Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2cncc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[5-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxylate (300 mg, 0.433 mmol) in pyridine (3.00 mL) cooled in an ice bath was added thionyl chloride (0.158 mL, 2.16 mmol). After being stirred at room temperature overnight (16 h), the brown reaction mixture was quenched with ice water and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel (0-20% B over 35 min. Bottle A=hexanes, Bottle B=EtOAc) provided 65 mg (46%) of desired product as a light yellow oil. LC-MS calculated for C16H19F3N2O2: (M+H) 329; found 329.1.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:10]([N+:28]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:31])[CH2:3]1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:10]([NH2:28])[CH:9]=2)=[N:6][NH:5][C:4](=[O:31])[CH2:3]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1N

Procedure:
10 gm of 5-methyl-6-(3-nitro-4-undecane carbonylamino-phenyl)-4,5-dihydro-2H-pyridazine-3-one were dissolved in 100 ml of dimethylformamide, and the solution was treated in the presence of 1 gm of 10% palladium charcoal with hydrogen for 1.2 hours at a pressure of 5 bar. After filtering off of the catalyst, the mixture was poured on ice and extracted with methylene chloride, and the organic phase was evaporated. The oily residue was further processed directly.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7](I)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:37]3[CH:38]=[N:33][CH:34]=[N:35][CH:36]=3)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(c1c(I)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1
Product: O=C(c1c(-c2cncnc2)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-cyclopropyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 63) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow amorphous solid. MS: 511.2 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([CH2:14][CH2:15][N:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>Cl.O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C(C)=O)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C(C)=O)CCC2
Temperature: 70 °C
Reaction time: 10 h
Yield: 88.8 %

Procedure:
162 mg of 1-acetyl-7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline was dissolved in 6 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1), and the reaction solution was then stirred at 70° C. for 10 hours. The reaction solution was cooled to a room temperature, and a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 127 mg of 1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one. This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (350 mg, 2.55 mmol) and 3,4-dichlorobenzyl alcohol (542 mg, 3.06 mmol) were dissolved in tetrahydrofuran (7.0 mL), and triphenylphosphine (803 mg, 3.06 mmol) and a 40% diethyl azodicarboxylate toluene solution (1.40 mL, 3.06 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (676 mg, yield: 89%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH:5]=[CH:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1>CO.O.O.C(OCC)(=O)C>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C@@H:2]2[C@@H:7]3[CH2:8][C@@H:4]([CH:5]=[CH:6]3)[C@@H:3]2[C:9]([NH2:11])=[O:10])[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2C=C[C@@H]1C2
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A light suspension of (+)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, trifluoroacetic acid (3 g, 11.27 mmol) and sodium bicarbonate (1.893 g, 22.54 mmol) in 39 ml of 2:1 methanol/water at room temperature was treated with 2,4,5-trichloropyrimidine (1.550 ml, 13.52 mmol). The resulting mixture was stirred at room temperature for 2 days, diluted with water (20 ml) and ethyl acetate (30 ml); the separated aqueous phase was extracted with ethyl acetate (4×20 ml) and the combined organic layers were washed with brine (20 ml), dried w/Mg2SO4, filtered and concentrated. The crude product was flash chromatographed (50 mm; 0.5 L 2% methanol in CH2Cl2 to 4% methanol in CH2Cl2) to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:37])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809 μmol) in dichloromethane (15 mL) was added triethylamine (250 μL, 1.78 mmol) and 2-nitrobenzoyl chloride (240 μL, 1.78 mmol). The solution was stirred at room temperature for 110 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.23 min, MH+ 459].
Reaction SMILES: C([O:4][CH2:5][CH:6]([OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[N+:13]([C:9]1[CH:8]=[C:7]([CH:6]([OH:16])[CH2:5][OH:4])[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CC(=O)OCC(O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(C(O)CO)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
2-Hydroxy-2-(3-nitrophenyl)ethyl acetate (18 g) was dissolved in MeOH (180 mL) and cooled to 0° C. K2CO3 (22 g) was added and the reaction stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, quenched by addition of water (100 mL) and extracted with ethyl acetate (2×100 mL). The EtOAc layer was dried over Na2SO4 and concentrated to give the crude title compound (13 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[C:4]([F:15])[C:5]([F:14])=[C:6]([O:8]C(OCC)=O)[CH:7]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[F:14][C:5]1[C:4]([F:15])=[C:3]([F:16])[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[OH:8]
Reactant: CCOC(=O)Oc1cc(N)c(F)c(F)c1F
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(O)c(F)c(F)c1F
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
1.27 g (5.40 mmol) of the above 5-amino-O-ethoxycarbonyl-2,3,4-trifluorophenol was dissolved in 5 mL of pyridine, 0.80 mL (6.5 mmol) of pivaloyl chloride was added under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 25 mL of methanol, 1.40 g (10.1 mmol) of potassium carbonate and 15 mL of water were added and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 2 by addition of 2N hydrochloric acid thereto and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1.20 g of 2,3,4-trifluoro-5-pivaloylaminophenol (two stage yield: 90%).
Reaction SMILES: Cl[CH:2]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:18]1([CH:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: ClC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2nn(-c3ccccc3)c3ccccc23)C2CCCCC2)cc1
Yield: 12.4 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-1-phenyl-1H-indazole (397 mg) synthesized in Example A14(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (305 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (76.9 mg, 12%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:13][NH2:14])(=O)[CH3:11].[N+]([O-])(O)=O.[OH-].[NH4+]>C(O)C>[CH3:11][C:10]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:14][N:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NN
Agent: [NH4+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1nncn1-c1ccccc1
Temperature: 25 °C

Procedure:
2.5 mol of phenyl isothiocyanate (Formula XXI of Chart B) is added to 0.5 mol of acethydrazide (Formula IV of Chart B) in 500 ml of absolute ethanol and refluxed for one hour, cooled and filtered. This is then dissolved in a solution of 28.0 gm sodium hydroxide in 400 ml of water and the mixture is refluxed for two hours. The reaction mixture is cooled in an ice bath and treated with 100 ml of concentrated hydrochloric acid. The resulting solid is filtered and recrystallized. 66.7 mmol of the solid is added to 53 ml of 20% nitric acid and heated on a steam bath. When the vigorous exothermic reaction is complete, an additional 53 ml of 20% nitric acid is added, and an additional 66.7 mmol of previous solid. Portions of the solid are reacted with nitric acid until all of the previous solid is reacted. After the final addition the reaction mixture is heated twenty minutes on a steam bath, cooled to ambient temperature and poured into cold 15% aqueous ammonium hydroxide solution. The subtitled product is extracted with chloroform, dried and concentrated to yield 3-methyl-4-phenyl-4H-1,2,4-triazole, (Formula XXIV, Chart B) mp 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[S].[C:10](=[S:12])=[S:11]>>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:8])[C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Cc1ccccc1N
Agent: [S]
Product: Cc1cccc2sc(S)nc12
Reaction time: 1.5 h
Yield: 46 %

Procedure:
Into a 500 ml reactor were charged o-toluidine (27 g), sulfur (8g), and carbon disulfide (22 g). Seventy minutes of electrically heating the system was required to elevate the temperature to 275°C (240 psig original pressure at 275°C). After 21/2 hours at 275°C (the pressure leveled out at 470 psig in 90 minutes) the heat source was removed and the reactor was cooled. The reaction mixture was mixed with 200 g water containing 16 g sodium hydroxide. Tar-like residue (18.5 g) was removed by decantation. Acidification of decantate with hydrochloric acid and filtration of the resulting mixture gave 21 g (46 percent yield) of crude 2-mercapto-4-methylbenzothiazole (m.p. 161°-173°C).
Reaction SMILES: [NH2:1][O:2][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].N1C=CC=CC=1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>ClC(Cl)C.ClCCl>[Si:3]([O:2][NH:1][C:16](=[O:27])[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)ONC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
(Aminooxy) (tert-butyl)dimethylsilane (1.00 g, 6.79 mmol) was dissolved in a mixture of dry pyridine (0.549 mL, 6.79 mmol) and dichloroethane (15 mL; dichloromethane could also be used), and a solution of 4-nitrophenyl chlorocarbonate (1.37 g, 6.79 mmol) in dichloroethane (7 mL) was added over 5 min. The resulting mixture was stirred at room temperature overnight and was then diluted with dichloromethane, washed twice with water, twice with saturated aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by chromatography (90 g silica gel, 20% EtOAc/hexanes eluent) to give the title compound (1.73 g, 81%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28]1[N:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)[CH3:26].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:34]([C:31]3[CH:30]=[N:29][C:28]([O:27][CH2:25][CH3:26])=[CH:33][N:32]=3)=[O:35])=[CH:19][CH:20]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:23])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N)cc1
Reactant: CCOc1cnc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOc1cnc(C(=O)Nc2ccc(CC[C@H]3[C@H](C)OC(C)(C)N3C(=O)OC(C)(C)C)cc2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of (4S,5S)-4-[2-(4-amino-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (120 mg) and 5-ethoxypyrazine-2-carboxylic acid (72.4 mg) in THF (3 ml) were added N-methylmorpholine (158 μl) and TBTU (230 mg). The reaction mixture was capped and shaken at 50° C. overnight. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, gradient: 0% to 70% EtOAc in hexane) to afford (4S,5S)-4-(2-{4-[(5-ethoxy-pyrazine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (167 mg, 96%). MS (ISP): 507.3 ([M+Na]+), 502.3 ([M+NH4]+), 485.3 ([M+H]+), 429.3 ([M-C4H8]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][Br:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (94.0 Og 0.41 mol), carbon tetrabromide (198.7 g 0.6 mol) and dichloromethane (1500 ml) at 0° under nitrogen was treated portionwise, over 45 min, with triphenylphosphine (135.2 g 0.515 mol). The mixture was stirred for 1 h at 10° and 1 h at 25° and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385), eluant cyclohexane: ethyl acetate (15:1, gradient to 10:1) to give the title compound as a clear liquid (81.8 g, 0.28 mol, 68%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]([CH3:40])[CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1O>O.C(O)(=O)C>[CH3:40][CH:34]1[C:33]([C:30]2[CH:31]=[CH:32][C:27]3[N:26]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:8][C:28]=3[CH:29]=2)=[N:38][NH:37][C:36](=[O:39])[CH2:35]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: O=C(O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cccs3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.6 g (0.02 mol) thiophene-2-carboxylic acid, 3.3 g (0.02 mol) 1,1′carbonyldiimidazole and 50 ml DMF are combined and the mixture is stirred for 30 min at RT, then 4.4 g (0.02 mol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one are added and the mixture is stirred for 4 h at 60° C. The reaction mixture is diluted with water and acidified with glacial acetic acid, the precipitated solid is filtered off, washed with water and isopropanol and then dried. The solid obtained is heated to 130° C. with 60 g polyphosphoric acid for 30 min, then poured onto ice water and then extracted with chloroform. The org. phase is washed with water, dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue is stirred with acetone/diethyl ether, filtered off and then recrystallised from isopropanol/dioxane.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([Cl:16])=[CH2:15])[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([Cl:16])=[CH2:15])[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=C(Cl)Cn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: C=C(Cl)Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 10.9 %

Procedure:
The title compound was prepared as a white powder in 10.9% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(2-chloro-2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][OH:29])[CH3:25]
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NO)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. Hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Further, hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were then added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (10 mg, yield 31%).
Reaction SMILES: C(OC(N1C2C(=CC(OC)=CC=2Cl)C=C1B(O)O)=O)(C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[N+:31]([C:29]1[CH:28]=[CH:27][C:26]([OH:30])=[CH:25][C:24]=1[Cl:23])([O-:33])=[O:32]
Reactant: Oc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: COc1cc(Cl)c2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)cc1Cl

Procedure:
Synthesis of 1-(tert-butoxycarbonyl)-7 chloro-5 methoxy-1H-indol-2-yl boronic acid is shown in Scheme 4. Meta-chlorophenol is nitrated with fuming nitric acid in acetic acid to yield 4-nitro-3-chlorophenol, compound 4-2. The phenol is methylated with dimethylsulfate and potassium carbonate in ethanol, producing compound 4-3, which is treated with vinyl Grignard reagent and cyclized to form the indole, compound 4-4. Compound 4-4 is protected with Boc and then treated with lithium diispropylamide and triisopropylborate to produce the protected substituted boronic acid 4-6.