Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([O-:13])(=O)[CH3:11].[K+].C(OC(=O)C)(=O)C.[N:22](OCCC(C)C)=O>C1(C)C=CC=CC=1.O>[C:10]([N:5]1[C:4]2[C:3](=[C:2]([Br:1])[CH:8]=[CH:7][CH:6]=2)[CH:9]=[N:22]1)(=[O:13])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1Br
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2c(Br)cccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-bromo-2-methylaniline (2.00 mL, 16.0 mmol) and potassium acetate (1.60 g, 16.3 mmol) in toluene (160 mL) was added acetic anhydride (4.54 mL, 48.0 mmol) at room temperature, and the mixture was stirred at 60° C. for 30 min. Isoamyl nitrite (3.22 mL, 24.0 mmol) was added, and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)C>[OH:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:11]3[N:10]=[C:9]4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:17])[NH:6][CH2:7][C:8]4=[CH:13][N:12]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: CC(C)N1C(=O)NCc2cnc(S(C)=O)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCC(O)CC4)cc3)nc21
Yield: 14.9 %

Procedure:
Prepared from 200 mg (0.79 mmol) of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 302 mg (1.57 mmol) of 1-(4-aminophenyl)-4-hydroxypiperidine and 182 μL (2.36 mmol) of trifluoroacetic acid in 3.2 mL of acetonitrile. After the workup, the crude residue is triturated in ethyl acetate/dichloromethane and filtered. The filtrate is concentrated further to produce a second crop of crystals. The two are combined and dried to give 45 mg (13%) of the title compound: mp>120° C. (dec).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C-:26]#[N:27].[K+].[OH-].[NH4+]>O.C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]#[N:27])[CH2:14][CH2:13]1
Reactant: [C-]#N
Reactant: Nc1ccccc1
Reactant: O=C1CCN(CC2=Cc3ccccc3CC2)CC1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
A mixture of 1-[(3,4-dihydro-2-naphthalenyl)methyl]-4-oxopiperidine (24.0 g), aniline (9.3 g), and glacial acetic acid (70 ml) is cooled to 30° C and heated with a solution of potassium cyanide (7.2 g) in water (20 ml). The resulting mixture is stirred for 16 hours at room temperature. The reaction mixture is poured into aqueous ammonium hydroxide and extracted with chloroform. The organic solution is dried and concentrated to give the title compound.
Reaction SMILES: Cl.[OH-:2].[K+].[OH2:4].C[N:6](C)[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=CC=1>C1(C)C=CC=CC=1>[NH:6]1[CH2:7][C@H:14]([OH:4])[CH2:13][C@H:10]1[C:11]([OH:12])=[O:2]
Reactant: [OH-]
Reactant: O
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.5 h

Procedure:
About 50 mg of the hepatic medial lobe prepared in Section (2) described above was weighed into a 13×100 mm screwed Pyrex tube (IWAKI, Catalog No.TST-SCR13-100), and hydrolyzed with 1 ml of 6 N HCl at 110° C. for 20 hours. The hydrolysate thus obtained was combined with 1 ml of 5 M potassium hydroxide, and the solution was filtered through a filter (0.22 μm, MILLIPORE, Catalog No.SLGP-R25LS), and the filtrate was collected. 1 ml of the filtrate thus recovered was combined with 1 ml of distilled water to use as a sample solution in the following procedure. 0, 1, 2 or 4 μl of the hydroxyproline conventional solution (corresponding to 0, 3, 6 or 12 μg of hydroxyproline, respectively) were combined with 2 ml of distilled water and used as conventional solutions. Each of the sample solutions and the conventional solutions was combined with 1.5 g of KCl, 0.25 ml of a 10% aqueous solution of alanine (pH 8.7) and 0.5 ml of a boric acid buffer, and the mixture was allowed to stand at room temperature for 30 minutes. The mixture was combined with 0.5 ml of the chloramine T solution, and allowed to stand for 25 minutes. This mixture was then combined with 1.5 ml of 3.6 M sodium thiosulfate (NACALAITESQUE, Catalog No.320-06) and 2.5 ml of toluene, and then capped and stirred for 5 minutes. After centrifuging the mixture at 1500 rpm for 5 minutes, the upper toluene layer was removed with suction and the remaining lower layer was collected. The solution thus obtained was kept at 100° C. for 30 minutes. The solution was cooled with a running water, combined with 2.5 ml of toluene again and then stirred for 5 minutes. The mixture was centrifuged at 1500 rpm for 5 minutes, and the toluene layer was collected. 1.25 ml of the toluene layer thus obtained was combined with 0.5 ml of the p-dimethylaminobenzaldehyde solution and allowed to stand at room temperature for 30 minutes, and then the mixture was examined for its absorbance at 560 nm. By producing a calibration curve from the values of the hydroxyproline conventional solutions (hydroxyproline 0 μg serving as a blank), the following equation was obtained. Amount of hydroxyproline (μg)=17.416×[(absorbance of sample)−(absorbance of blank)]−0.1619, R2=0.9954
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1.[Li+].[OH-].Cl.[CH3:10]COC(C)=O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[CH:5]1[C:4]2[C:3](=[CH:18][CH:17]=[CH:16][CH:20]=2)[CH:2]=[CH:10][C:6]=1[OH:1]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: C1=CCOC=C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
Acrylic acid (1.36 mL, 20.0 mmol) was added to a solution in which 2-naphthol (1.44 g, 10.0 mmol) and AMBERLIST (produced by Aldrich, strong acid, 1.0 g) serving as an ion-exchange resin were dissolved into toluene (30 mL), while the solution was agitated. The resulting mixed solution was refluxed for a day. The resulting suspension was filtrated through celite, and the solvent was removed by distillation in a vacuum. The residue was refined by silica gel flash chromatography (dissolution medium hexane-EtOAc=20:1 (v/v)) to obtain a pyran derivative (1.78 g, 9.0 mmol, yield 90%). A solution in which the resulting pyran derivative (1.78 g, 9.0 mmol) was dissolved into THF (40 mL) was blended with 1-N LiOH (30 mL) and the resulting reaction mixed solution was agitated at room temperature for 6 hours. The resulting reaction mixed solution was poured into 1-N HCl (100 mL), extraction with EtOAc was performed two times, and washing was performed with a saline solution. Organic layers were mixed and dried with anhydrous Na2SO4. The solvent was removed by distillation in a vacuum. The residue was refined by silica gel flash chromatography (dissolution medium hexane-EtOAc=4:1 to 1:1 (v/v)) to obtain 2-Naphthol compound S2, that is, 3-(2-hydroxynaphthalen-1-yl)propanoic acid (4.05 g, 18.7 mmol) at a yield of 62%. The spectrum data thereof are as described below. In this regard, various 2-naphthol compounds used as starting materials in examples described later were synthesized by this method.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)Oc1nc(Cl)ccc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)Oc1nc(Cl)ccc1C#N
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 6-chloro-2-isopropoxy-nicotinamide (2.87 g, 13.37 mmol) and pyridine (6.48 mL, 80.22 mmol) in acetonitrile (25 mL) was added phosphorus oxychloride (3.68 mL, 40.13 mmol) over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was neutralized with 1N NaOH at 0° C. until pH reached to 7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous layer was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (2.1 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 5.34-5.20 (m, 1H), 1.33 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[CH:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:11]3[N:10]=[CH:9][N:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:12]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1cccc(-n2cnc(C(=O)O)c2)n1
Product: Cc1cccc(-n2cnc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)c2)n1
Yield: 55.3 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (0.190 g, 0.933 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.2 g, 0.718 mmol). The product was purified by recrystallization from acetonitrile. Yield 55.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 2.53 (s, 3H), 4.31-4.52 (m, 3H), 7.01 (d, 1H), 7.29 (d, 1H), 7.72 (d, 1H), 7.87-7.96 (m, 3H), 8.02-8.04 (m, 1H), 8.35 (d, 1H), 8.40 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13]>COC(OC)N(C)C.C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:1][N:2]([CH3:11])[CH3:3])[C:3]1=[O:13]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Agent: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=C1C(=O)c2ccccc2N(C)C1=O

Procedure:
A suspension of 1-methyl-4-hydroxy-2(1H)-quinolinone (1.0 gm) in dimethyl formamide dimethyl acetal (5 ml) and methylene chloride (2.0) was refluxed for 1 hour. The resulting dark orange solution was evaporated under reduced pressure to give 1-methyl-3-dimethylaminomethylene-(1H)-quinolin-2,4-dione.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:3]([CH2:2][F:1])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC(CF)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC(CF)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-fluoromethyl-2-phenylethanol (1.0 g, prepared as described by Bergmann, et al., J. Chem. Soc., 1961, 3448-3452) in DCM (30 mL) at 0° C. under nitrogen was added triethylamine (1.36 mL) followed by dropwise addition of methanesulfonyl chloride (0.6 mL). The mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 1.3 g of the title compound. MS CI, (M++H)=233, (M++H −CH3SO3H)=138.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ccc(Br)cn1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine and 5-bromo-2-ethynylpyridine. Yield: 1.00 g (62% of theoretical); C21H23BrN2O (M=399.324); calc.: molpeak (M+H)+: 399/401 (Br); found: molpeak (M+H)+: 399/401 (Br); HPLC-MS: 4.64 minutes (method A).
Reaction SMILES: C(#N)C.[C:4]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:23][CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[Br-:23].[C:28]([C:27]([F:32])([F:31])[CH2:26][CH2:25][CH2:24][P+:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)C(F)(F)CCCBr
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(O)C(F)(F)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 5 °C
Reaction time: 30 h
Yield: 96.5 %

Procedure:
Acetonitrile (23 ml) was added to a mixture of triphenylphosphine (6.7 g, 25.7 mmole) and Part (6) compound (4.6 g, 21.2 mmole). The solution was heated at gentle reflux under magnetic stirring for 30 hours. Toluene (46 ml) was then added and the reaction was brought to reflux for a brief period. The reaction was allowed to cool to 5° C. and kept overnight. The resulting white precipitates were collected, washed with cold acetonitrile/toluene (1/2), and dried in a heated vacuum oven (60° C.~5 mmHg) to give the title bromide (9.8 g, 20.4 mmole, 96.5%) as white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:33])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:28]5[O:29][CH2:30][O:31][C:27]=5[C:26]([C:32]([NH:34][CH:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[O:33])=[CH:25][CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c3c2OCO3)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c3c2OCO3)CC1
Temperature: 160 °C

Procedure:
To 2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 7-amino-N-(1-methylpiperidin-4-yl)benzo[d][1,3]dioxole-4-carboxamide (Intermediate 223; 98 mg, 0.35 mmol) in 4-methyl-2-pentanol (3 mL) was added p-toluenesulphonic acid monohydrate (139 mg, 0.73 mmol) and the reaction mixture heated at 160° C. by microwave irradiation for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14]#[N:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14](=[O:25])[NH2:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=CC#N)CN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=CC(N)=O)CN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
5.4 g of 7-chloro-1-methyl-2-cyanomethylene-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine are introduced portion-wise into 26 ml of concentrated sulfuric acid and are dissolved therein while the mixture is slowly heated-up to a temperature of 50° C. The solution is kept at a temperature of 50° C. for 1 more hour. For working-up after cooling the solution is poured onto ice, the sulfuric acid is neutralized with diluted sodiumhydroxide solution and the raw product is extracted with methylenechloride. The organic phase is separated, washed with water to neutral reaction and dried over sodium sulfate. After filtration and evaporation of the solvent under vacuum, a residue is obtained and is crystallized by trituration with ether. After re-crystallization from ethanol, 7-chloro-1-methyl-2-carbamoylmethylene-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine, having a melting point of 212° to 217° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O.Cl>CN(C)C=O>[Cl:11][C:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[N:9][OH:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccnc1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
Dissolve 2-chloropyridine-3-carboxaldehyde oxime (2.50 g, 0.016 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.14 g, 0.016 mol) in small portions along with a small amount of gaseous hydrochloric acid. Stir for 3 hours. When TLC analysis indicates the reaction to be complete, pour into ice/water. Extract with diethyl ether and wash the combined extracts with water and dry over sodium sulfate. Concentrate the extracts to give 3.00 g (98%) of crude product as an off white solid. MS(FD): (M)+ 190.0, 192.0 m/z.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C-]#N.[Na+].CS(C)=O.C(Cl)(Cl)Cl>O>[C:4]1([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1C=CC(=O)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
10 g of methoxy chalcone and 2.05 g of sodium cyanide are dissolved into 100 ml of dimethyl-sulfoxide, and then reacted during 24 hours. After the reaction, the reacted solution is mixed with chloroform and stirred together with distilled water so as to extract impurities. After removing the solution phase, the solution is decompressed at a room temperature in order to eliminate chloroform. After recrystallizing the remained solid phase in methanol, the solution is dried under vacuum, thus obtaining 4-hydroxychalcone for photoreaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)=[O:22]>>[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-aminoacetophenone gave the tide compound as an off-white solid, mp 191-194° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][CH2:22]4)=[CH:15][N:14]3[CH:24]=2)=[CH:7][CH:6]=1)(=O)C.[F:25]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F.C(=O)([O-])O.[Na+]>C(#N)C>[CH:21]1([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:24]([F:25])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=4)[N:12]=3)[CH:15]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)Oc1ccc(-c2cn3cc(OCC4CC4)ccc3n2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(-c2nc3ccc(OCC4CC4)cn3c2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
A mixture of 4-[6-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-2-yl]phenyl acetate (425 mg), 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (1.25 g) and acetonitrile (6 mL) was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the obtained compound was dissolved in methanol (6 mL). 1M Aqueous sodium hydroxide solution (0.66 mL) was added at room temperature, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the mixture was neutralized with 1M hydrochloric acid, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-brown powder (54 mg).
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][NH:10][C:11]2=[O:17].Cl[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CC(O)=O>[CH3:16][C:15]1[C:6]([O:5][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:17])[NH:10][CH:9]=[CH:8]2
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(=O)[nH]ccc23)n1
Temperature: 130 °C

Procedure:
DMSO (65 mL) was added to a vial containing 5-hydroxy-6-methylisoquinolin-1(2H)-one (5.50 g, 31.4 mmol) and 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (6.93 g, 31.4 mmol). Cesium carbonate (30.7 g, 94.2 mmol) was added to the vial, and the vial was sealed and heated to 130° C. for 16 hours. The vial was allowed to cool to ambient temperature and the mixture was diluted with water (˜1 L) and neutralized with AcOH. The precipitate was filtered to afford 6-methyl-5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)isoquinolin-1(2H)-one. MS (M+H)+ 360.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:24])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CI
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A suspension of 4.00 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)-ethyl]dihydrofuran-2-(3H)-one (Example 11f)) in 240 ml of DMF/dioxane, 1:1, is reacted, under an N2 atmosphere, with 8.1 g (24.88 mmol) of Cs2CO3 and 0.77 ml (12.44 mmol) of methyl iodide. After 18 h, the reaction mixture is poured onto 190 ml of ice-water, and this mixture is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring with hexane in an ultrasonication bath affords the title compound: TLC Rf (C)=0.43; tRet (II)=13.5 min; FAB-MS (M+H)+ =336.