Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](N)=[O:13])[CH2:5]1.[ClH:19]>O>[Cl:19][CH2:8][CH2:7][CH:6]1[CH2:5][N:4]([CH3:3])[C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: Cl
Reactant: CN1CCC(Oc2ccccc2C(N)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CC(CCCl)Oc2ccccc2C1=O

Procedure:
To 54 g (1.35 mole) of sodium hydroxide in 800 ml of water was added 148 g (0.67 mole) of 2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture brought to reflux for 18 hr. The pH was adjusted to 7 with hydrochloric acid and the solution filtered and concentrated. The residue was boiled with 400 ml of isopropanol and filtered. The filtrate was concentrated and the residue (which crystallized) was refluxed with 300 ml of thionyl chloride for 0.5 hr. and concentrated in vacuo. The residue was dissolved in 300 ml of chloroform and the solvent boiled off in vacuo. The residue was redissolved in chloroform, 150 ml of triethyl amine added and the mixture refluxed 1 hr. The solution was concentrated in vacuo and the residue partitioned between 400 ml of ethyl acetate, 400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. The organic layer was washed twice with water and once with dilute sodium hydroxide, dried with sodium sulfate and concentrated. The residue was crystallized from isopropanol-water. Yield of product was 75 g (47%), m.p. 97°-107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>CN(C=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-methylnicotinic acid (5.00 g, 36.5 mmol) in DMF (150 mL), 1-hydroxybenzotriazole (4.92 g, 36.5 mmol), N-ethyl-N-(3-dimethylaminopropyl)carbodimide hydrochloride (8.38 g, 45.7 mmol) and 4-methylmorpholine (16.0 mL, 145.8 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 30 minutes after which N,O-dimethylhydroxylamine hydrochloride was added (3.55 g, 36.5 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and 0.2 N NaHCO3. The phases were separated and the aqueous phase was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 1.11 g of the desired product (yield: 29%).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][C:8]([F:21])=[CH:9][CH:10]=2)[C:5]1=[O:22].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57]([NH2:60])(=[O:59])=[O:58].NC1C=CC(OCC2C=CC=CC=2)=CC=1S(N)(=O)=O>>[O:58]=[S:57]1(=[O:59])[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[NH:50][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]3[C:6]([C:5]=2[OH:22])=[CH:7][C:8]([F:21])=[CH:9][CH:10]=3)=[N:60]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCC1(CCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Agent: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 14H for the compound of Example 5C, and also substituting 2-aminobenzenesulfonamide for the compound of Example 2D. 1H NMR (300 MHz, DMSO-d6): δ 0.58 (m, 2 H) 0.67 (m, 6 H) 0.93 (m, 2 H) 2.01 (m, 2 H) 2.17 (m, 2 H) 7.72 (m, 7 H) 13.48 (s, 1-H).
Reaction SMILES: CC(O)=O.O.[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[CH2:12][CH2:11][CH2:10]2>CCO.[Fe]>[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[NH2:16])[CH2:12][CH2:11][CH2:10]2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1N)CCC2
Temperature: 90 °C

Procedure:
5-Amino-6-nitroindane (4 g) is dissolved in 10 mL of MeOH, 30 mL of H2O and 20 mL of H2SO4, and cooled to 0° C. A solution of 1.72 g of NaNO2 (24.9 mmol) in 5 mL of H2O is added dropwise, keeping the temperature of the reaction below 8° C. The mixture is allowed to stir for 30 minutes. This mixture is then added dropwise to a mixture of CuBr (1.8 g, 12.5 mmol) and 6 mL of 48% HBr in 30 mL of H2O that is heated to 60° C. The reaction is cooled and added to H2O and EtOAc. The organic layer is separated and the solvents evaporated in vacuo to give a residue that is purified by silica gel chromatography (75% hexane/EtOAc) to give 5-bromo-6-nitroindane. A mixture of this indane (2.59 g, 12.2 mmol), 4.88 g (27.2 mmol) of tetramethyltin, 0.1 g of Pd(OAc)2 (0.45 mmol), 0.3 g (O-tol) 3P (0.98 mmol), 7 mL of Et3N and 7 mL of DMF is heated in a sealed tube to 65° C. for 3 days. The mixture is acidified with 1 N HCl and extracted with EtOAc. The organic layer is washed with saturated brine and dried over Na2SO4 and the solvents are evaporated in vacuo to give a residue that is purified by column chromatography (80% hexane/EtOAc) to give 5-methyl-6-nitroindane. To a mixture of 1.3 mL of HOAc and 7.3 mL of H2O heated to 90° C. is added 2.22 g of Fe. The mixture is heated until the gas evolution subsides. A solution of 1.9 g of 5-methyl-6-nitroindane (10.7 mmol) in 50 mL of EtOH is added dropwise and the reaction is heated to reflux for 30 minutes. The mixture is extracted twice with CH2Cl2. The combined organic layers are washed with saturated brine and dried over Na2SO4 and the solvents evaporated in vacuo to give a residue that is purified by column chromatography (75% hexane EtOAc) to give 6-methyl-5-aminoindane (also named 5-methyl-6-aminoindane).
Reaction SMILES: [CH2:1]([N:5]([CH2:44][CH2:45][CH2:46][CH3:47])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CCO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6]([N:5]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])=[N:9]2)=[C:15]([C:23]([N:25]2[C@H:34]([CH2:35][O:36][Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:39])[CH3:38])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[CH:16]=1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(N)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)—N,N-dibutyl-1-(2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxamide (3.0 g, 4.5 mmol) in EtOH (50 mL) was added 10% Pd—C (0.3 g) followed by stirring under H2 balloon pressure at RT for 3 h. The reaction mixture was filtered through celite, the bed was washed with EtOH (150 mL) and the filtrate was concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as an ‘off white’ solid 2.0 g (69%). Rf=0.45 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 7.40-6.82 (m, 5H), 6.80-6.20 (m, 3H), 5.74-5.50 (m, 2H), 5.10-4.00 (m, 2H), 3.99-2.20 (m, 9H), 2.20-2.00 (m, 3H), 1.60-0.58 (m, 23H), 0.00-0.04 (m, 6H); LC-MS: m/z 632.6 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:21])([CH3:20])[CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:2][CH2:3][C:4]([CH3:21])([CH3:20])[CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)C(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (7 g, 22.21 mol) in THF was added with LiAlH4 (1.27 g, 33.31 mol). The reaction mixture was stirred overnight at rt. Water was added and extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the crude product (S)-tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (6.6 g, 100%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.69 (m, 4H), 3.32 (m, 1H), 1.82 (m, 1H), 1.54 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H), 1.22 (m, 1H), 0.91 (m, 3H), 0.72 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][OH:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH3:2].[C:39](Cl)(=[O:42])[CH2:40][CH3:41]>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:42])[CH2:40][CH3:41])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Reactant: CCC(=O)Cl
Product: CCOc1cc(CC(=O)NC(COC(=O)CC)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1

Procedure:
Prepared analogously to Example 37 from benzyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate with propionyl chloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](B(O)O)=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.I/[C:45](/[CH3:51])=[CH:46]\[C:47]([O:49][CH3:50])=[O:48]>O.C(COC)OC>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:45](/[CH3:51])=[CH:46]\[C:47]([O:49][CH3:50])=[O:48])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCCCCCO[Si](C)(C)C(C)(C)C)cc21
Reactant: COC(=O)/C=C(/C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(/C)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C

Procedure:
A mixture of tetrakis(triphenyl-phosphine)palladium (155 mg), 3-[5-(tert-butyldimethylsilyloxy)pentyloxy]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleneboronic acid (300 mg, 0.67 mmol), a 2M solution of potassium carbonate in water (0.67 ml) and methyl (Z)-3-iodo-2-butenoate (Ma, S. & Lu, X.; J. Chem. Soc. Chem. Com., pp. 1643-1644 (1990)) (182 mg) in dimethoxyethane (DME) (10 ml) was heated to reflux for 24 h. The solution was poured into a mixture of water and ethyl acetate. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The desired compound was purified by flash chromatography on a silica column.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][CH:9]([F:12])[CH2:10][OH:11].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>CCOCC.CCCCCC>[F:8][CH:9]([F:12])[CH2:10][O:11][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1
Reactant: OCC(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(OCC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
With reference to the document (J. Med. Chem., (1994), 37, 3977-3985), sodium hydride (3.36 g, 55%, 77.1 mmol) was added to a solution of DMF (100 mL) containing 2,2-difluoroethanol (5.75 g, 70.1 mmol) over 5 minutes under nitrogen gas flow under ice-cooling. The mixture was stirred at the same temperature for 10 minutes, and then a solution of DMF (40 mL) containing 4-fluorobenzaldehyde (9.56 g, 77.0 mmol) was added dropwise thereto over 5 minutes. The mixture was stirred at room temperature for 4 hours and was then poured into ice water (500 mL). The resulting mixture was extracted with ether:hexane (300 mL, 1:1, v/v) three times. The extracted organic layer was washed with water (300 mL) three times and then with saturated brine, and was dried over anhydrous magnesium sulfate. Then, the solvent was evaporated to give a crude product. An ether/hexane mixture solution (20 mL, 1:10, v/v) was added to the crude product, and the supernatant fluid was removed. This procedure was repeated four times in total to wash the crystals to give 10.1 g of the title compound (colorless crystalline solid, yield: 77%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[O:15][CH2:14][CH2:13][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[O:15][CH2:14][CH2:13][O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCCCC1(CCCCc2ccccc2)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: Cc1ccccc1
Product: O=CCCCCCCCC1(CCCCc2ccccc2)OCCO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
8-[2-(4-Phenyl-butyl)-[1,3]dioxolan-2-yl]-octan-1-ol (830 mg, 2.48 mmol) was dissolved in toluene (4.2 mL), and 4-acetamide-2,2,6,6-tetramethylpiperidine 1-oxyl (2.6 mg, 0.0122 mmol) and an aqueous solution of 5% sodium bicarbonate (4.2 mL, 2.50 mmol) were then added. The mixture was then cooled to 0° C. An aqueous solution of 12% sodium hypochlorite (1.55 mL, 2.50 mmol) was added over 15 minutes. The mixture was then stirred at room temperature for 3 hours, and extracted twice with ethyl acetate (50 mL). The organic layer was then concentrated under reduced pressure. The residue was purified on Biotage (diol, n-hexane/ethyl acetate) to obtain 528 mg of the title compound (1.59 mmol, 64% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:12][Br:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)C.Br>C(O)C>[Br:13][CH2:12][C:6]1([CH2:5][OH:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)OCC1(CBr)CCCCC1
Agent: Br
Solvent: CCO
Product: OCC1(CBr)CCCCC1
Yield: 70 %

Procedure:
42 g of the 1-acetoxymethyl-1-bromomethylcyclohexane resulting from the preceding stage and dissolved in 80 cm3 of ethanol were heated under reflux for 6 hours, in the presence of 3 cm3 of 48% hydrobromic acid. The ethanol was evaporated off and the oil obtained was distilled. 1-Bromomethyl-1-hydroxymethyl-cyclohexane was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Agent: Br
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c2cc(O)ccc2n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere in a 500 single-neck round bottom flask equipped with a condenser and a magnetic stirrer, a solution of 2.00 g (9.62 mmol) of 4-chloro-6-methoxy-2-methylquinoline and 150 mL of 48% hydrobromic acid was heated under reflux for 90 minutes. Upon cooling to room temperature, the reaction solution was evaporated under reduced pressure to afford a solid residue. The residue was slurried in chloroform filtered and washed with chloroform. The solid was next slurried in a mixture of saturated aqueous sodium carbonate and ethyl acetate for 15 minutes, filtered and washed successively with saturated aqueous sodium carbonate, water and ethyl acetate. After air drying there was obtained 741 mg (40%) of 4-chloro-2-methylquinolin-6-ol: m.p. 233° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([CH:23]([CH2:34][C:35]2[N:36]=[N:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:23]([CH2:34][C:35]2[N:36]=[N:37][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:39][CH:40]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:17]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)c(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a solution of tert-butyl({5-bromo-6-[(6-phenylpyridazin-3-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (239 mg, 0.329 mmol) obtained in Example 1-(a) in ethanol (3.3 ml) were added triethylamine (322 μl, 2.31 mmol) and 10% palladium-active carbon (55% hydrate) (48 mg), followed by stirring at room temperature for 6 hours under hydrogen atmosphere at 1 atm. After completion of the reaction, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1→1:10 (V/V)) and then to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:0 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (153 mg) as a white foam. (Yield: 72%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:25][C:24]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]([CH3:14])([CH3:12])[CH3:15])=[O:18])[CH2:25][C:24]=3[CH:26]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A suspension of 5-bromo-3-nitropyridin-2-amine (4.84 g, 22.2 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (6.51 g, 22.2 mmol), dichloro[1,1-bis(diphenyl)phosphino]ferrocenepalladium (II) dichloromethane adduct (1.60 g, 10 mol %) in dioxane (75 mL) and water (15 mL) was degassed with nitrogen, and then cesium carbonate (14.46 g, 44.4 mmol) was added. The reaction mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, water (150 mL) was added and stirred for 30 min to give a precipitate. The product 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (8.1 g, 94% yield) was collected by filtration, dried under vacuum. MS (EI) for C19H22N4O5: 387.1 (MH+).
Reaction SMILES: Cl.[C:2](=N)(OCC)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[CH2:3]([C:2]1[NH:22][C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1nc2cc(C(=O)OC)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 128.8 %

Procedure:
5.47 g of ethyl pentanimidoate hydrochloride (J.A.C.S., Vol. 64, p. 1827 (1942)) were added to a solution of 5 g of methyl 3,4-diaminobenzoate in 60 ml of tetrahydrofuran, and the mixture was stirred for 3 hours and 30 minutes at 90° C. The tetrahydrofuran was evaporated off and 50 ml of a saturated solution of sodium bicarbonate were added. The mixture was extracted with methylene chloride and the extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 9 g of product which was crystallized from isopropyl ether to obtain 6.65 g of the desired product melting at 114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[NH2:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](=O)([O-])[O-:30].[Na+].[Na+].C(Cl)(Cl)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[NH:28][C:29](=[O:30])[N:20]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2N)CC1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2[nH]c(=O)n3Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-(2-amino-3-benzylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.176 g, 0.459 mmol) in 1 mL dichloromethane was added 1 mL of 2M aqueous sodium carbonate. Phosgene (0.261 mL of a 1.93 M solution in toleuene, 0.504 mmol) was added dropwise to the stirring solution over five minutes. Stirring was continued for two hours as a fine white precipitate was formed. The solid was filtered and dried under a stream of nitrogen to give 0.112 g of 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a fine white powder. MS: 409 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>C1COCC1.[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
The methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate was then dissolved in THF (15 mL) and 3 N NaOH (5 mL). The mixture was heated (60° C., 2 h) and then concentrated and acified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over MgSO4. The crude product was purified by silica chromatography (0-15% MeOH/CH2Cl2) to afford 0.3 g of as 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid an orange solid. Mass calculated for C27H37NO4=439.59; found: [M−H]+=438.3.