Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[C:3](C)([O-:5])C.[K+].[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]>C1COCC1>[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:3]=[O:5])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(C2CCC(=O)CC2)O1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C=O)CC2)O1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Methoxymethyltriphenylphophnium chloride (55.23 g) and THF (300 ml) were placed in a reaction vessel, and the solution was cooled to −20° C. Potassium t-butoxide (16.0 g) was added, and the stirring was continued for another 1 hour. Then, 4-(5-propyltetrahydro-2-furanyl)cyclohexanone (15 g) in a THF (100 ml) solution was added dropwise, and the stirring was continued for another 1 hour. The reaction mixture was warmed to room temperature, and the mixture was separated after the addition of water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (toluene:ethyl acetate=18:1), and the resultant product was dissolved in acetone (200 ml) and hydrochrolic acid (6 M) (200 ml) was added, and then the stirring was continued at room temperature for another 1 hour. The mixture was extracted with toluene (100 ml) after the addition of water (200 ml). The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4-(5-propyltetrahydro-2-furanyl)cyclohexanecarboaldehyde (12.2 g).
Reaction SMILES: Br[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>O1CCCC1>[F:31][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12
Reactant: O=C1NCCn2c3c(c(Br)c21)CCCC3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1NCCn2c3c(c(F)c21)CCCC3
Temperature: -78 °C
Yield: 16.3 %

Procedure:
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 134a (40 g, 148.62 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), followed by the addition of n-BuLi (2.4 M) (218 mL, 3.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred at −40° C. for 3 h. To this was added a solution of N-fluorobenzenesulfonimide (98.7 g, 313.33 mmol, 2.10 equiv) in tetrahydrofuran (200 mL) dropwise with stirring at −78° C. The resulting solution was stirred at room temperature for 3 h, quenched by the addition of 200 mL of water and extracted with 3×500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (30 g) was purified by Prep-HPLC with the following conditions (mobile phase, A: 0.05% trifluoroacetic acid/water; B: CH3CN; gradient: 10% B-25% B) to afford 5.05 g (16%) of 134b as a white solid. MS: [M+H]+ 209. 1H NMR (300 MHz, CDCl3) δ 6.16 (br, 1H), 3.90-3.86 (m, 2H), 3.65-3.62 (m, 2H), 2.53-2.47 (m, 4H), 1.88-1.80 (m, 2H), 1.77-1.72 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N+:19]#[C-:20]>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]=[CH:20][N:2]([CH3:1])[CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CNC=Nc1ccccn1
Reactant: [C-]#[N+]c1ccc(C)cc1C
Solvent: Cc1ccccc1
Product: Cc1ccc(N=CN(C)C=Nc2ccccn2)c(C)c1
Yield: 20.5 %

Procedure:
A mixture of N-methyl-N'-(2-pyridyl)-formamidine (2.5 g, 0.0185 m), 2,4-dimethylphenylisocyanide (2.4 g, 0.0185 m), cuprous oxide (trace amount) and dry toluene (60 ml) was heated on a steam bath with occasional agitation for 4 hours. The reaction mixture was then cooled, filtered through "Hyflo" (diatomaceous earth) and alumina, and the toluene filtrate evaporated to dryness in vacuo to yield a viscous oil. The oil was triturated with 60°-80° petroleum ether to yield a white solid. Crystallisation of this solid from ether/60° -- 80° petroleum ether yielded the product, 5-(2,4-dimethylphenyl)-3-methyl-1-(2-pyridyl)-1,3,5-triazapenta-1,4-diene, (1.0 g) m.p. 100°.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[N:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=NN1CCNCC1
Reactant: ClCc1cccs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=NN1CCN(Cc2cccs2)CC1
Yield: 91.5 %

Procedure:
2-Chloromethylthiophene (prepared as described by F. F. Blicke and J. H. Burkhatter in J. Amer. Chem. Soc., 64, 477, 1947) (5.0 g, 0.038 mole) was added to acetone (100 ml) containing N-nitrosopiperazine (5.4 g, 0.038 mole) (prepared as described in U.S. Pat. No. 2,907,767), anhydrous potassium carbonate (6.0 g, 0.04 mole) and a catalytic amount of potassium iodide (1 small crystal). The mixture was heated under reflux for 3 hours, cooled, treated with water (50 ml) evaporated to 1/3 volume and extracted with ethylacetate (3×150 ml). The combined extracts were dried (anhydrous K2CO3), filtered and evaporated in vacuo to yield N-nitroso-N'-2-thenylpiperazine (7.35 g, >99%) as a straw coloured oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[ClH:1].[ClH:1].[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][C:6]3=[O:14])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1oc2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cl
Product: O=c1oc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.9 parts of 3-(3-chloropropyl)-2(3H)-benzoxazolone, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The oily residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off over hyflo and the clear filtrate is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. The formed hydrochloride salt is filtered off and triturated in 2-propanol. It is filtered off again and dried, yielding 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2(3H)benzoxazolone dihydrochloride; mp. 212.4° C.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([O:25]C)=[C:17]([CH3:27])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:19]1[C:18](=[O:25])[C:17]([CH3:27])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(C)c(Cc2ccc(C=CC(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
The compound (589 mg, 1.58 mmol) obtained in Step 1 was dissolved in a mixture of acetonitrile (30 ml) and water (10 ml), to which was added CAN (1.38 g, 2.52 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (5% methanol-methylene chloride) to yield the title compound (452 mg, 1.32 mmol, yield 84%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH:12]=[CH:11][C:10]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35]>CN(C=O)C.C(N(CC)CC)C>[CH2:2]([N:39]1[CH2:38][CH2:37][N:36]([C:34](=[O:35])[CH2:33][CH2:32][C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:26][C:25]4[CH:24]=[N:23][N:22]([CH3:27])[C:21]=4[NH:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)=[O:16])=[CH:14][C:9]=2[CH3:8])[CH2:41][CH2:40]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCNCC1
Reactant: CCCCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one from Example E47 (2.29 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=543.4
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[O:33])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:32]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[OH:33])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 2.04 ml, 3.27 mmol) was added dropwise to a solution of benzothiophene (0.48 g, 3.58 mmol) in anhydrous THF (10 ml) at −78° C. over 5 minutes. The reaction solution was stirred at −78° C. for 10 minutes, and then at room temperature for 20 minutes. A solution of 4-bromonaphathalene-2-carbaldehyde (0.73 ml, 3.11 mmol) in anhydrous THF (5 ml) was added dropwise to the resulting reaction mixture at −78° C. and stirred at −78° C. for two hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resulting mixture was extracted with diethyl ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.0 g, 75.6%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>CCOC(C)=O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=2)=[CH:27][CH:26]=1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
4-[1-(4′-tert-Butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoic acid methyl ester (718 mg) is taken into MeOH (10 mL), followed by the addition of 5N NaOH (1 mL). The reaction is stirred for 4 h, diluted with EtOAc, washed with aqueous HCl and brine. The organic portion is dried over MgSO4, and concentrated to afford 510 mg of the titled compound, which is used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.O1CCCC1.N1CCCC1>O1CCOCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in dipolar aprotic solvents like tetrahydrofuran, 1,4-dioxane is reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 6-15 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9][OH:10].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27](CBr)=[CH:26][CH:25]=1.[CH2:33]1COCC1>C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:25]=[CH:26][C:27]([CH:9]([C:8]2[S:7][C:6]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)=[N:5][C:4]=2[CH3:3])[O:10][CH3:33])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(OC)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Cool (−5° C.) a suspension of NaH (84 mg, 60% dispersion in mineral oil, 2.05 mmol) in THF (4 mL) and add a solution comprised of 2-([4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl)-methanol (546 mg, 2 mmol) and 4-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol) in THF (5 mL). Stir the resulting mixture for 5 min then the remove the cold bath and stir for an additional 3 hr. Quench the reaction with 1M HCl solution, dilute with ethyl acetate, wash with brine and dry over Mg SO4. Concentrate this solution under vacuum and purify the residue by flash chromatography (eluting with 20% ethyl acetate in heptane) to give the product (377 mg) as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])#[N:2].[Cl-].[OH:29][NH3+:30].C(=O)([O-])O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[NH2:2]/[C:1](=[N:30]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:26][CH2:27]1)=[O:23]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Yield: 78.9 %

Procedure:
A solution of 5-(3-cyanopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (366 mg, 1.0 mmol) obtained in Example 1207, hydroxyammonium chloride (139 mg, 2.0 mmol, 2.0 eq.) and sodium hydrogen carbonate (168 mg, 2.0 mmol, 2.0 eq.) in DMSO (5 ml) was stirred at 90° C. for 5 hr. Saturated brine (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (315 mg, 79%).
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][NH2:16])[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])[CH3:19]>CCCCCC.C(OC(=O)C)C>[CH3:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30]([NH:16][CH2:15][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[CH2:9][O:8]1)=[O:31])[CH3:17]
Reactant: CC1(C)COC(CN)(C2CCCCC2)OC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a stirred solution of (2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylamine (2.27 g 0.100 mole) in 40 ml of n-hexane/ethylacetate (5:1) is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Precipitated solid is filtered, washed with n-pentane/ether (1:1) and dried, yielding 3.85 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylurea.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C([O-])(O)=O.[Na+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>O.C(OCC)(=O)C>[NH:1]([C:32]([O:31][CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1)=[O:33])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Tyr(3-tBu)-OMe (1.1 g) in H2O (10 ml), 0.7 g (6.57 mmol) of NaHCO3 and 0.92 ml (6.57 mmol) of Z-Cl were added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:2) to give Z-Tyr(3-t-Bu)-OMe in the amount of 1.44 g (85%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:27])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]2[C:5]([Cl:27])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:10]=1)=[O:26]
Reactant: O=C(Nc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(C(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzamide (50.0 mg, 0.124 mmol) in water (0.09 mL), methanol (0.48 mL) and acetic acid (0.19 mL) was added iron (17 mg, 0.31 mmol) powder in small quantities. When the addition was completed, the mixture was stirred at 0° C. for 3 h, 3 eq additional iron powder was added. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (32 mg, 69%). LCMS for C17H13Cl2N5O (M+H)+: m/z=374.0, 376.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, 1H), 9.42 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=7.9, 7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.10-7.05 (m, 2H), 6.90 (dd, J=8.2, 0.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[OH:7][CH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.CCOCC>[CH2:15]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])CCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=C(O)CCCOCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
4.0 g (60%, 0.1 mol) of sodium hydride were washed in hexane and mixed with 30 ml of dry DMSO, and the resulting admixture was stirred at 60° C. on an oil bath for 1 hour under a nitrogen gas flow. The mixture was stirred at room temperature, and dry DMSO containing 12.6 g (0.1 mol) of sodium 4-hydroxybutyrate (100 ml) was added. After stirring at room temperature for 2 hours, the reaction solution was cooled on an ice bath, 0.2 mol of benzyl bromide was added, and the reaction was carried out at room temperature for 2 hours. After solidification, 0.5 L of ether was added, the admixture was filtered, the resulting residue was washed with ether (300 ml×3), and the filtrate was concentrated under vacuum. The resulting residue was mixed with 100 ml of methanol, 100 ml of 8% sodium hydroxide were added, and the admixture was stirred at 60° C. for 15 hours. After drying under vacuum, the resulting concentrated residue was washed with ether (200 ml×2), and the ether layer was extracted with 1 N sodium hydroxide (50 ml). All aqueous layers were combined, neutralized with concentrated hydrochloric acid (pH<4) and then extracted with ether (100 ml×5). The ether layer was extracted with 2 N sodium hydroxide (50 ml×3), all water layers were neutralized with concentrated hydrochloric acid (pH<4), and further extracted with ether. The resulting product was washed with an aqueous saturated sodium chloride solution, dried on magnesium sulphate, and then concentrated under vacuum. 9.42 g of 4-benzyloxybutyric acid was obtained as a pale yellow oil.