Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:3]1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:39])[NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:23][CH:22]=1.Cl>O.C(OCC)(=O)C.CN(C)C=O>[CH2:32]([O:31][C:29]([NH:28][C:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH2:17][N:6]2[CH2:5][CH2:4][N:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2](=[O:1])[C:7]2=[O:8])=[CH:26][CH:25]=1)=[NH:39])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Reactant: COC(=O)CN1CCNC(=O)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCN(CCCOc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 1.2 g of methyl (2,3-dioxopiperazin-1-yl)acetate, 0.26 g of sodium hydride (60%, oil) and 12 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes. Then, 2.52 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane was added thereto and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled and then added to a mixed solvent of 40 ml of ethyl acetate and 40 ml of water. After the pH was adjusted to 1 with 2N hydrochloric acid, the aqueous layer was separated. To the aqueous layer was added 40 ml of ethyl acetate and the pH was adjusted to 10 with potassium carbonate. The organic layer was separated and the aqueous layer was extracted with three 20-ml portions of ethyl acetate. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=30:1) to obtain 1.17 g of methyl [4-[3-(4-benzyloxycarbonylamidinophenoxy)propyl]2,3-dioxopiperazin-1-yl]acetate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:39]([O:47][CH2:48][CH3:49])(=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([N:43]3[CH2:44][CH2:45][CH:40]([C:39]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:42]3)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1ccncc1
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)C2CN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC(=O)N2N(C)C2CCN(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazine carboxylic acid (0.18 g) obtained in Example 110, ethyl isonicotinate (0.068 ml) and 1-hydroxy-1H-benzotriazole monohydrate (0.068 g) in DMF (4.4 ml) was combined with WSC (0.096 g) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain ethyl 1-[[4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinyl]carbonyl]-4-piperidinecarboxylate as a colorless powder. Then a mixture of this material with 1N sodium hydroxide (1.14 ml) and methanol (4.0 ml) was stirred at 40° C. for 30 minutes. The reaction mixture was cooled, and the reaction system was adjusted at pH 5 with 1N hydrochloric acid, and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% conc. aqueous ammonia-containing 25% aqueous solution of acetonitrile) to obtain the title compound (0.07 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17]OC)([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:20])[C:3]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=2[S:23](=[O:40])(=[O:39])[N:22]=1.O>CC#N.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[NH2:17][C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=3[S:23](=[O:40])(=[O:39])[N:22]=2)[C:4]1=[O:20]
Reactant: CONC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Product: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of Example 18B (205 mg, 0.36 mol) in CH3CN (16 mL) was added H2O (1.1 mL) and molybdenum hexacarbonyl (66 mg, 0.25 mol) and the solution was refluxed for 2 hours. After cooling to room temperature the solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (3% methanol/chloroform) to give the title compound as a colorless solid (163 mg, 81%): 1H NMR (d6-dmso) δ 14.34 (s, 1H), 9.64 (s, 1H), 8.59 (br s, 2H), 8.13, 8.11 (d, 1H), 7.94 (s, 1H), 7.71-7.49 (m, 4H), 7.27, 7.24 (d, 1H), 2.06-1.96 (m, 1H), 1.91-1.81 (m, 1H), 1.50 (s, 9H), 1.42-1.18 (m, 1H), 1.18-0.94 (m, 1H), 0.75-0.66 (m, 6H), 0.66-0.59 (m, 1H); MS (ESI) m/z 541 (M+H+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
To a tetrahydrofuran solution (10 mL) of 1-benzhydrylazetidin-3-one (3.23 g, 13.61 mmol), a 1M-tetrahydrofuran solution of ethylmagnesium bromide (13.61 mL, 27.22 mmol) was added at −78° C. under a nitrogen stream, and the mixture was allowed to warm to −10° C. over 5 hours. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 15 minutes. Then, the reaction liquor was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration, and the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate/n-hexane=1/9 to 6/4), to obtain the title compound (2.18 g, 60%) as an oily matter.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[C:21]2[CH:20]=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1)=[O:12].O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C.O1CCCC1>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[O:12])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Reaction time: 2 h
Yield: 60 %

Procedure:
To (2-fluoro-3-nitro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-5-y)-methanone (38, 0.581 g, 2.03 mmol) in 20 mL of ethanol and 20 mL of tetrahydrofuran, stannous chloride dihydrate (1.58 g, 7.00 mmol) was added and the reaction placed in an oil bath at 60° C. After 2 hours, the reaction was poured into a beaker with 75 mL each of water and saturated sodium bicarbonate and 100 mL of ethyl acetate. The resulting milky suspension was treated with celite and the suspension was vacuum filtered through a thin pad of celite. The resulting clear layers of the filtrate were separated and the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a gradient of 1-6% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (39, 312 mg). MS (ESI) [M+H+]+=257.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C.ClCCl>[S:16]([O:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCO)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCOS(C)(=O)=O)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)propan-1-ol (2.35 g) in triethylamine (2.5 mL) and dichloromethane (50 mL) stirred at a temperature close to 0° C. is added dropwise methanesulfonyl chloride (1.7 mL). The mixture is stirred overnight, concentrated under reduced pressure, dissolved in ethyl acetate. The organic layer is washed successively with water, a 0.1N aqueous hydrochloric solution, a saturated aqueous sodium hydrogenocarbonate solution and water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with heptane/ethyl acetate 7/3 as eluent. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 3 g of 3-(3,4-dimethoxyphenyl)propan-1-ol mesylate used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=[C:11]([S:24][CH2:25][CH2:26][CH3:27])[N:10]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:14]([NH2:15])=[C:13]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:12]=[C:11]([S:24][CH2:25][CH2:26][CH3:27])[N:10]=1
Reactant: CCCSc1nc(Nc2ccccc2Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCSc1nc(Nc2ccccc2Cl)c(N)c(N2CCOCC2)n1
Temperature: 25 °C

Procedure:
A mixture of the product from step (ii) (0.82 g) and iron powder (1.2 g) in glacial acetic acid (40 ml) was stirred at room temperature until the starting material was consumed. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organics were dried (MgSO4) and evaporated under reduced pressure. Crude yield 0.82 g
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.I[CH3:22]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CI
Solvent: CN1CCCC1=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -3 °C
Reaction time: 3 h

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about −3° C. A 1 M solution of NaAHMDS (11.919 kg, 1.1 eq.) was added over a period of 80 minutes maintaining the temperature below 4° C. Iodomethane (1.858 kg) was added over a period of 10 minutes maintaining the temperature below 35° C. The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23° C. followed by iodomethane (0.188 kg). The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred overnight. The temperature was adjusted to 10° C., concentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure, the temperature was adjusted to 20° C., and water (53.31 kg) was slowly added over about 60 minutes maintaining the temperature at about 23 to 25° C. The temperature was adjusted to about 10° followed by stirring overnight. The reaction mixture was filtered, the filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. The filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C., water (20.70 kg) was slowly added over about 85 minutes maintaining the temperature at about 73 to 76° C., after 20 minutes cooled to about 11° over about 3 hours and stir overnight. Collect the solid by filtration, rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under a stream of nitrogen, followed by drying in an oven for 4 days to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.
Reaction SMILES: COCCOC.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Ethylene glycol dimethyl ether (2.0 mL), water (0.60 mL), thiophene-2-boronic acid (0.054 g), sodium carbonate (0.093 g), and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) were added to tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-bromobenzoate (0.20 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain 0.19 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(thiophen-2-yl)benzoate as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:19]([CH3:21])[CH3:20])=[CH:13][C:14]([O:17]C)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:19]([CH3:20])[CH3:21])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(OC)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(O)cc12
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of the product of Step 2 (170 mg, 0.56 mmol) in CH2Cl2 (5 mL) at 0° C. was added slowly BBr3 1.0 M in dichloromethane (2.8 mL, 2.8 mmol) dropwise. The reaction mixture was warmed to r.t. for 30 minutes then cooled to −78° C., quenched with MeOH (5 mL), extracted with CH2Cl2, and washed with a saturated aqueous solution of NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg).
Reaction SMILES: [F:1][C:2]([C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1)([CH:7]([CH3:9])[CH3:8])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO>[F:1][C:2]([C:10]1[N:11]=[C:12]([O:18][CH3:19])[CH:13]=[C:14]([O:16][CH3:17])[N:15]=1)([CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)(c1nc(OC)cc(OC)n1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(F)(C(=O)O)C(C)C)n1
Yield: 91.7 %

Procedure:
Methyl 2-fluoro-3-methyl-2-(4,6-dimethoxypyrimidin-2yl)butanoate (1.0 g) (see Example 9 below) was dissolved in methanol (7 ml), and was treated with 5N sodium hydroxide solution (1.5 ml) at 5°-10° C. The methanol was evaporated off, and the residue was treated with water, then made acid with 5N hydrochloric acid, saturated with sodium chloride, and extracted with ether. The ethereal solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. The product obtained by evaporation of the ether was triturated with pentane, yielding the desired product (0.87 g).
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Temperature: 50 °C

Procedure:
Sodium (1.11 g, 48.2 mmol) was dissolved in dry methanol (30 ml) and heated to 50° C. Dimethyl malonate (5.87 ml, 51.4 mmol) was added over 15 min. The mixture was heated to reflux and a suspension of 15-bromopentadecanoic acid (5 g, 15.6 mmol) in dry methanol (50 ml) was added over 45 min. The resulting mixture was refluxed for another 30 min. After cooling to RT, water was added and the mixture was concentrated. Water was added to the residue an made alkaline with 1 N NaOH and extracted with ether (1×50 ml). The aqueous layer was acidified with 1N HCl and extracted with ether (3×30 ml). The combined organic layers was dried (Na2SO4) and concentrated to give the title compound in 98% (5.7 g) yield.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].[C:11]1([O:17][CH:18](Cl)Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[O:17]([CH:18]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP([O-])OCC
Reactant: ClC(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethylphosphite (20.6 ml) was added dropwise at 20° C. to a stirred suspension of 55% sodium hydride (6.24 g) in dimethylformamide (90 ml). After stirring for a further 15 minutes, the mixture was cooled to 0° C., and dichloromethyl phenyl ether (9.27 g) was added dropwise. Stirring was continued overnight at 45° C., and the mixture was cooled in ice, diluted with water, neutralized and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated in vacuo to yield an oil which was purified by chromatography on silica gel. Eluent: ether-acetone 85:15. The pure title compound was obtained as a colourless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Sodium hydride (60% in mineral oil) (0.620 g, 15.5 mmol) was placed in a 100 mL round bottom flask under argon. Dry DMF (30 mL) was added, followed by portion wise addition of 2-chloro-4-hydroxypyridine (1.339 g, 10.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then slowly warmed to RT. A solution of 5-chloro-2,4-difluoronitrobenzene (2 g, 10.33 mmol) in DMF (4.4 mL) was added to the suspension, and the mixture was placed in a 90° C. oil bath to heat for 15 hours under argon. The reaction mixture was then cooled to RT and diluted with ethyl acetate (100 mL), washed with 10% aqueous LiCl (3×100 mL) and brine (2×100 mL), dried (MgSO4) and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine as a bright yellow oil (1.415 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.56 (dd, 1H), 8.35 (dd, 1H), 7.88 (dd, 1H), 7.32 (dd, 1H), 7.18 (m, 1H); MS (ESI) m/z: 303.0 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([NH:26][C:27]3[CH:46]=[CH:45][C:30]([C:31]([N:33]([CH3:44])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH2:42][OH:43])=[O:32])=[CH:29][CH:28]=3)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH3:44])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH:42]=[O:43])=[O:32])=[CH:45][CH:46]=3)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCO)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCC=O)cc2)cc1
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of oxalyl chloride (127 mg) in dichloromethane (20 ml) was added dimethyl sulfoxide (78 mg) at −78° C. and the solution was stirred at the same temperature for 10 minutes. A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyethoxy)phenyl]benzamide (400 mg) in dichloromethane (5 ml) was added to the mixture at −78° C. After being stirred at −78° C. for 20 minutes, triethylamine (0.50 ml) was added to the mixture at the same temperature and the cooling bath was removed. The mixture was stirred at ambient temperature for 3 hours and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(formylmethyloxy)phenyl]benzamide (399 mg) as an amorphous. To a mixture of the crude obtained aldehyde (399 mg) and hydroxylamine hydrochloride (174 mg) in ethanol (20 ml) was added potassium carbonate (173 mg) in water (2 ml) and the solution was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (30 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyiminoethoxy)phenyl]benzamide (288 mg) as an amorphous.