Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1C2C(=CC=CC=2)CCC1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a mixture of 308 mg (purity: 98%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added tetralin (2.76 g) and 334 mg (5.67 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 324 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 64%) and 2.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:19])[C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)C1CCNCC1
Temperature: 27.5 °C
Reaction time: 6 h
Yield: 127.6 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) in DCM (400 mL) was added trifluoroacetic acid (150 mL) and the resulting mixture was stirred for 6 h at 25-30° C. After completion of the reaction, the solvent was removed under reduced pressure to afford 40 g of N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][OH:29].C[O-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([O:29][CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: CO
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
5-Amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and a methanol solution (about 28%; 200 mg) of sodium methoxide were added to methanol (2 ml), and the mixture was stirred at 45° C. for 3 days. Acetic acid (80 mg) was added to the reaction mixture, and the mixture was heated under reflux for 1 hour. After the reaction mixture was allowed to cool, deposits were collected by filtration and washed with methanol and diisopropyl ether in that order to obtain the title compound (122 mg) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:9]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1cc(C2=CCCC2)ccn1
Yield: 41.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 33a by using the 2-amino-4-chloropyridine (1.07 g, 8.32 mmol), 2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.61 g, 8.29 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(303 mg, 0.414 mmol), potassium carbonate (4.59 g, 33.2 mmol) and DMF (15 mL), to yield the title compound (552 mg, 41%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=3)[C:12]=2[C:13]([O:15]CC[Si](C)(C)C)=[O:14])[N:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=3)[C:12]=2[C:13]([OH:15])=[O:14])[N:3]=1
Reactant: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylsilylethyl 2-(4-chloro-6-methoxypyrimidin-2-yl)oxy-6-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate (4.0 g) was dissolved in 30 ml of DMF. To this solution, tetrabutylammonium fluoride trihydrate (5.9 g) was added, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, water and a small amount of an aqueous potassium hydrogen sulfate solution were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crystals thereby obtained were washed with a mixture of hexane and IPE to obtain the above identified compound as white crystals (3.2 g). (Melting point: 150°-152° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10](SC2N=C(C)C=C(C)N=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([O:27][C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C@@H:34]1[CH2:38][C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:36][NH:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:35]2[CH2:36][C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:38][C@H:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[O:11])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-p-Nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (719 mg) was added to 770 mg of (2R,4R)-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine in 7 ml of tetrahydrofuran and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with brine, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=CC=[CH:45][CH:44]=1>C(O)CCC>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:48]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:43][CH2:44][CH3:45]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.0 gram of p-toluenesulfonic acid monohydrate in 10 ml of n-butyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine n-butyl ester di(p-toluenesulfonate) in 95% yield: mp. 160°-164° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O.[OH-].[Na+]>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 98 %

Procedure:
Dissolve 1.0 g (3.25 mmol) of the corresponding nitrile (prepared as described in Example 81) in diethyl ether (70 mL). Add lithium aluminum hydride (250 mg, 6.6 mmol) and stir at room temperature for 3 h. Quench the reaction by adding 8 drops water, 8 drops 5N NaOH and 16 drops water. Filter the inorganic solids and wash with ether. After drying (MgSO4) and concentration, the title compound was obtained in 98% yield as a colorless oil, MS (ES) 312 (N+1). HPLC shows 98% purity.
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>[Cl-].[Cl-].[Zn+2].ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 200 mg (1.15 mmol) of 4-chlorobicyclo[3.2.1]oct-3-en-2-one, 16 mg (0.12 mmol) of ZnCl2, 324 mg (1.15 mmol) of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 166 mg (1.27 mmol) of diisopropylethylamine and 5 ml of toluene is stirred at room temperature under a nitrogen atmosphere until a clear brown solution having a white sediment is formed. With stirring, the reaction mixture is then maintained under moderate reflux for 26 hours in an oil bath. The reaction mixture is then cooled to ambient temperature and 30 ml of dichloromethane are added. The solution is then washed twice with water (20 ml each time), then twice with 0.1M hydrochloric acid (20 ml each time) and again twice with water (15 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuum, 284 mg of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13]([CH2:14][C:15]([F:18])([F:17])[F:16])=[O:39])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2Cl)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2Cl)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 103.3 %

Procedure:
0.15 g of 5-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 90mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 1 hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.16 g of 5-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH4+].[OH-]>[Rh].O>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ncccc1O
Agent: [Rh]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1NCCC[C@@H]1O
Reaction time: 8 h
Yield: 11.3 %

Procedure:
A suspension of 3-hydroxypicolinic acid (1 g, 7.19 mmol) and 5 wt. % rhodium on carbon (200 mg) in a mixed solvents of conc. NH4OH (35 mL) and water (5 mL) in a pressure bottle was stirred under hydrogen at 80 psi overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo to dryness to give 118 mg of the title compound (racemate). MS (ES): m/z 146 [M+1]+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:8]=[C:9]=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]>C(Cl)(Cl)Cl.ClCCCl>[C:3]([NH:8][C:9]([NH:2][CH3:1])=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: CN
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)NC
Yield: 99.9 %

Procedure:
To a solution of methylamine (0.35 g; 11.29 mmol) in chloroform (30 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform, 1,2-dichloroethane and methylamine were evaporated under reduced pressure to give 1-methacryloyl-3-methylurea (1.42 g), which was recrystallized from a mixture of benzene and hexane to give colorless plates. M.P., 112°-113.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:39])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:21](=[O:28])[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>Cl.C(OCC)C>[C:30]([CH2:29][N:20]1[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:17](=[CH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:39])[CH2:13][CH2:12]2)[C:18]2[CH:38]=[CH:37][CH:36]=[CH:35][C:19]1=2)([OH:32])=[O:31]
Reactant: CCOC(=O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol (Example 18)(1.0 g) was solved in 1M hydrogen chloride in diethyl ether and stirred at room temperature for 24 hours. Aqueous sodium hydroxide and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound (250 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1([C:28]2[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[CH:31]=[N:30][CH:29]=[C:28]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:33]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cncc(N2CCOCC2)n1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cncc(N3CCOCC3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 92.7 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4carboxamide (75 mg, 0.27 mmol), 6-morpholin-4-ylpyrazine-2-carboxylic acid (55.9 mg, 0.27 mmol), HATU (101.5 mg, 0.27 mmol), HOBT (36 mg, 0.27 mmol) and DIPEA (140 μl, 0.80 mmol) in DMF (3 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with hydrochloric acid (0.5M, 2×20 ml), aqueous sodium hydrogen carbonate (20 ml) and dried (magnesium sulphate). Evaporation of the solvents under vacuum gave N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-morpholin-4-ylpyrazine-2-carboxamide (118 mg, 94%). NMR; δH [2H6]—DMSO 10.17,(1H, s), 8.62,(1H, t), 8.54,(1H, s), 8.47,(1H, s), 7.93,(2H, d), 7.80,(1H, dd), 7.70,(1H, d), 7.45,(2H, d), 7.31,(1H, d), 3.73,(8H, m), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.20 min, MH+472.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11]Br)=[C:6]([NH2:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:10][CH2:11][NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)NCCO2
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 0.848 mmol) and K2CO3 (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at 60° C. for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (170 mg, 94%) as a yellow oil. LCMS: 214 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 3.26 (m, 2H), 4.08 (t, J=4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J=1.6 Hz, 1H).
Reaction SMILES: [P:1]([OH:8])([OH:7])([O:3][CH2:4][CH2:5][NH2:6])=[O:2].C(N(CC)CC)C.[CH3:16][C:17]1[C:23](=[O:24])[C:22]2[N:25]3[C@@:29]([O:36][CH3:37])([C@H:30]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[C:21]=2[C:19](=[O:20])[C:18]=1OC)[C@H:28]1[NH:38][C@H:27]1[CH2:26]3.C(=O)(O)[O-].[Na+]>O.CO>[CH3:16][C:17]1[C:23](=[O:24])[C:22]2[N:25]3[C@@:29]([O:36][CH3:37])([C@H:30]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[C:21]=2[C:19](=[O:20])[C:18]=1[NH:6][CH2:5][CH2:4][O:3][P:1]([OH:8])([OH:7])=[O:2])[C@H:28]1[NH:38][C@H:27]1[CH2:26]3
Reactant: NCCOP(=O)(O)O
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(NCCOP(=O)(O)O)C3=O)N1C[C@@H]1N[C@@H]12
Reaction time: 8 h

Procedure:
A solution of 2-aminoethyl dihydrogen phosphate (56 mg, 0.4 mmol) in water (0.35 ml) and triethylamine (0.3 ml, 2 mmol) was added to mitomycin A (referred to hereinafter as "MMA") (140 mg, 0.4 mmol) in methanol (6 ml) and the reaction was allowed to proceed at room temperature overnight. 1.4 ml of saturated aqueous sodium bicarbonate was then added and the solution was partitioned between water and methylene chloride. The aqueous phase was concentrated to dryness and several portions of methanol were added and evaporated. The residue was taken up into methanol, filtered, and applied to a 2×10 cm C-18 (reverse phase) silica column. The product was eluted with water and all volatile material was evaporated. Methanol was added and evaporated as before and the residue was dried for 24 h under high vacuum in a desiccator with phosphorus pentoxide. The mitomycin phosphate derivative, MOP, was obtained as a fine blue powder (190 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[NH4+].[I-:12].[K+].II.C1(O)C=CC=CC=1>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:12])[C:3]=1[OH:9]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: [I-]
Agent: II
Agent: [K+]
Agent: [NH4+]
Solvent: Oc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1cc(Br)c(O)c(I)c1
Temperature: 60 °C

Procedure:
2-Bromo-4-methylphenol (10.11 gm, 54.05 mmol) was mixed with concentrated ammonium hydroxide (50 ml) and methanol (20 ml). Potassium iodide (17.94 g, 108 mmol), iodine (13.72 g, 54.05 mmol) and water (60 ml) were mixed to give a dark brown solution which was added in portions to the phenol solution. Additional methanol (200 ml) was added in portions as precipitating product made the mixture too viscous to stir. When all the iodine solution had been added the mixture was heated to 60° C. till the brown color faded. The mixture was cooled, filtered and the solid rinsed three times with water. The solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and stripped to give 2-Bromo-4-methyl-6-iodophenol as an oil that crystallized on standing. The filtrate and water rinses were concentrated and extracted twice with ethyl acetate, dried over magnesium sulfate, filtered and stripped to give additional 2-bromo-4-methyl-6-iodophenol for a total of 16.24 g, 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:32]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[C:25]([I:32])[C:17]([C:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)NC(=O)c1c(C)cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Temperature: 100 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
In a solution of 0.24 g of methyl N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl]carbamate synthesized in Synthetic Example 19 and 0.12 g of N-iodosuccinimide in 3 mL of N,N-dimethylformamide, 0.0112 g of palladium (II) acetate was added, and stirred under nitrogen atmosphere at 100° C. for 4 hours. After the completion of the reaction, the reaction mixture was poured in a solution of 0.03 g of sodium thiosulfate in 30 mL of water, and extracted with ethyl acetate (30 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 0:1 to 3:2) to obtain 0.11 g of the aimed product as colorless resinous substance.