Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:21][NH2:22]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[C:15]([OH:17])=[N:21][NH:22][C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: NN
Agent: Cl
Product: Oc1n[nH]c2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (10.0 g, 34 mmol, Aldrich) and hydrazine (30 mL, 824 mmol, Aldrich) was stirred at RT for 48 h. The volatile solvents were removed in vacuo, and the residue was azeotroped with MeOH (1×), then recrystallized from MeOH to obtain the title compound MS (ESI, pos. ion) m/z: 230 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20]1C(O)=CC=CC=1C.[OH-].[K+].CC(O)=O>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: CS(=O)(=O)c1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1N=Nc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
For these studies, half of the diazonium salt from example 1 was added to a solution of m-cresol (0.285 g, 2.34 mmol) and KOH (0.13 g, 2 mmol) in THF. The resulting red mixture was stirred for 0.5 h and then neutralized with HOAc to give a orange solid. This solid was filtered and recrystallized from THF/Hexanes to give 0.35 g (58%) of Compound 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C(OCC)(=O)C>[C:23]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[O:10])=[C:4]([CH3:22])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Cc1cc(Br)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 150 °C
Yield: 69.7 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)C12-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1.[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][C:15]=1F.O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[S:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[NH2:17]
Reactant: Sc1nccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2nccs2)c(Cl)c1
Reaction time: 4 h

Procedure:
To a suspension of 3.8 g sodium hydride (60% in mineral oil) in 100 ml of dimethylformamide was added slowly a solution of 10.0 g of 2-mercapto thiazole in 100 ml of dimethylformamide. After 15 min a solution of 15.0 g 3-chloro-4-fluoro nitrobenzene in 50 ml of dimethylformamide was added. After 4 hrs, the mixture was poured into water. The resulting solid was collected, washed with water, and dried in vacuum. This material was mechanically stirred at reflux in a mixture of 830 ml of methanol, 230 ml of water, 37.0 g of ammonium chloride, and 30.1 g of iron powder for 4 hrs. The boiling mixture was filtered. The solvent was removed from the filtrate and the residue was extracted with hot ethyl acetate. The ethyl acetate solution was filtered through a short silica gel column. The solvent was removed and the residue was recrystallized from ether hexane giving 17.7 g of an off white solid.: mass spectrum electrospray, m/e): M+H 243.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH3:22].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC(C)([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
To a suspension of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in a mixture of 100 parts by volume of ethanol and 5 parts by volume of ethyl orthoacetate is added 1 part of concentrated sulfuric acid with stirring. The mixture is further stirred for 30 minutes, and about 100 parts by volume of a saturated aqueous sodium bicarbonate solution is added. The mixture is concentrated under reduced pressure. The resulting crystals are collected by filtration, washed with water and dried to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine as colorless crystals. Recrystallization from acetone-n-hexane gives colorless needles melting at 226°-227° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C#N)ccn1
Yield: 110.8 %

Procedure:
2-Chloro-4-cyanopyridine (115.5 g) in methanoldioxan (1:1, 850 ml) was added to a solution of sodium methoxide (prepared from 20.8 g sodium) in methanol (285 ml) and the mixture was heated under reflux for 2.5 hours and then allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation to 200 ml and water (400 ml) was added. The solid which precipitated was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%), m.p. 93°-95.5°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl.O>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:32])[C:17]=2[N:26]=1
Reactant: [NH4+]
Reactant: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (32.7 g of 77% pure material, 146 mmol) was added over a period of five minutes to a solution of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20.0 g, 73.1 mmol) in chloroform (500 mL); the reaction mixture was stirred at ambient temperature for one hour. Ammonium hydroxide (200 mL) was added, and then p-toluenesulfonyl chloride (16.7 g, 87.7 mmol) was added in portions over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for one hour, and then water (200 mL) was added. The aqueous layer was separated and extracted with dichloromethane (2×200 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 32 g of crude product as a tan solid. The crude product was dissolved in dichloromethane (50 mL), and the resulting solution was divided into two portions. Each portion was purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) using a FLASH 65I silica cartridge (also available from Biotage, Inc.) (eluting with ethyl acetate:methanol in a gradient from 98:2 to 85:15) to provide 11.24 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([CH:15](C(C)=O)[C:16]([O:18]CC)=[O:17])[CH:8](C(C)=O)[C:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([CH2:15][C:16]([OH:18])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(C)=O)C(c1ccc(OC)cc1)C(C(C)=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Yield: 16.1 %

Procedure:
A mixture of ethyl 2,2'-(4-methoxybenzal)-bis-acetoacetate (30 g), ethanol (450 ml) and 50% sodium hydroxide (450 g) is refluxed vigorously for 1.0 hour. Water (150 ml) is added and most of the ethanol is removed by distillation in vacuo. The concentrate is acidified with concentrated hydrochloric acid and is extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, evaporated, and the residue is crystallized from benzenemethanol to afford 3.3 g of 3-(4-methoxyphenyl)glutaric acid, melting point 147°-150° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[NH:13][C:12]2=[O:25])=[CH:7][CH:6]=1.Cl>O1CCCC1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[NH:13][C:12]2=[O:25])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(-n2c(=O)cc(-c3ccccc3Cl)[nH]c2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
7.0 g of the obtained 3-(4-methoxymethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione was dissolved in 100 ml of tetrahydrofuran and then added dropwise with 10 ml of concentrated hydrochloric acid with stirring at room temperature. The mixed solution was further stirred at room temperature for 12 hours and extracted with 200 ml of ethyl acetate. The organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 4.5 g of 3-(4-hydroxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10](I)[C:3]=12.[N:15]1([C:20]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)[CH:21]=3)[C:3]=12
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: CC(C)n1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)n1cc(-c2cccc(N3CCCC3)c2)c2c(Br)ccnc21
Temperature: 65 °C
Yield: 23.5 %

Procedure:
A mixture of 4-bromo-3-iodo-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D10) (2.80 g, 7.67 mmol), (3-(pyrrolidin-1-yl)phenyl)boronic acid (1.612 g, 8.44 mmol), bis(triphenylphosphine)palladium(II) chloride (0.538 g, 0.767 mmol) and 2M sodium carbonate aqueous solution (9.59 mL, 19.18 mmol) in ACN (35.0 mL) was heated at 65° C. for 2 hours and then allowed to cool to RT. The mixture was evaporated to dryness and the residue partitioned between water (50 mL) and ethyl acetate (150 mL). The aqueous phase was separated and extracted with additional ethyl acetate (100 mL). The organic extracts were combined, washed with brine (50 mL), dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica eluting with cyclohexane and ethyl acetate (0-35%) to give an impure material which was further purified on silica eluting with cyclohexane and ethyl acetate (0-25%). The appropriate fractions were combined and evaporated to dryness producing the title compound (692 mg). LCMS (A): m/z (M+H)+ 384/386, C20H22BrN3 requires 383/385 (acidic).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Br:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:16]>CO>[NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Br:15])=[CH:8][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: N
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Solvent: CO
Product: NC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
25.8 g (93.8 mmol) of methyl 2-amino-5-bromo-4-nitro-benzoate were dissolved in 800 ml of methanol and saturated with ammonia at -40° C. Subsequently, the mixture was stirred at room temperature overnight. The solution was concentrated and the residue was triturated with methylene chloride. The precipitate was filtered off under suction and dried. 18.3 g (75%) of 2-amino-5-bromo-4-nitro-benzamide were obtained as orange coloured crystals;
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
A mixture of 3 g of 2,4-dihydroxy-3-propylacetophenone, 2.5 g of ethyl bromoacetate, 2.3 g of anhydrous potassium carbonate, and 30 ml of methyl ethyl ketone was refluxed for 5 hours. Then, the solvent was removed under reduced pressure and after addition of 50 ml of toluene, the mixture was washed with water, a diluted aqueous solution of sodium hydroxide, and water successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was recrystallized from a mixture of toluene and n-hexane to provide 2.8 g of ethyl (4-acetyl-3-hydroxy-2-propylphenoxy)acetate (melting point: 66° to 66.5° C.).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH:34](Cl)(Cl)[Cl:35].C(OCC)(=O)C>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:34]/[Cl:35])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C=O)cc3)CC2=O)CC1
Reactant: ClC(Cl)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(/C=C/Cl)cc3)CC2=O)CC1

Procedure:
To a suspension of chromiun (II) chloride (737 mg) in THF (10 ml) was added a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-formylbenzenesulfonyl]-2-piperazinone (466 mg) and chloroform (0.160 ml) in THF (7 ml), and the mixture was refluxed for 1 hour. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (235 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N.C(=O)([O-])O.[Na+]>CN(C)C=O.CN1CCOCC1.C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[C:4]([NH:9][C:19](=[O:20])[CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cc(N)cc(Cl)c1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-1,3-phenylenediamine (1.22 g), N-Boc-glycine (500 mg) and (1-cyano-2-ethoxy-2-oxoethylideneaminoxy)dimethylamino-morpholino-carbenium hexafluorophosphate (1.83 g) in N,N-dimethylformamide (5 mL), N-methylmorpholine (628 μL) was added at room temperature, and the mixture was stirred at 130° C. for 5 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate) to obtain tert-butyl (2-((3-amino-5-chlorophenyl)amino)-2-oxoethyl)carbamate (B10, 273 mg) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CC(O)=O.[OH-].[Na+]>ClCCl.ClCCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CN3CCN(C)CC3)c2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 (Example 9, 1.0 eq) and 1-methyl-piperazine (1.09 eq) in equal volume of 1,2-dichloroethane and dichloromethane was added AcOH (0.96 eq) Sodium triacetoxyborohydride (1.5 eq) was then added. The reaction mixture was stirred at room temperature for 2 h. Aqueous NaOH was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organic layer was then dried over Na2SO4, filtered and concentrated to give a residue that could be purified by silica gel chromatography (eluent: 9/1 CH2Cl2/methanol then 9/1/0.05 CH2Cl2/MeOH/NH3H2O). Yield 67%. MS m/z 473.3 [M+H]+; 1H NMR (300 MHz, CDCl3) 0.61 (m, 2H), 0.86 (m, 2H), 2.26 (s, 3H), 2.30 (s, 3H), 2.52 (brs, 8 H), 2.90 (m, 1H), 3.60 (s, 2H), 5.87 (brs, 1H), 6.30 (brs, 2H), 7.45 (m, 3H), 7.70 (m, 2H), 7.83 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: ClCc1ccccc1
Product: C/C(=C\c1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and benzyl chloride there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid benzyl ester of melting point 113°-114° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:29]>O1CCOCC1>[ClH:29].[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][NH:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [3-({[(3-nitrophenyl)sulfonyl]amino}methyl)phenyl]carbamate (1.00 g, 2.45 mmol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (10 mL) and stirred at rt for 2 h. After concentration, the crude off-white powder product (0.97 g) was used in the next step. (Molecular Formula (MF)=C13H13N3O4S; LCMS calculated for C13H13N3O4S (M+H)+: m/z=308.0. 1H NMR (400 MHz, CD3OD): δ 8.55 (t, J=2.0 Hz, 1H), 8.44 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 8.20 (ddd, J=7.6, 2.4, 1.2 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.40 (m, 2H), 7.36 (dd, J=7.6, 1.2 Hz, 1H), 7.23 (ddd, J=8.0, 2.4, 1.2, 1H), 4.21 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O
Yield: 82.6 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and ethanesulfonyl chloride (36 mg, 282 μmol) were reacted with one another for 3 h. This gave the title compound as a colorless solid (99 mg, 83% of theory).