Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10]1)=[O:6]
Reactant: C=CC(=O)OC
Reactant: NCC1COc2ccccc2O1
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CC1COc2ccccc2O1
Reaction time: 16 h
Yield: 95 %

Procedure:
7.57 g (88 mmol) of acrylic acid methyl ester are added to a solution of 6.61 g (40 mmol) of 2-aminomethylbenzo-1,4-dioxan [J. Augustin et al., J. Med. Chem. 8, 446 (1965)] in 80 ml of methanol and the whole is stirred for 16 hours at 50°. After cooling, the reaction mixture is concentrated by evaporation in vacuo. 12.82 g (95%) of N,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-amine are obtained in the form of a reddish oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C)C=O.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>S(Cl)(Cl)=O>[CH2:15]([N:17]([CH2:18][CH3:19])[C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:16]
Reactant: O=C(O)c1ccccn1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A slurry of picolinic acid (10.2 g, 83.3 mmol) in 100 mL of thionyl chloride was stirred at ambient temperature for 10 min. Dimethylformamide (0.5 mL) was carefully added dropwise via a syringe. After 3 hours the mixture became a clear, homogeneous solution. Excess thionyl chloride and dimethylformamide were removed under reduced pressure. The residue was azeotroped 3× with dry toluene, dissolved in 100 mL of dichloromethane, cooled to 0° C. and treated dropwise with diethylamine (34.5 mL, 330 mmol) over a 12 minute period. The reaction mixture was stirred for 72 hours at ambient temperature and then filtered through a pad of Celite® filter aid. The filtrate was poured into 200 mL of water. The organic phase was collected and the aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic extracts were washed successively with 1N NaOH, water, and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by normal phase flash chromatography eluting with 100% ethyl acetate. Like fractions containing product were combined and concentrated under reduced pressure to give N,N diethylpicolinamide 14. (12.6 g, 70.8 mmol). 1H NMR (400 MHz, Chloroform-d) δ 8.47 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.71-7.62 (m, 1H), 7.45 (ddd, J=7.8, 1.9, 0.8 Hz, 1H), 7.27-7.17 (m, 1H), 3.46 (q, J=7.1 Hz, 2H), 3.26 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H). LCMS: (M+H)+, 179.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I-:11].[Na+].Cl[O-].[Na+]>>[I:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=C(O)c1cccc(O)c1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc(I)c(O)c1

Procedure:
3-Hydroxybenzoic acid (V) is iodinated in the presence of sodium iodide and of sodium hypochlorite in order to give 4-iodo-3-hydroxybenzoic acid (VI).
Reaction SMILES: N[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=[C:13]([CH2:17][CH2:18]C(O)=O)[C:14]([OH:16])=[O:15]>C(O)(=O)C.Cl.O>[C:17]1([CH2:13][C:14]([OH:16])=[O:15])[C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3][N:2]3[CH:18]=1
Reactant: NN1CCCc2ccccc21
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cn2c3c(cccc13)CCC2
Yield: 42.9 %

Procedure:
17 g of 1-amino-1,2,3,4-tetrahydroquinoline (preparation see Example 1B) and 20 g of 2-ketoglutaric acid were heated under reflux at a temperature of 80° C. for 2 hours in a mixture of 160 ml of acetic acid and 11.4 ml of concentrated hydrochloric acid. To work up the reaction mixture the solid residue which remained was taken up in water and extracted with ethyl acetate. The organic phase was separated and extracted with 20% strength aqueous sodium hydroxide solution. The alkaline (pH=9) aqueous phase was separated and acidified to pH=4 by addition of aqueous 10% strength hydrochloric acid solution, and a precipitate formed. The solution was extracted with ethyl acetate. The organic phase was evaporated. 10.6 g of crude 5,6-dihydro- 4H-pyrrolo-[3,2,1-ij]quinoline-1-acetic acid were obtained as a solid residue.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]([CH:37]3[CH2:38][CH2:39]3)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CBr)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OC(C)(C)C)c2)c1)C1CC1
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(tert-butoxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (96.1 mg) in DMF (3.31 mL) were added ethyl 3-(3-(bromomethyl)phenyl)-3-cyclopropylpropanoate (124 mg) and potassium carbonate (91 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (142 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:31])[CH:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.[B-](F)(F)(F)[F:38].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1>[C:3]([O:7][C:8](=[O:31])[C:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)([F:38])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(F)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (0.96 g, 24.0 mmol) in THF (75 mL) cooled to 0° C. was added a solution of di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (described above) (9.66 g, 23.0 mmol) in THF (150 mL) under nitrogen. The resulting orange solution was stirred at 4° C. for 15 minutes. DMF (225 mL) was added followed by Selectfluor (8.15 g, 23.0 mmol). The reaction was warmed to ambient temperature and stirred for 4 hours under nitrogen. The reaction was quenched with ammonium chloride solution and partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (2-20% ethyl acetate/hexanes) gave a mixture of starting material and product. This was resubjected to above reaction conditions and purified in a similar manner to give a pale yellow solid. 1H NMR (DMSO-d6) δ 8.21 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 4.33 (q, J=7.3 Hz, 2H), 1.44 (s, 18H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:10])[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CC(CC)CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)cc(N)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N)cc(NCCN2CCCCC2)c1
Yield: 80 %

Procedure:
3,5-Diaminobenzonitrile prepared from step A of example 19 (511 mg, 3.84 mmol), 1-(2-chloroethyl)piperidine hydrochloride (707 mg, 1 eq) and DIEA (1.97 mL, 3 eq) were refluxed in 50 mL of 2-methylbutan-1-ol for 24 h. The reaction mixture was then evaporated to give 751 mg of expected compound which was used in the next step without further purification. m/z (ESI) 245.3 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:4]([C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([CH:4]4[CH2:1][CH2:2][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(O)C1CCC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4-cyclobutanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (45.6% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.97, 6.97, 3.82-3.64, 3.57-3.49, 3.26, 2.43-2.27, 2.22-2.05 2.02-1.81, 1.50, 0.75, 0.46, 0.08. MS (ES+) m/z 358 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[N+:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])([O-:21])=[O:20]
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1C(C)(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Into a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condenser, addition funnel and cooling bath is placed 50 grams of 1,1,2,3,3-pentamethyl indane having the structure: ##STR36## in admixture with 100 grams of acetic acid. While maintaining the reaction mass at 25° C., 40 grams of fuming nitric acid is added over a period of 0.5 hour. The reaction mass is then stirred for a period of 6 minutes. Over a period of 10 minutes while maintaining the reaction mass at 20°-22° C., 10 grams of concentrated sulfuric acid is added to the reaction mass. The reaction mass is then heated to a temperature in the range of 26°-30° C. with stirring and maintained at that temperature for a period of four hours. At the end of the four hour period, the reaction mass is added to water and a solid is formed which precipitates out. The resulting crystals are washed with two 500 ml portions of water. The crystals melt at 99.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][C:11](=[O:13])[CH3:12])[C:7]([CH3:15])([CH3:14])[C:6]=2[CH:16]=1.[CH3:17][N:18](C)C=O.[C-]#N.[Na+]>O>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][C:11](=[O:13])[CH3:12])[C:7]([CH3:15])([CH3:14])[C:6]=2[CH:16]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: CC(=O)OC1Oc2ccc(Br)cc2C1(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(=O)OC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 3 h

Procedure:
The product from stage (a) (4 g), cuprous cyanide (1.8 g) and dimethylformamide (10 ml) were boiled under reflux with stirring for three hours. The mixture was then cooled, and a solution of sodium cyanide (4.5 g) in water (18 ml) was added. After stirring for 1 hour, the product was extracted into ether, the ethereal extract being washed with water (twice), dried over magnesium sulphate, and run down. Recrystallisation of the residue from ethanol gave 1.8 g of pure product, mp 140°-142° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([N:25]([CH3:26])[C:24]1[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:30]([O:32][CH3:33])=[O:31])=[CH:19][CH:18]=2)([CH3:29])[CH3:28]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 4-(trifluoromethyl)phenylboronic acid (273 mg, 1.44 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and water (3 drops), and the reaction mixture was stirred for 4 hours at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and then purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate as a light yellow solid (158 mg, 82%).
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.CC(OC)(C)C>CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:1])=[O:11])[CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous NH4OH (40%, 250 mL) was added dropwise at 0° C. to a suspension of 4-chloro-pyridine-2-carbonyl chloride (75 g, 533 mmol) in EtOAc. Upon addition, the temperature rose to 30° C. The mixture was stirred for 2 h at RT then kept at RT for 12 h without stirring. MTBE (250 mL) was added to the mixture and the resulting emulsion was filtered. The solid was washed with EtOAc. The MTBE/EtOAc layer was washed twice with water and once with 5% Na2CO3, then dried over MgSO4 and concentrated under vacuum. The resulting solid was suspended in EtOAc several times and filtered out to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:21][N:20]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Yield: 90.6 %

Procedure:
Prepared according to Method D Step A from (3-chloro-2-fluoro-phenyl)-(4-methoxyphenyl)-methanone (0.84 g, 3.2 mmol), hydrazine hydrate (1.0 mL, 32 mmol) and DMAP (0.39 g, 3.2 mmol) to give the product (0.75 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[N:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].ClC1C2C(=CC(O)=CC=2)N(C)C=1C1C=CC(O)=CC=1N(CC)CC>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26]
Reactant: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(OC)cc2n1C
Agent: CCN(CC)c1cc(O)ccc1-c1c(Cl)c2ccc(O)cc2n1C
Product: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(O)cc2n1C
Yield: 37.9 %

Procedure:
Synthesized from [2-(3-chloro-6-methoxy-1-methyl-1H-indol-2-yl)-5-methoxyphenyl]diethylamine (96 mg) according to an analogous synthetic method to Example 364 described below, 3-chloro-2-(2-diethylamino-4-hydroxyphenyl)-1-methyl-1H-indol-6-ol (37 mg) and 3-chloro-2-(2-diethylamino-4-methoxyphenyl)-1-methyl-1H-indol-6-ol (35 mg) were obtained.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:12][CH:11]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24]([CH2:25][O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:14][CH:15]=1)=[O:26])[CH3:29]
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of 60% sodium hydride was gradually added to 10 ml of a DMF solution of 666 mg of 3-[4-(hydroxymethyl)phenylcarbonyl]pyridine under ice cooling. The reaction solution was stirred at room temperature for 1 hour, then 0.4 ml of 2-bromoethyl acetate was added and the mixture was stirred under the same reaction conditions for 3 hours. After the reaction was completed, the reactive product was diluted with water, extracted with ethyl acetate, and the resultant product was washed with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the desired compound in an amount of 336 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]([C:16]([OH:28])([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](OC)=[O:18])=[N:14][N:15]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C@H:38]([N:40]=[C:41]=[O:42])[CH3:39])=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([C:16]1([C:13]2[NH:12][C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:15][N:14]=2)[O:28][C:41](=[O:42])[N:40]([C@@H:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH3:39])[C:17]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(O)(Cc1ccccc1)c1nnc(-c2cc(OC)cc(OC)c2)[nH]1
Reactant: C[C@@H](N=C=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2nnc(C3(Cc4ccccc4)OC(=O)N([C@H](C)c4ccc(F)cc4)C3=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate (7 mg) in 1 mL of THF was added NaOH (4 mg) and (R)-1-fluoro-4-(1-isocyanatoethyl)benzene (15 mg). The resulting mixture was stirred at ambient temperature overnight. The resulting mixture was diluted with ethyl acetate, and then quenched with water. The organic layer was concentrated and purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 30% to 100% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 517.2 (M+1). IC50 value=C rating.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[CH2:2]([O:4][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C
Yield: 86.3 %

Procedure:
A solution of potassium t-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in absolute ethanol (100 ml) and the reaction mixture heated in a sealed vessel at 170° C. for 20 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue dissolved in water (200 ml) and the solution acidified to pH 3 with hydrochloric acid and extracted with dichloromethane (4×200 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound (27.4 g, 41%) as a white solid. δ (CDCl3): 1.53 (3H, t), 4.69 (2H, q), 7.13 (1H, m), 8.37 (1H, d), 8.48 (1H, d).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14].I[CH3:16]>CN(C=O)C>[CH3:16][O:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:4]2[NH2:3]
Reactant: Nc1cccc2c(O)cccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c(N)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a stirred suspension of NaH (7.5 g, 188.0 mmol) in DMF (500 mL) was added a solution of 5-amino-1-naphthol (25.0 g, 157 mmol) dropwise at 0° C. After the addition, mixture was stirred for 30 min at 0° C. and for 1 h at RT. Then a solution of iodomethane (9.82 mL, 157 mmol) in DMF (25 mL) was added dropwise to the mixture at 0° C. and the reaction mixture was allowed to RT and stirred overnight. It was slowly quenched with ice and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford the title compound (23.0 g, 85%).
Reaction SMILES: [OH-].[K+].[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10](Cl)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[CH2:16]([OH:18])[CH3:17]>O>[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([O:18][CH2:16][CH3:17])[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cnn(C(C)(C)C)c(=O)c1C

Procedure:
(Method B): In a mixture of 25 ml of ethanol and 25 ml of water was dissolved 4.7 g of potassium hydroxide and the 5.0 g (0.025 mol) of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone was added thereto. The resulting mixture was stirred under reflux for 26 hours. After ethanol was distilled off, the reaction mixture was added with 100 ml of water and extracted with 100 ml of chloroform. The chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and free of solvent by distillation to give 5.2 g of a crude product. The crude product was recrystallized from 30 ml of hexane to give 4.5 g of 2-tert.-butyl-5-ethoxy-4-methyl-3(2H)-pyridazinone.