 H), 4.43 (d, 1 H), 4.64 (m, 1 H), 6.05 (d, 1 H), 8.10 (s, 1 H), 8.35 (s, 1 H), 9.05 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH2:17]([O:24][CH2:25][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCOCc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COCc1ccccc1

Procedure:
A mixture of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (50 ml) were stirred together until all the solid material had dissolved, before a solution of chloromethyl benzyl ether (see Preparation 1a and 1b) (10 mmol) in dichloromethane (10 ml) was added with stirring at room temperature. The mixture was stirred for 3 hours at room temperature before the solvent was distilled off. The residue was triturated with water (40 ml), extracted into chloroform (3×40 ml) and the dried (MgSO4) solution evaporated; yield 2.40 g (96%). The product was purified by trituration with ether and had m.p. 125° C. (acetone). 1H NMR (CDCl3): δ4.68 (CH2Ph), 5.32 (CH2O), 7.30 (Ph), 7.72 and 8.48 (H-4, H-6, J 3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(Cl)c(Oc2ccccc2)cnn1C1CCCCO1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 2.50 g, 10.03 mmol) in acetonitrile (111 mL, 0.09M) was treated with potassium carbonate (1.38 g, 10.03 mmol) and phenol (944 mg, 10.03 mmol). The resulting reaction mixture was heated at reflux for 3 h and then was allowed to cool to 25° C. The reaction mixture was then partitioned between water (150 mL) and methylene chloride (3×100 mL). The combined organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 30% ethyl acetate/hexanes) afforded 4-chloro-5-phenoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.84 g, 92%) as a clear oil; ES+-HRMS m/e calcd for C15H15N2O3Cl [M+H+] 307.0844, found 307.0843.
Reaction SMILES: C[C:2]1[C:16](C)=[CH:15][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:14])[CH2:11][CH2:12][NH2:13])=[N:8][C:4]=2[CH:3]=1.NC1NC2C=CC=CC=2N=1>>[NH:6]1[C:5]2[CH:15]=[CH:16][CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][NH2:13]
Reactant: Cc1cc2nc(NC(=O)CCN)[nH]c2cc1C
Agent: Nc1nc2ccccc2[nH]1
Product: NCCC(=O)Nc1nc2ccccc2[nH]1

Procedure:
Synthesis took place in analogy to the preparation of 26 starting from (1.60 g; 12 mmol) of 2-aminobenzimidazole. 1.20 g; ESI-MS [M+H+]=205.2
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH2:8][CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[I:18]>CN(C=O)C.CCOCC.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH3:9])=[CH:13][C:12]=1[I:18]
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(Cl)c(I)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Add 2 g (14.5 mmol) of K2CO3 and 1.16 mL (14.5 mmol) of iodoethane to a solution of 2.45 g (9.6 mmol) of 4-chloro-3-iodophenol in 30 mL of DMF. Heat the reaction mixture at 50° C. while stirring for 3 h, then distribute in 200 mL of ether/water 1:1 mixture. Wash the organic phase with 3×50 mL of water then dry over Na2SO4 and concentrate under reduced pressure. We obtain 2.38 g of 1-chloro-2-iodo-4-ethoxybenzene in the form of oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(#N)C>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)CNc1ncccc1N

Procedure:
A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (19.6 g, 0.1 mole) in 160 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (2.0 g) at ~55° C. overnight. The reaction mixture was warmed with acetonitrile and filtered through a Celite pad. The pad was washed with hot acetonitrile and the filtrate was evaporated to a solid. A 1.2-g sample of this solid was recrystallized from methanol-acetonitrile to give a light yellow solid, which was dried under high vacuum at room temperature to give 0.4 g, of title compound, m.p. 153°-55° C. with decomposition.
Reaction SMILES: C[C:2]1[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.C[CH2:24][N:25]=[C:26]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>CO.CN(C)C=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([C:3]3[CH:2]=[N:10][CH:9]=[CH:8][C:4]=3[C:5]([N:25]([CH3:26])[CH3:24])=[O:7])[S:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1nccc(C(=O)O)c1-c1nc(-c2ccc(Cl)cc2)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(=O)c1ccncc1-c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
The compound (141) (170 mg, 0.5 mmol) was dissolved in methanol (10 ml)-1N NaOH aq. (10 ml) and the mixture was stirred at 40° C. for one hr. The pH of the reaction mixture was adjusted to around 6, and the precipitated solid was collected by filtration, which was dried in vacuo and dissolved in dimethylformamide (3 ml) together with WSC (117 mg, 0.6 mmol), HOBt (85 mg, 0.6 mmol) and dimethylamine (27 mg, 0.6 mmol). The mixture was stirred at 30° C. for 2 hrs. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as white crystals (120 mg, 35%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[N:8]([CH2:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=O)[N:7]=C(C(F)(F)F)O1>C(#N)C>[NH2:7][N:8]1[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:2]([CH3:1])[C:4]1=[O:3]
Reactant: CN
Reactant: CC(C)(C)C(=O)Cn1nc(C(F)(F)F)oc1=O
Solvent: CC#N
Product: Cn1c(C(C)(C)C)cn(N)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 ml of aqueous methylamine solution (40%) are added to a solution of 12.6 g of 2,3-dihydro-2-oxo-3-tert-butylcarbonylmethyl-5-trifluoromethyl-1,3,4-oxadiazole in 50 ml of acetonitrile. After the slightly exothermal reaction has subsided, the reaction mixture is stirred for 2 hours at room temperature and then for 14 hours at 80° and then evaporated the liquid residue is treated with ice-water, and the aqueous mixture is extracted three times by shaking with ethyl acetate. The combined ethyl acetate phases are dried and evaporated, and the oily orange residue is recrystallized from hexane. This gives the title compound in the form of pale yellow crystals which melt at 100°-105°.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Solvent: O
Product: FC(F)CNCc1ccccc1
Yield: 48.4 %

Procedure:
An amount of 1152 g (11.1 mol) of 2,2-difluoro-1-chloroethane and 403 g of benzylamine (3.695 mol) are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 700 g of water are added and the aqueous phase is separated. The aqueous phase comprises benzylamine hydrochloride, which is converted back into free benzylamine by addition of sodium hydroxide solution. The organic phase is first distilled at standard pressure, the unreacted 2,2-difluoro-1-chloroethane being distilled off. Vacuum distillation is then again carried out (at approximately 200 mbar), the remaining traces of 2,2-difluoro-1-chloroethane being distilled off. An amount of 306 g of N-benzyl-2,2-difluoroethanamine is obtained as distillation residue with a purity of 98.9%. This corresponds to a yield of 95.6%, based on the benzylamine reacted. It is possible, by renewed distillation, to obtain N-benzyl-2,2-difluoroethanamine in a purity of greater than 99%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:15][CH2:14][O:13]1>>[OH:13][CH2:14][CH2:15][O:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Nc1nc2c(O)cccc2o1
Product: Nc1nc2c(OCCO)cccc2o1
Yield: 46 %

Procedure:
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 4-hydroxy-2-amino-1,3-benzoxazol* (0,97 g, 6.5 mmol) and ethylene carbonate (0.63 g, 7.1 mmol). Solid; yield 46%; mp 124-126° C. Anal. (C9H10N2O3) C, H, N. *Previously described in J Chem. Soc. 1960, 2369-2370.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[OH:9].[CH:20]([C:22]1[C:23]([C:27]([NH:29][CH3:30])=[O:28])=[N:24][NH:25][CH:26]=1)=O.[BH3-]C#N.[Na+]>ClCCCl>[OH:9][CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:20][C:22]1[C:23]([C:27]([NH:29][CH3:30])=[O:28])=[N:24][NH:25][CH:26]=1
Reactant: CNC(=O)c1n[nH]cc1C=O
Reactant: Nc1ccccc1C(O)c1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)c1n[nH]cc1CNc1ccccc1C(O)c1cccc2ccccc12
Reaction time: 5 h
Yield: 3.6 %

Procedure:
To a solution of product (5-B) (0.4 g 1.6 mmol) in DCE (20 mL) was added product (3-C) (0.25 g, 1.6 mmol) at rt under argon. The reaction was stirred for about 5 h, and then NaBH3CN (0.5 g, 8 mmol) was added and stirred overnight. The reaction was quenched by saturated NH4Cl (20 mL) and extracted with DCM/MeOH (20:1 v/v, 20 mL×2). The combined organic phases were dried over Na2SO4 and concentrated and purified by Prep-HPLC to give compound 4 (22 mg, 5%) as a white solid. 1H NMR (300 MHz, d-DMSO): δ 13.04 (br, 1H), 8.14-7.32 (m, 9H), 7.04-6.36 (m, 4H), 5.98-5.85 (m, 2H), 4.47 (d, 2H), 2.72 (d, 3H). LC-MS (M+H)+=387. 1H-NMR (in DMSO), LC-MS, MS, and HPLC (column: Thermo, 2.4 μm, 4.6×100 mm; mobile phase: H2O (0.05% TFA)-ACN (0.05% TFA), ACN from 10% to 100% in eight minutes; total flow rate: 1.0 mL/min) spectroscopy experiments were conducted to provide the data in FIGS. 3A-3C and FIGS. 4A-4B for compound 4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O.CO.O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCBr)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 107A (2.44 g, 8.9 mmol) and lithium hydroxide monohydrate (750 mg, 17.9 mmol) in THF-H2O-MeOH (15:7:7, 29 mL) was stirred at 60° C. for 2.0 hr. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and concentrated in vacuo to remove most organic solvents. The mixture was washed with 1:1 mixture of ethyl acetate-ether and the aqueous layer was acidified with 2.0 N HCl to pH 5.0. The precipitate was collected by filtration, rinsed with water and dried under high vacuum to give 107B as a crystalline solid (1.64 g, 71%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](OCC)=[O:28])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[Na+]>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=[O:28])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
Add diisobutyl aluminum hydride (1 M in toluene, 30 mL, 30 mmol) over 5 minutes to a solution of 1-(benzyloxycarbonyl)-4-(ethoxycarbonyl)piperidine (7 g, 24 mmol) in anhydrous dichloromethane (150 mL) at −78° C. under a nitrogen atmosphere. Stir the reaction mixture at this temperature for 30 minutes and then add 10% aqueous sodium tartarate (100 mL) followed by dichloromethane. Stir the reaction mixture at room temperature overnight. Separate the phases and extract the aqueous phase with dichloromethane. Wash the combined organic phases sequentially with 10% aqueous sodium tartarate, water, and saturated aqueous sodium chloride. Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate to provide 3.15 g (53%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]2[C:59]=1C=C[C:62](=[O:69])[NH:63]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NC[C@@H](C1C=CC(O)=C(NC=O)C=1)O[Si](C(C)(C)C)(C)C>>[Si:1]([O:8][C@H:9]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]([NH:63][CH:62]=[O:69])[CH:59]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c(NC=O)c6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 153, using Intermediate 13 in place of Intermediate 2. ES/MS calcd. C51H57N6O8SSi+ 941.4. Found m/z=941 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:42])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A24 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.95 (m, 2H), 2.14 (m, 2H), 3.07 (s, 3H), 3.55 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 5.72 (m, 1H), 7.40 (m, 1H), 7.79 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.70 (m, 2H), 10.20 (s, 1H). Exact mass calculated for C22H22N6O6S 498.13, found 499.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[Cl:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1cc(Cl)ccc1Cl
Temperature: 50 °C
Yield: 50.1 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 444 mg, 2.0 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 274 mg, 1.44 mmol), copper(II) acetate (363 mg, 2.0 mmol) and triethylamine (280 μL, 2.0 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (265 mg, 50%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42].CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:12])[C:7](=[O:9])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42]
Reactant: NCCCCO
Reactant: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)NCCCCO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.3 %

Procedure:
A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester (400 mg, 1.2 mmol, 1 equiv.) in DMF (10 mL) was added to EDCI (337 mg, 1.8 mmol, 1.5 equiv.). The solution was stirred at room temperature under N2 for 40 min. 4-Amino-1-butanol (0.11 mL, 1.2 mmol, 1 equiv.) was added, followed by addition of Et3N (0.41 mL, 2.9 mmol, 2.5 equiv.) and DMAP (72 mg, 0.59 mmol, 0.5 equiv.). The mixture was stirred overnight under N2. The reaction mixture was then poured into cold water and a solid precipitated from the solution. The solid was collected by filtration and dried under vacuum to give 229 mg of 4-[(Biphenyl-4-carbonyl)-amino]-4-(4-hydroxy-butylcarbamoyl)-butyric acid methyl ester in 47% yield. MS (ESI) m/z 413.