Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH:11]([OH:13])[CH3:12].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH:11]([O:13][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:12])[CH3:10]
Reactant: CC(C)O
Reactant: N#Cc1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ncccc1C#N
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
A mixture of 2-chloronicotinonitrile (1.0 g, 7.2 mmol), 2-propanol (0.87 g, 14.4 mmol), KOH (0.81 g, 14.4 mmol) and 18-crown-6 (1.8 g, 2.89 mmol) in toluene (30 mL) was stirred at 60° C. for 16 h. The reaction mixture was quenched with water and the organic phase was separated and then washed with water (×5). The organic phase was dried over Na2SO4 and concentrated to yield crude 2-isopropoxy-nicotinonitrile (1.1 g, 94%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:26])[CH2:13][N:14](C(OCC2C=CC=CC=2)=O)[CH3:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:26])[CH2:13][NH:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CN(C)C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=O)CNC)CC1
Reaction time: 12 h

Procedure:
To a solution of 830 mg 4-[2-(Benzyloxycarbonyl-methyl-amino)-acetyl]-piperazine-1-carboxylic acid ethyl ester in 30 ml ethanol were added 100 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 490 mg colorless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](B(O)O)=[C:8]([O:15][CH3:16])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:18]3[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]4[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]4)=[CH:20][CH:19]=3)=[C:8]([O:15][CH3:16])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(-n2ccnc2)ccc1B(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-n2ccnc2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
To a microwave vial was added (4-(1H-imidazol-1-yl)-2-methoxyphenyl)boronic acid (120 mg, 0.55 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-1 (156 mg, 0.55 mmol), potassium phosphate (351 mg, 1.65 mmol), Pd2(dba)3 (25.2 mg, 0.028 mmol), and SPhos (22.6 mg, 0.05 mmol), followed by addition of 1,4-dioxane (2 mL)/H2O (0.5 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 100° C. in the microwave for 40 min. The reaction mixture was concentrated in vacuo and adjusted to pH 3 by 1 M HCl aqueous solution, then loaded on an SCX column. The column was washed with methanol and eluted with 2 N NH3 in methanol. The product-containing fractions were concentrated to afford 6-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine (90 mg, MS: 421.4 [M+H+]).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(Cl)CCl.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>C(Cl)Cl>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:29]
Reactant: Cc1ccc(-c2cccnc2)cc1-c1ccc(N)cc1
Reactant: Cc1cnccc1C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cnccc1C(=O)Nc1ccc(-c2cc(-c3cccnc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
Amide Coupling Reaction: To a solution of 2′-methyl-5′-(pyridin-3-yl)biphenyl-4-amine n (40 mg, 0.15 mmol) in DCM (3 mL) was added EDC (85 mg, 0.45 mmol) and 3-methylisonicotinic acid (40 mg, 0.3 mmol). The solution was stirred at room temperature for 6 hr before it was concentrated and chromatographied to give Compound 20 (50 mg, 88%).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.[OH-].[Na+]>CS(C)=O.O>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)([C:3](=[O:6])[CH2:4][CH3:5])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: CCC(=O)C(O)c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)C(O)(Cc1ccc(C)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Hydroxy-1-(4-morpholinophenyl)-butan-2-one, one equivalent of 4-methylphenylmethyl bromide and 1.2 equivalent of sodium hydroxide are suspended in dimethyl sulfoxide and the resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with the same amount of water and extracted several times with dichloromethane. The combined organic extracts are dried over sodium sulfate and evaporated to give crude 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one as a viscous oil. The compound is purified by chromatography on silica gel (eluant: hexane/ethyl acetate 9:1). Pure 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one is thus obtained as colorless crystals with a melting point of 160° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 15 μL (0.11 mmol) benzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:23][CH2:24][CH3:25].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:11][C:10]=3[N+:9]([O-:35])=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1nc2cnc3cc(OC4CCOC4)ccc3c2n1CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3cc(OC4CCOC4)ccc3c2n1CC(C)C
Yield: 51.3 %

Procedure:
The method described in Part M of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol) with mCPBA (1.07 g, 3.72 mmol). The crude product was purified by column chromatography on silica gel to afford 0.588 g of 1-(2-methylpropyl)-5-oxido-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)C.C(O)(=O)C.C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8]2[NH:18][C:12]3[C:17]([CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
1-(5-bromo-2-hydroxyphenyl)ethanone (7.1 g, 33 mmol) and phenylhydrazine (4.3 g, 40 mmol) were stirred in 45 mL of dry ethanol. Acetic acid (27 drops) was added and the mixture was refluxed for 5 hours. After cooling to room temperature, the precipitates were collected by filtration to provide the crude product as a light yellow solid, which was stirred in 100 mL of xylene and 50 g of polyphosphoric acid at 85° C. for 8 hours. Water was added to the warm crude, and then the mixture was stirred for 10 minutes before poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (petroleum ether:EtOAc=10:1) provided 4-bromo-2-(1H-indol-2-yl)phenol as a light yellow powder (2.1 g, 22.1%). 1H-NMR (CDCl3, 400 MHz) δ 10.08 (s, 1H), 9.56 (s, 1H), 7.88 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.14˜7.19 (m, 2H), 7.08 (t, J=7.2 Hz, 1H), 6.8˜56.88 (m, 2H). MS (M+H)+: 288/290.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][CH:13](C(=O)C)[NH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Cl>ClCCl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH2:15][NH:14][CH2:13][CH2:12][C:11]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C1CCc2sc(-c3ccc(F)cc3)nc2N1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(-c2nc3c(s2)CNCC3)cc1

Procedure:
Prepared in analogy to example E (b) from 1-[2-(4-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4]pyridin-5-yl]-ethanone and hydrochloric acid. Chromatography (SiO2; dichloromethane/methanol 95:5) yields the title compound as a yellowish solid. MS (m/e): 235.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:21]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CC1
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CC1
Yield: 82 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (63 mg, 82%) which was obtained as an off white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH2:11][CH:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([CH2:20][C:21]#[N:22])[C:13]=2[CH3:23])[CH2:9][C:8](=[O:24])[C:7]=1[C:25](=[O:28])[CH2:26][CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[OH:5][C:6]1[CH2:11][CH:10]([C:12]2[C:13]([CH3:23])=[C:14]([CH2:20][C:21]#[N:22])[C:15]([CH3:19])=[C:16]([C:1](=[O:3])[CH3:2])[C:17]=2[CH3:18])[CH2:9][C:8](=[O:24])[C:7]=1[C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)C1=C(O)CC(c2c(C)c(CC#N)c(C)c(C(C)=O)c2C)CC1=O
Temperature: 0 °C

Procedure:
Acetyl chloride (1.34 g, 17.0 mmol) was added to an ice cooled mixture of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (2.65 g, 8.15 mmol) and aluminium chloride (4.15 g, 33.4 mmol) in carbon disulfide (100 ml). The mixture was refluxed for 4 h, cooled and added cautiously to 10% hydrochloric acid (50 ml) and ice (50 ml). The organic solvent was allowed to evaporate from the mixture then the aqueous layer was extracted with ethyl acetate, the organic extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with an increasing gradient of ethyl acetate in methylene chloride). After an initial fraction of unreacted starting material, 3-hydroxy-2-propionyl-5-(3-acetyl-5-cyanomethyl-2,4,6-trimethyl phenyl)cyclohex-2-en-1-one was obtained as a colourless solid (1.5 g, 50%), which was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.12 (3H,t); 2.23 (3H,s); 2.25 (3H,s); 2.47 (6H,s); 2.4-4.1 (7H,m); 18.08 (1H,s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NCC(O)=O)(OC(C)(C)C)=O.C(O)C1C=CC=CC=1>>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: OCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldrich) using General Procedure X, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=167.5° C.). The reaction was monitored by tlc (Rf=0.35 in 2% MeOH/CH2Cl) and the product was purified by flash chromatography using 2% MeOH/CH2Cl2 as the eluent.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Reactant: Clc1ccc(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cnc2c(OCc3ccc(Cl)cc3Br)cccn2c1=O
Yield: 108.2 %

Procedure:
To 4.7 g of 9-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-3-carboxylic acid, ethyl ester, 7.2 g of 2-bromo-4-chlorobenzyl bromide and 200 ml of ethyl methyl ketone is added 3.3 g of anhydrous potassium carbonate. The mixture is stirred and heated under reflux for 18 hours, cooled and filtered. The filtrate is concentrated in vacuo to give 9.5 g of a viscous gum. This is dissolved in 100 ml of chloroform and the chloroform solution is washed with 60 ml of 5% aqueous potassium hydroxide. The chloroform solution is separated, washed with 25 ml of saturated aqueous sodium chloride, dried, and concentrated to give 7.4 g of a viscous gum. This gum is crystallized in 250 ml of 1:1 toluene-Skellysolve E to give 3.6 g of green crystals that sinter at 155° and melt at 162°-165°. A second recrystallization from 225 ml of 2-propanol gives the yellow crystalline named product, m.p. about 167°-169°. The yield is about 2.95 g.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[O:57][C:58]([F:61])([F:60])[F:59].[C:62]([O:66][C:67]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)=[O:68])([CH3:65])([CH3:64])[CH3:63].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:62]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[O:57][C:58]([F:61])([F:60])[F:59])[CH2:71][CH2:70]1)=[O:68])([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc([N+](=O)[O-])ccc2OC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A mixture of 0.048 g palladium(II)-acetate (0.214 mmol) and 0.133 g BINAP (0.214 mmol) in 7 mL toluene was heated to 60° C., stirred for 10 min. and the obtained suspension was added dropwise to a solution of 0.51 g 2-bromo-4-nitro-1-(trifluoromethoxy)benzene (1.783 mmol), 0.343 g tert.butyl-piperazine-1-carboxylate (1.842 mmol) and 0.232 g sodium tert-butoxide (2.414 mmol) in 8 mL of toluene. The thus obtained reaction mixture was treated at 130° C. for 1.5 h in a commercial microwave oven. The organic layer was washed with water, the aqueous phase was extracted with dichloromethane and the combined organic layers were extracted with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was further purified via silica gel chromatography using a ISCO Companion system (eluent cyclohexane-ethyl acetate 5-25%) to yield 0.413 g of product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[N:7][C:2]([N:1]5[CH2:28][CH2:29][CH2:30][S:31]5(=[O:33])=[O:32])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1

Procedure:
Using (6-amino-4-methylpyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.0 g) described in Preparation Example 141 and 3-chloropropane-1-sulfonyl chloride (0.69 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (636 mg) was obtained.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH2:8]Br>CN(C)C=O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH2:8][S:2][CH3:1]
Reactant: C[S-]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1CSC
Reaction time: 16 h
Yield: 92.3 %

Procedure:
Sodium thiomethoxide (0.469 g) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.5 g) in dimethylformamide (25 ml). The mixture was stirred for 16 h, solvent removed at reduced pressure and the residue dissolved in ethyl acetate and washed with water and brine, dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (1.2 g) as a yellow solid
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][C:7]1=[O:12].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C(OCC)(=O)C.O>C(O)C.N1CCCCC1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[S:8]1[CH2:9][C:10](=[O:11])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]1=[O:12]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCCN1C(=O)CSC1=O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCN1C(=O)CS(=Cc2ccccc2Cl)C1=O
Yield: 34.5 %

Procedure:
A solution of 400 mg of 3-(3-methoxy-n-propyl)-2,4-thiazolidinedione and 260 mg of 2-chlorobenzaldehyde in 4 ml of ethanol with one drop of piperidine was refluxed for 4 hours. The mixture was then worked up with ethyl acetate and water. The crude product was purified on a silica gel column (5% methanol in dichloromethane) to provide 200 mg of 1-(2-chlorophenylmethylene)-3-(3-methoxy-n-propyl)-2,4-thiazolidinedione. (P15 can also be obtained from Aldrich Chemical.).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH3:4].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.O>CN(C=O)C.CCOCC>[CH:22]1([CH2:21][N:6]2[C:7]3[C:12](=[C:11]([C:14]([F:17])([F:15])[F:16])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[CH2:3][CH3:4])[CH2:24][CH2:23]1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1
Reaction time: 0.05 h
Yield: 64.2 %

Procedure:
To a slurry of hexanes-washed NaH (0.0112 g, 0.279 mmol) in DMF (1 mL) at 0° C. was added a solution of 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0332 g, 0.139 mmol) in DMF (1 mL), dropwise over 3 min. The mixture was stirred 30 min and bromomethylcyclopropane (0.030 mL, 0.28 mmol) was added via syringe. The mixture was stirred 5 h at rt, diluted with Et2O, poured into water, and the layers were separated. The aqueous layer was extracted with Et2O (×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by RP-HPLC (C18 column, MeCN/H2O with 0.1% TFA), affording 0.0261 g of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.55-7.47 (m, 2H), 6.59 (s, 1H), 4.07 (d, J=6.4 Hz, 2H), 2.84 (q, J=7.4 Hz, 2H), 1.44 (t, J=7.5 Hz, 3H), 1.24-1.01 (m, 1H), 0.66-0.57 (m, 2H), 0.41-0.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: NCc1ccc(F)cc1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Yield: 52.3 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol) and 4-fluorobenzylamine (165 mg, 1.32 mmol) were dissolved in 20 mL THF, DIEA (0.45 mL, 2.64 mmol) was added dropwise, HATU (401 mg, 1.06 mmol) was added under ice-water-bath, reacted at room temperature for 4 h, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, the solid was separated with silica gel separation (dichloromethane:methanol=100:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(4-fluorobenzyl)pyrimidine-5-carboxamide 206 mg, yield 52%.