Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[C:13](OC=C)(=O)[CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.[Hg]=O.O>[OH:12][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH:13]([CH3:14])[O:1][C:2]=2[CH:3]=1
Reactant: C=COC(C)=O
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Agent: O=[Hg]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1Oc2ccc(CCO)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A suspension of 1.0 g of 3,4-dihydroxyphenylacetic acid, 1.4 g of vinyl acetate, 6 mg of mercury oxide (yellow) and 0.03 ml of boron fluoride/ethyl etherate in 9 ml of toluene was stirred at room temperature for 14 h. The reaction mixture was diluted with ethyl acetate and washed with water and an aqueous common salt solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off. An oil thus obtained was dissolved in 10 ml of tetrahydrofuran and the solution was added dropwise to a suspension of 0.5 g of lithium aluminum hydride in tetrahydrofuran under cooling with ice. The mixture was stirred at room temperature for 1 h. 0.5 ml of water, then 0.5 ml of a 15% aqueous sodium hydroxide solution and finally 1.5 ml of water were added thereto and an insoluble matter was filtered off. The filtrate was concentrated and treated according to silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain 0.8 g of the intended compound in the form of a colorless oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>O>[CH3:14][N:12]([CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH3:13]
Reactant: CN(C)CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)CC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product of the corresponding [(1,4-dioxaspiro[4.5]dec-8-yl)-methyl]-dimethylamine (88 mmol) was dissolved in water (40 ml), combined with conc. hydrochloric acid (59 ml) and stirred for 20 h at RT. The reaction mixture was extracted with diethyl ether (2×100 ml), the aqueous phase was alkalized with 5N NaOH with ice cooling, extracted with dichloromethane (3×100 ml), dried and evaporated. The products were obtained as white solids or oils.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>CN(C=O)C.O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]2)[S:6]1(=[O:22])=[O:21]
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Temperature: 70 °C
Yield: 57.2 %

Procedure:
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.61 g, 1.56 mmol) was dissolved in 5 mL of DMF along with 430 mg (3.1 mmol) of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl piperidin-4-ylcarbamate. The solution was heated to 70° C. for 16 hours then poured in water. The solution was extracted 2× with ethyl acetate and the water layer discarded. The combined organic phase was washed 3 times with brine, then dried (MgSO4) and concentrated. The residue was subjected to Biotage chromatography (10-50% ethyl acetate-hexane) to afford 0.45 g (55%) of tert-butyl (1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-yl)carbamate. MS (ES) m/z 505.1; HPLC purity 97.9% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff.Ph=9.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=N)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2C)cc1
Yield: 88.1 %

Procedure:
5′-Amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (2.15 g), 4-morpholin-4-yl benzoic acid (1.27 g), N-methylmorpholine (2.05 ml), 1-hydroxybenzotriazole (826 mg) and 1-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride (1.17 g) in dry DMF (30 ml) was stirred at 20 C for 18 h. Then the DMF was evaporated and the residue partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with 1-2% methanol in dichloromethane gave a colourless solid (2.4 g)
Reaction SMILES: C(NCC(C)C)C(C)C.[CH3:10][C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C1(C)C=CC=CC=1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH:13]([CH:14]=[O:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)CCC=O
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of diisobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O>[N:11]1([C:8]2[N:7]=[C:6]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=3)[N:5]=[C:4]3[C:9]=2[N:10]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:3]3[CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to a mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol) and morpholine (63 μl, 0.72 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled and then partitioned with chloroform and water, and the organic layer was washed again with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=10:0 to 25:1 to 20:1) to give the title compound (75 mg, 67%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[CH:23]1([CH:29]=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(CC3CCCCC3)CC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in 6(2) (228 mg, 0.70 mmol), cyclohexanecarboxaldehyde (94 mg, 0.84 mmol) in dichloromethane (11 mL) was added sodium triacetoxyborohydride (312 mg, 1.40 mmol) at room temperature, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (80 mL), extracted with dichloromethane (50 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 213 mg (72%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O>S(=O)(=O)(O)O.O>[OH:23][C:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])[C:9](=[O:22])[C:10]=2[C:11]([NH2:19])=[CH:12][CH:13]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: OB(O)O
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
30 parts of 1,5-dinitroanthraquinone are stirred in 300 parts of 28% strength oleum for 4 hours at 50° to 60° C. 15 parts of boric acid are then added with cooling and dissolved. The reaction mixture is then diluted with 57.5 parts of 78% sulphuric acid and 156 parts of water, while cooling is continued, and stirred for 15 hours at room temperature. The reaction mixture is discharged onto 2,000 parts of ice, and the product is filtered off with suction and washed with warm water until neutral. After the product has been stirred with 500 parts of a 10% strength aqueous pyridine solution at 90° to 100° C., filtered off with suction and washed, 16 parts of 1-hydroxy-4-amino-8-nitroanthraquinone are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)n1
Yield: 51.1 %

Procedure:
To 26.8 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml anhydrous methylene chloride was added 67.0 g of 2-isopropoxycarbonylbenzenesulfonyl isocyanate in 100 ml anhydrous methylene chloride. The resultant suspension was stirred at ambient temperature for 72 hours, and filtered to yield 40.0 g of the desired product as a white solid, m.p. 193°-196° C. The solid showed infrared absorption peaks at 1700 and 1710 cm-1 consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(isopropoxycarbony)-benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-].[Na+].OO.C(OC(C)C)(=[O:45])C>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH2:29][OH:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reactant: CC(=O)OC(C)C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c(OCc2ccccc2)c(CCCCO)c(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene (1.1 g, 2.85 mmol) in THF (15 mL) was treated with 9-BBN (560 mg, 4.27 mmol, 1.5 equiv.) at room temperature. After 2.5 h the clear colorless solution was treated with 2.5 M aqueous NaOH (6 mL, 15 mmol), was added followed by slow, dropwise addition of 35% w/w H2O2 (5 mL, 58.5 mmol). During addition, the internal reaction temperature was kept below 35° C. by ice bath immersion. The biphasic solution was stirred for 1.5 h at room temperature, 35 mL isopropyl acetate added and the layers separated. The aqueous phase was extracted 3×25 mL isopropyl acetate and the combined organics washed 2×25 mL saturated aqueous NaCl and dried over Na2SO4. Flash chromatography (gradient elution 10-60% EtOAc/heptane) yielded 741 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butan-1-ol as a clear colorless oil. M++H at 405 m/z;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>CC1C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Reactant: O=C(Cl)CCCCl
Solvent: Cc1ccccc1
Product: O=C(CCCCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 35 parts of 4-fluoro-N-(4-fluorophenyl)benzenamine, 107 parts of 4-chlorobutanoyl chloride and 130 parts of methylbenzene was stirred for 2 hours at reflux temperature. The reaction mixture was washed with a sodium chloride solution, dried, filtered and evaporated. The residue was distilled to remove the excess of 4-chlorobutanoyl chloride, yielding 47 parts (95.0%) of 4-chloro-N,N-bis(4-fluorophenyl)butanamide as a residue (int. 69).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:66]=[C:67]1[CH:71]=[CH:70][C:69](=[O:72])[N:68]1[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([NH:80][NH2:81])=[O:79]>>[O:72]=[C:69]1[CH:70]=[CH:71][C:67](=[O:66])[N:68]1[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([NH:80][NH:81][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:79]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:29])([F:28])[F:27])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:27])([F:29])[F:28])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C(F)(F)F)c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and 1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103 mg) in DMF (dry) (1.5 ml) was added NaH (19.12 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)#[N:13]
Reactant: NO
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cccc(B(O)O)c1

Procedure:
In a three-necked flask with a capacity 3 liters, 123.4 g of the 3-formylphenylboronic acid prepared in Production Example 2, 68.6 g of hydroxylamine hydrochloride, 1050 ml of formic acid and 112.1 g of sodium formate are placed and mixed with each other. The resultant mixture liquid was heated for 8 hours while refluxing. The resultant reaction mixture liquid was left to stand in the ambient atmosphere for one night. Thereafter, in the case where a precipitate was generated in the reaction mixture liquid, this mixture liquid was agitated while cooling with ice and, in the case where no precipitate was generated in the reaction mixture liquid, the mixture liquid was mixed with a small amount of precipitation seed particles and agitated. From the resultant reaction mixture liquid, the solid precipitate was collected, by filtration and dried. The target compound, 3-cyanophenylboronic acid was obtained in an amount of 82.0 g. The yield thereof was 68%. The results of the 1H-NMR measurement of the target compound (200 MHz, δ ppm, CDCl3) were shown below.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[I:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[I:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(I)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Yield: 39.6 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 1.13 mmol) was dissolved in dry N,N-dimethylformamide (4 mL) and heated to 95°-105° C. N-Iodosuccinimide (534 mg, 2.3 mmol as 95%) was added in portions over 5.5 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Elution with 10% ethyl acetate-hexanes followed by solidification from ethanol-water gave (±)(1R*, 2S* 3S*, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as a white powder (255 mg, 40%), m.p.152.5°-153° C.; 1H-NMR(DMSO-d6)δ: 8.32 and 7.94 (both s, 2, 2 aromatic CH), 5.8-5.7 (m, 1, OCH), 5.4-5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.35-4.2 (m, 2, OCH2), 2.7-2.6 (m, 1, CH), 2.35-2.25 (m, 2, CH2), 2.11, 2.08, and 1.93 (all s, 3 each, 3 CH3); mass spectrum(CI) 569 (M +1).
Reaction SMILES: [P].[NH3:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[NH4+].[NH4+].[NH4+].[P:11]([OH:14])([OH:13])[OH:12]>O>[P:3](=[O:4])([OH:7])([OH:6])[OH:5].[P:11]([OH:14])([OH:13])[OH:12].[NH3:2]
Reactant: O=P([O-])([O-])[O-]
Agent: N
Agent: OP(O)O
Agent: [NH4+]
Solvent: O
Product: O=P(O)(O)O

Procedure:
To produce 9.6-34-0 compound, phosphorous acid, ammonia and water are merely added to the reactor and mixed appropriately at the temperature and pH set forth previously. To produce 9.8-34-0 orthopolyphosphoric acid via a polymerization reactor, phosphorus acid, ammonia, and water are added to the reactor. Alternatively, premanufactured 10-34-0 ammonium phosphate, phosphorous acid, ammonia and water are all added to the reactor. However, using premanufactured 10-34-0 ammonium phosphate is not preferred since such use may result in some hydrolysis thereby adversely affecting product stability. To produce 8.8-29-0 compound solution, orthophosphoric acid, phosphorous acid, ammonia and water are added to the reactor. Alternatively, premanufactured 8-24-0 compound, phosphorous acid, ammonia and water are added to the reactor. The following is an example of commercial production:
Reaction SMILES: N[C@H](C(O)=[O:14])CC1C2C(=CC=CC=2)NC=1.[NH2:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:14])=[CH:21][CH:20]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Trp, Phe
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][C:8]([CH3:24])=[C:9]([CH:23]=1)[C:10]([CH:12](C(OCC)=O)C(OCC)=O)=[O:11].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][C:8]([CH3:24])=[C:9]([C:10](=[O:11])[CH3:12])[CH:23]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Yield: 48.3 %

Procedure:
A mixture of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g) and sulfuric acid (1 ml) in acetic acid (6 ml) and water (5 ml) was refluxed for hours. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The oily residue was purified by column chromatography on silica gel (25 g) eluting with a mixture of toluene and ethyl acetate (10:1) to give crystals of 5'-(2,4-difluorophenoxy)-2'-methyl-4'-nitroacetophenone (0.69 g).