Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Br:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[N:17][C:18]=1[CH3:19].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([N:20]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:16]=[N:17][C:18]=1[CH3:19]
Reactant: Cc1ncc(N)cc1Br
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C

Procedure:
A mixture of phthalic anhydride (3.7 g, 25 mmol), 5-bromo-6-methylpyridin-3-amine (3.9 g, 20.85 mmol) and sodium acetate (1.5 g, 25 mmol) in glacial acetic acid (44 ml) was refluxed for overnight. After cooling down to room temperature, the precipitate was collected by vacuum filtration, washed with water, and dried to afford the title compound. MS (m/z) 318.91 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([OH:16])=[O:15])=[CH:6]2.[ClH:17]>C(OC(=O)C)(=O)C>[ClH:17].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]([C:14]([OH:16])=[O:15])[CH2:6]2
Reactant: COc1cc2cc(C(=O)O)[nH]c2cc1OC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)NC(C(=O)O)C2
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The suspension of 10.8 g of 5,6-dimethoxyindole-2-carboxylic acid in 150 ml of acetic anhydride is heated at the steam bath for 15 minutes and the mixture evaporated at 65°-70°. The residue is added to the mixture of 30 g of sodium bicarbonate and 200 ml of water and the mixture heated at the steam bath for 20 minutes. It is filtered, cooled and acidified with concentrated hydrochloric acid, filtered again and the residue suspended in 300 ml of methanol. The suspension is hydrogenated overnight in the presence of 1 g of platinum oxide at room temperature and atmospheric pressure. Removal of the catalyst and evaporation of the solvent yields the crude 1-acetyl-5,6-dimethoxyindoline-2-carboxylic acid. Hydrolysis in 90 ml of 2N hydrochloric acid under reflux overnight, washing with diethyl ether and evaporation of the aqueous solution yields the hygroscopic 5,6-dimethoxyindoline-2-carboxylic acid hydrochloride. It is esterified with ethanolic hydrogen chloride at room temperature for 3 hours to give the 5,6-dimethoxyindoline-2-carboxylic acid ethyl ester showing IR-bands at 3500 and 1740 cm-1.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:30][CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:34][CH:31]([NH:30][C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[O:29])=[CH:15][CH:14]=3)[N:10]=2)[CH2:32]1
Reactant: Cc1ccc(NC(=O)Nc2ccc(-c3nc(NC4CN(C(=O)OC(C)(C)C)C4)nc(N4CCOCC4)n3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(NC4CNC4)nc(N4CCOCC4)n3)cc2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-methyl-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 130 mg (0.23 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 40 (37%); (M+H) 461.5.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][C:4]([O:6]C)=O.[Na]>CO>[CH3:10][O:9][C:1]([CH:2]1[C:4](=[O:6])[CH2:3][CH:2]([C:1]([O:9][CH3:10])=[O:8])[C:4](=[O:6])[CH2:3]1)=[O:8]
Reactant: COC(=O)CCC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Temperature: 76 °C
Yield: 81 %

Procedure:
To a stirred solution of dimethyl succinate (400.1 g., 98.7% purity, 2.7 mole) and dry methanol (13 g., 0.4 mole) at 30° C. under nitrogen is added over 1.5 hour a stirred slurry of finely divided sodium (22.1 g., 0.96 mole) in dimethyl succinate (83.4 g., 0.57 mole). The temperature rises to 45° C. maximum. The mixture is heated to 76° C. and the methanol stripped off over two hours. Additional dimethyl succinate is added (200 g., 1.38 mole) to maintain the fluidity of the reaction. On completion of methanol distillation, methanol is added (400 g., 12.5 mole) and the mixture cooled to 30° C., filtered and the excess dimethyl succinate washed out with dry methanol. The resulting filtercake is reslurried in methanol and added to 15% aqueous sulfuric acid (330 g.), cooled to 24° C. then filtered, washed with water to remove the sodium sulfate, and dried. A yield of 81% of theory dimethyl succinylsuccinate is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:40]([O:42][C:43]1[CH:62]=[CH:61][C:46]([O:47][CH:48]2[CH2:51][N:50]([C:52]3[CH:57]=[CH:56][C:55]([C@@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=3)[CH2:49]2)=[CH:45][CH:44]=1)[CH3:41]>CN(C=O)C>[CH2:40]([O:42][C:43]1[CH:62]=[CH:61][C:46]([O:47][CH:48]2[CH2:49][N:50]([C:52]3[CH:57]=[CH:56][C:55]([C@@H:58]([NH:60][C:6]([C:2]4([CH3:1])[CH2:3][CH2:4][CH2:5]4)=[O:8])[CH3:59])=[CH:54][CH:53]=3)[CH2:51]2)=[CH:45][CH:44]=1)[CH3:41]
Reactant: CC1(C(=O)O)CCC1
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)C4(C)CCC4)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 0.011 g (0.10 mmol) 1-methyl-cyclobutanecarboxylic acid in 1 mL DMF are added 0.035 mL (0.20 mmol) DIPEA and 0.032 g (49.1 mmol) TBTU. The mixture is stirred for 15 min at rt. Subsequently 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) are added and stirring is continued for 12 h at rt. The mixture is directly purified by HPLC to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N:5][C:4](=[O:7])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[C:12]([C:6]1[NH:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1=NC(=O)N=C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g of benzoyl chloride. The solution is warmed at 60° C. for 4 hours, poured over ice water, slurried with ether and the resulting solids filtered and dried to yield the title compound. M.P. 250°-54° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7](B(O)O)[CH:8]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2Br)[CH:27]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2[C:7]2[CH:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[CH:5][C:6]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:27]=1)[CH3:23]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using [5-trifluoromethyl-2-(benzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid and 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=O.Cl>CN(C)C=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=1)=[O:6])[CH3:9]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.3 g, 33.5 mmol) in dimethylformamide (50 mL) was added dropwise ethyl 2-mercaptoacetate (2.95 mL, 27 mmol) at 0° C. under an atmosphere of argon. After stirring at room temperature for 15 minutes, 2-chloro-5-nitrobenzaldehyde was added. The mixture was then stirred at 100° C. for 6 h, cooled to room temperature and poured into hydrochloric acid (250 mL, 1M). The precipitate was filtered off, washed with water (3×50 mL), dried under reduced pressure and recrystallised from ethyl acetate to give the title compound (5.5 g, 82%) as a solid, mp 163° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(S(=O)(=O)Cl)cc(C)c1F
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(=O)O)cc(C)c1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
4-Fluoro-3,5-dimethylbenzenesulphonyl chloride (5.56 g, 25 mmol) was added in portions to a solution of anhydrous sodium sulphite (6.0 g, 47.6 mmol) and sodium bicarbonate (4.2 g, 50 mmol) in water (25 ml) at 70° C. with vigorous stirring. When the addition was complete, the mixture was heated and stirred at 70° C. for a further 2 hours. The mixture was allowed to cool. The solid which crystallised from the solution was collected by filtration, dissolved in the minimum amount of water, and acidified to pH 1 with 2M hydrochloric acid. The resultant precipitate was extracted with ethyl acetate (3×75 ml) and the extracts were combined and dried (MgSO4). The solvent was evaporated. The solid residue was triturated with ether, collected by filtration, washed with ether and dried in vacuo to give 4-fluoro-3,5-dimethylbenzenesulphinic acid (4.7 g). This was converted directly to its sodium salt by addition to a solution of sodium methoxide (1 equivalent) in methanol and evaporation of the solution.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([CH3:24])=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:20]([CH3:24])=[CH:19][N:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 40.0 mg, 1.00 mmol) in 2 mL of DMF at room temperature was added 1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3 portions. After 30 minutes of stirring at room temperature, 2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added as a solution in 1 mL DMF. The reaction mixture stirred for 3 h at room temperature. The reaction was quenched with saturated sodium bicarbonate solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane) to afford the desired compound as an off-white solid (78 mg, 24% yield). MS/ES+: m/z=326.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccc1
Reaction time: 5 h

Procedure:
To a solution of benzyl cyanide (4.93 mL, 42.7 mmol) in CCl4 (275 mL) were added dibenzoyl peroxide (517 mg, 2.13 mmol) and N-bromosuccinimide (9.12 g, 51.2 mmol). The reaction mixture was heated to reflux and stirred for 5 hours and concentrated in vacuo to a volume of 100 mL. The solution was partitioned between CHCl3 and saturated NaHCO3 solution, and the aqueous layer was extracted with several portions of CHCl3. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford a yellow oil. Purification was achieved by flash column chromatography on silica gel using a gradient elution of 0-20% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the title compound as a pale yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.61-7.58 (m, 2H), 7.53-7.45 (m, 3H), 6.59 (s, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[Cl:17])[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc(CSc2cn3ccsc3n2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1c(SCc2ccccc2)nc2sccn12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
6-Benzylthioimidazo[2,1-b]thiazole (2.0 g) is dissolved in a mixture of 8 ml of dichloromethane and 40 ml of carbon tetrachloride. N-Chlorosuccinimide (1.2 g) is added to the solution during 10 minutes and stirred for an hour at room temperature. The insoluble product is filtered off and the filtrate is purified by silica gel chromatography (eluent: ethylacetate) to give 2.0 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1([C:15]#[N:16])[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C(Cl)Cl.CO.[NH4+].[OH-]>>[NH2:16][CH2:15][C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: N#CC1(N)CCCN(Cc2ccccc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: NCC1(N)CCCN(Cc2ccccc2)C1

Procedure:
This material was obtained in analogy to example 65, step A] from known 3-amino-1-benzyl-piperidine-3-carbonitrile (CAS 153931-24-9, 1.23 g) by reduction with diisobutylaluminiumhydride (20% in toluene, 14.2 mL) as a colorless glass (458 mg) after silica gel chromatography (DCM/methanol/NH4OH 9:1:0.1). MS (ESI): 220.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(Cl)Cl>[C:11]1([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccn1
Reactant: Clc1ccnc2scc(-c3ccccc3)c12
Solvent: ClCCl
Product: c1ccc(-c2csc3nccc(NCc4ccccn4)c23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-3-phenyl-thieno[2,3-b]pyridine (47 mg, 0.19 mmol) and 2-aminomethyl pyridine (0.5 ml, 4.85 mmol) were placed in a 10 ml glass tube. The vessel was sealed with a septum and placed in the microwave cavity. Using microwave irradiation the temperature was ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 90 minutes. After cooling to room temperature, the temperature was ramped to 200° C. and held at this temperature for 30 min. After cooling, the reaction mixture was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give (3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine. Yield=14 mg, 23%.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:20]#[C:21][C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.[NH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.O>[CH:37]1[C:38]2[CH:26]([NH:25][C:22](=[O:24])[C:21]#[C:20][C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(C#CC(=O)O)ccc1-n1cnc(C)c1
Reactant: NC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C#CC(=O)NC2c3ccccc3-c3ccccc32)ccc1-n1cnc(C)c1
Yield: 37.1 %

Procedure:
A DMF (2 mL) solution of [3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propiolic acid (74 mg) and 9-aminofluorene (65 mg) and BOP (133 mg) and N,N′-IPEA (77 μL) was agitated at room temperature overnight. Water and chloroform were added to the reaction solution, the organic layer was partitioned and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex NH, elution solvent:heptane-ethyl acetate system), and 45 mg of the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C@@H:12]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH3:22]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:20]([O:18][CH2:17][C@@H:14]1[CH2:15][CH2:16][C@H:12]([C:10]2[O:9][N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:11]=2)[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: OC[C@H]1CC[C@@H](c2nc(-c3ccncc3)no2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CCCOC[C@@H]1CC[C@H](c2nc(-c3ccncc3)no2)C1

Procedure:
cis-[3-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclopentyl]methanol (Preparation 5) was reacted with 1-bromopropane in the presence of tetrabutylammonium iodide, using a similar procedure to that described in Example 106, to afford the title compound: RT=3.69 min, m/z (ES+)=288.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in hexanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>CC(N(C)C)=O>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[CH2:21][CH2:22]1)[CH3:11]
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3cc(C)nc(N)n3)CC2)ccc1OC
Yield: 11 %

Procedure:
A solution of 4-chloro-6-methyl-pyrimidin-2-ylamine (21.5 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 40 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 6.1 mg (11%) of the title compound. MS (ISP): 372.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(Oc2ccccc2Cl)c1O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)cccc1Oc1ccccc1Cl

Procedure:
A mixture of 6-(2-chlorophenoxy)-o-cresol (0.3 g), acetic acid (5 ml) and acetic anhydride (5 ml) was refluxed under heating for 7 hours. The reaction mixture was evaporated, and the oily residue was dissolved in diethyl ether, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and then evaporated to give oily 2-chlorophenyl 2-acetoxy-3-methylphenyl ether (0.4 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:31]=[C:30]([NH2:32])[NH:29][N:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:10][C:3]1([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:32][C:30]2[NH:29][N:28]=[C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:34])[F:33])=[CH:20][N:19]=4)[CH2:22][CH2:23]3)[C:31]1=2
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(C(F)(F)F)cn4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a solution of 3-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1H-pyrazol-5-amine (880 mg, 2.83 mmol) produced in Reference Example 10 in acetic acid (10 mL), and the mixture was stirred at 60° C. for 2 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol=100/0-96/4 (gradient)] and further purified by silica gel column chromatography [elute: hexane/ethyl acetate=60/40-0/100 (gradient)] to obtain the title compound (610 mg, yield: 48%).