Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si]([N:24]=[N+:25]=[N-:26])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO>[NH:17]1[C:16]([CH2:15][NH:14][CH2:13][C:12]2[CH:18]=[CH:19][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:26][N:25]=[N:24]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCCCCCc1ccc(CNCC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CNCc2nnn[nH]2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me3SiN3 (0.36 ml; 2.71 mmol) and 1M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 75±5° C. for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et2O and dried to give a title compound (0.069 g; 84%) as colourless solid. 1H-NMR (CD3OD) 7.32 (d, 2H, J=8.0 Hz); 7.21 (d, 2H, J=8.0 Hz); 4.72 (s, CD3OH); 4.34 (s, 2H); 4.16 (s, 2H); 2.59 (t, 2H, J=7.76 Hz); 1.57 (t, 2H, J=7.19 Hz); 1.25 (m, 10H); 0.84 (t, 3H, J=6.93 Hz);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH3:32])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].Cl.CO[C:32]1C=C(C2C(C)(CCC)C(=O)N(C3CCNCC3)N=2)C=C[C:37]=1OC.ClCC(OC(=O)CCl)=O>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH2:17][CH2:32][CH3:37])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for A1 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B8) and chloroacetic anhydride as starting compounds.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN(C)[CH:22]=[C:23]([F:26])[CH:24]=O.FC(F)(F)C(O)=O>O1CCOCC1>[F:26][C:23]1[CH:22]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]2=[N:1][CH:24]=1
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Reactant: CN(C)C=C(F)C=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Reaction time: 72 h

Procedure:
13.487 g (51.228 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for example 20A in WO 00/06569) were initially charged in 300 ml of dioxane, and 6 g (51.228 mmol) of 3-(dimethylamino)-2-fluoroacrylaldehyde (preparation described in Justus Liebigs Annalen der Chemie 1970; 99-107) were added at RT. Subsequently, 4.736 ml (61.473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux while stirring for 3 days. After cooling, the mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were subsequently extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (22 g) was subsequently purified by chromatography on silica gel (eluent: dichloromethane). This gave 5.67 g (35% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.O[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:17][N:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)sc2C)no1
Reaction time: 72 h
Yield: 46.1 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolylmethanol (0.80 g), methyl 2-(2-hydroxyphenyl)acetate (0.45 g), tributylphosphine (1.05 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g) at room temperature and the mixture was stirred for 3 days. The precipitated crystals were filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (0.55 g, 47%) of methyl 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29].Cl>CN(C=O)C.CCCCCC>[CH2:28]([O:27][C:26]([N:7]([C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])[C:5](=[O:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:30])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: C=CCC(CCCCCC)C(=O)N[C@H](C)c1cccc(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCC(CCCCCC)C(=O)N(C(=O)OCC)[C@H](C)c1cccc(OC)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 0.40 g (1.3 mmol) of N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine (diastereomer ratio (1R,2S):(1R,2R)=77:23) in 2 ml of DMF was added to a solution of 151 mg (3.8 mmol) of sodium hydride in 2 ml of DMF at room temperature, and the reaction was allowed to proceed at 50° C. for 1 hour. To the reaction mixture was added 0.48 ml (5.0 mmol) of ethyl chlorocarbonate, and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added dropwise to a mixed solution composed of 5 ml of a 1 N aqueous solution of hydrochloric acid and 5 ml of hexane with ice cooling, and the resulting mixture was extracted with two 20-ml portions of hexane. The organic layer was washed with 5 ml of a saturated aqueous solution of sodium chloride and concentrated under reduced pressure to give 0.49 g of a crude product. The crude product was purified on a silica gel column (ethyl acetate:hexane=20:1) to give 0.224 g of the title compound as a colorless oil (yield 46%, (1R,2S):(1R,2R)=77:23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([OH:13])=[CH:11][CH:10]=[N:9][C:8]=12)([O-])=O.C1CCCCC=1.[ClH:20]>[Pd].C(O)(=O)C>[ClH:20].[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:12]([OH:13])=[CH:11][CH:10]=[N:9][C:8]=12
Reactant: O=[N+]([O-])c1cnn2c(O)ccnc12
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1=CCCCC1
Product: Nc1cnn2c(O)ccnc12

Procedure:
0.35 g of 3-nitropyrazolo[1,5-a]pyrimidin-7-ol, 20 cc of acetic acid, 1.6 g of cyclohexene and 85 mg of 10% palladium-on-charcoal were introduced into a 50 cc 3-necked round-bottomed flask fitted with a magnetic stirrer and equipped with a condenser and a thermometer. The medium was refluxed for 1h30' and the catalyst was then filtered off through Celite. After evaporation of the acetic acid, the solid obtained was taken up in 2 cc of refluxing concentrated hydrochloric acid for 2 h 30'. After evaporation of the solvent, an off-white solid was collected.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([O:33]C)=[C:9]2[C:22](=[CH:23][CH:24]=1)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:14]([O:25]C)=[C:13]([O:27]C)[C:12]([O:29]C)=[C:11]([O:31]C)[C:10]2=1.O>ClCCl>[OH:6][C:7]1[C:8]([OH:33])=[C:9]2[C:22](=[CH:23][CH:24]=1)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:14]([OH:25])=[C:13]([OH:27])[C:12]([OH:29])=[C:11]([OH:31])[C:10]2=1
Reactant: COc1ccc2c3ccccc3c3c(OC)c(OC)c(OC)c(OC)c3c2c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c3ccccc3c3c(O)c(O)c(O)c(O)c3c2c1O
Temperature: 25 °C

Procedure:
Boron tribromide (8.6 g, 0.034 mol) in dry dichloromethane (80 ml) was added to hexamethoxytriphenylene (2 g, 0.0049 mol) in dry dichloromethane (100 ml) under a dry nitrogen atmosphere at -80° C. The mixture was allowed to warm to room temperature overnight. Water was added and the dichloromethane was removed under reduced pressure. The crude product was filtered off. The hexahydroxytriphenylene was purified by recrystallisation from water.
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([NH:36][C:37]([NH:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=Nc1ccccc1
Agent: CC[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride mono-ethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 1.37 mL (12.6 mMol) phenyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.40 gm (70%) N-phenyl-N′-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea. This material was dissolved in methanol and to it was added an equivalent of methanolic hydrogen chloride. The solution was then concentrated under reduced pressure and the residual oil crystallized from ethanol to give the title compound.
Reaction SMILES: [Cl-].[NH4+:2].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=O>>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]#[N:2]
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: N#Cc1ccc(Cl)cc1Cl
Temperature: 230 °C
Yield: 699.5 %

Procedure:
The reaction was performed as in Example 1. The following reactants were charged to the reactor: 2,4-DCBTC (132.8 g, 0.5 mol), ammonium chloride (28.1 g, 1.05 eq), and 2,4-dichlorobenzoyl chloride (13.3 g). The mixture was heated at 230° C. for 14 h. Distillation of the reaction mixture gave pure 2,4-dichlorobenzonitrile (2,4-DCBN) (76.4 g, 89% yield, melting point: 59°-60° C.).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6]([CH3:12])[C:3]=1[CH2:4]Cl.[NH2:13][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:15].C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6]([CH3:12])[C:3]=1[CH2:4][NH:13][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:15]
Reactant: CCCCCC(C)N
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccccc1
Product: CCCCCC(C)NCc1c(C)c(C)cc(C)c1C

Procedure:
36.5 g (0.2 mol) of 2,3,5,6-tetramethylbenzyl chloride, 46.0 g (0.4 mol) of 2-aminoheptane and 100 ml of benzene are refluxed for 2 hours. The solvent is then removed in vacuo. A solution of 8 g (0.2 mol) of sodium hydroxide in methanol is then added to the residue to liberate the free base. The reaction product is separated from the precipitated sodium chloride by means of a suction filter, and the excess of 2-aminoheptane is removed by vacuum distillation. The 2-(2,3,5,6-tetramethylbenzyl)aminoheptane obtained is then treated with ethereal hydrochloric acid to convert it into the hydrochloride which is recrystallised from methanol/ethyl acetate. The melting point of the hydrochloride is 155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:26])=[C:6]([C:22]([F:25])=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.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(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[C:22]([F:25])=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:26])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:35]2)[CH2:30][O:29]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 94.8 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.837 g, 2.27 mmol) in N,N-dimethylformamide (50 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.559 g, 2.83 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.505 g, 3.40 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.732 g, 5.66 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (1.180 g, 95%) as a pale yellow solid: HR-ES-MS m/z calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2514, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.38-1.49 (m, 1H), 1.50-1.67 (m, 1H), 1.68-1.84 (m, 1H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 3.96-4.19 (m, 5H), 4.27 (d, J=18.7 Hz, 1H), 4.31-4.40 (m, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.7, 4.7 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.11-7.22 (m, 1H), 7.27 (dt, J=9.7, 1.5 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24](O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17].O>N1C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc2c(O)cccc2cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2c(OS(=O)(=O)C(F)(F)F)cccc2cc1Cl
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added at −20° C. under an atmosphere of argon to a solution of 3-chloro-8-hydroxy-naphthalene-2-carboxylic acid ethyl ester (1.82 g, 7.28 mmol) in pyridine (55 ml). After 1 hour at 0° C., an additional portion of trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added, and stirring was continued at 0° C. for another 1.5 hours. Cold water (4° C., 100 ml) was carefully added, and the reaction mixture was extracted with EtOAc (1 liter in total). The combined organic layers were washed with concentrated aqueous NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (slow gradient of hexane/EtOAc 100:0 to 90:10) afforded the title compound (2.45 g, 88%, inseparable 1:1.3 mixture of regioisomers A:B) as an oil. 1H NMR (400 MHz, CDCl3): δ=8.56 (s, 1H isomer B), 8.40 (s, 1H isomer A), 8.12 (s, 1H isomer A), 8.01 (s, 1H isomer B), 7.93-7.91 (m, 1H isomer A), 7.81 (d, J=8.6 Hz, 1H isomer B), 7.62-7.51 (m, 2H isomer A+2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A+2H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A+3H isomer B). 19F NMR (377 MHz, CDCl3): δ=−73.02. MS (ES+): 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1Cl
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of 5.734 g (13.1 mmol) 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol, and 14.83 g (65.6 mmol) tin chloride dihydrate was heated to reflux under N2. Removed heat at 2½ hours and added a large volume of ice water. Made basic with sodium bicarbonate and stirred for 2 hours. With mixture still basic, extracted with chloroform, stirred organic layer with Darco, dried with sodium sulfate and filtered. Stripped solvent and dried in vacuo, giving 2.86 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=407.3, 409.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>CN(C)C=O>[F:17][C:18]([F:20])([F:19])[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(F)(F)F)cc1
Yield: 84.1 %

Procedure:
According to Reference Example 8-2, by use of 4-methoxybenzaldehyde (500 mg, 3.67 mmol) dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (101 mg, 0.734 mmol) and (trifluoromethyl)trimethylsilane (1.09 mL, 7.34 mmol), the mixture was stirred and reacted at room temperature, at 80° C. for 7 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol (Compound CJ) (636 mg, yield: 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reaction time: 6 h
Yield: 98.5 %

Procedure:
Dissolve 4-bromo-2,6-dimethyl-phenol (20.1 g, 100 mmol) in DMF (250 mL) under nitrogen. Add cesium carbonate (48.9 g, 150 mmol) and benzyl bromide (13.1 mL, 110 mmol) and heat at 70° C. stirring mechanically for 6 h. Dilute with water (400 mL) and extract with 3/1 diethyl ether/hexanes (2×400 mL). Wash combined organics with brine (300 mL) and then dry (MgSO4), filter and concentrate in vacuo to give 28.67 g (99%) of the title compound as an oil which solidified on standing. 1H NMR(CDCl3): δ7.51-7.37 (m, 5H), 7.22 (s, 2H), 4.82 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:33])[N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:48][C:49]1[CH2:53][O:52][C:51](=[O:54])[CH:50]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:33])[N:27]3[CH2:28][CH2:29][N:30]([CH2:48][C:49]4[CH2:53][O:52][C:51](=[O:54])[CH:50]=4)[CH2:31][CH2:32]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC(=O)N2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: O=C1C=C(CBr)CO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C=C(CN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.19 mmol) in DMF (3 mL) was added DIEA (48.8 mg, 0.38 mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (66.4 mg, 0.38 mmol). The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (34.0% up to 39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 53.4 mg (45%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-dihydrofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24) [M+H]+=627.1, RT=1.55 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.2, 7.0 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.12 (s, 1H), 5.25 (s, 2H), 4.91 (s, 2H), 3.51 (t, 4H, J=5.4 Hz), 3.41 (s, 2H), 2.50-2.40 (m, 4H).