Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH2:25])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH:25][C:30](=[O:32])[CH3:31])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
1-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methanamine (0.1 g) was dissolved in THF (10 ml), and was added acetic anhydride (0.04 g) thereto. The mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure to give residual material which was purified by silica gel chromatography, to obtain the desired compound (63 mg) in a yield of 58%.
Reaction SMILES: CC1C=CC2C(=CC=C(OC(=O)C)C=2)C=1.[C:16]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([C:30](O)=[O:31])[CH:24]=[CH:23]2)(=[O:18])[CH3:17]>>[C:16]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([CH:30]=[O:31])[CH:24]=[CH:23]2)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Agent: CC(=O)Oc1ccc2cc(C)ccc2c1
Product: CC(=O)Oc1ccc2cc(C=O)ccc2c1
Reaction time: 2.4 h

Procedure:
The 2-methyl-6-acetyloxynaphthalene obtained in the first half of Example 1 was not recrystallized from acetic anhydride prior to oxidation, but was directly oxidized with molecular oxygen in the presence of the same catalyst as in Example 1 in the same reactor as in Example 1. The reaction time was 2.4 hours. After the reaction, the product was analyzed. The conversion of 2-methyl-6-acetyloxynaphthalene was 55.5 mole%, and the yield of 6-acetyloxy-2-naphthoic acid was 40.0 mole% (selectivity 72 mole%). At this time, 8.88 mole% of 6-acetyloxy-2-naphthaldehyde was formed.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH2:11])[C:6](=[CH:9][CH:10]=1)[O:7][CH3:8].[N:14]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][C:5]=1[NH:11][NH2:14]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1NN
Yield: 74 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-trifluromethyl-o-anisidine (V, R1=R2=H, R3=CF3), (22.7 g), NaNO2 (9.02 g), and SnCl2.2H2O (60 g). Workup gave 18.1 g (74%) of (2-methoxy-5-trifluoromethylphenyl)hydrazine which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ7.23 (d, J=2.0 Hz, 1 H), 7.05 (dd, J=8.2, 2.0 Hz, 1 H), 6.81 (d, J=8.3 Hz, 1 H), 3.89 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:8][CH:7]=1)=[O:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([OH:5])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(O)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 12 (1 g, 2.9 mmol) in MeOH (10 mL), Pd/C (10 wt %) was added and the mixture stirred at rt under H2 atmosphere. Upon completion of the reaction (monitored by LCMS), the mixture was filtered through celite and the filtrate evaporated to give a yellow oil which solidified upon standing. Calculated mass=345. Observed mass=345.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][Si](C)(C)C)[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[CH3:22].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[OH:1][C@H:2]1[CH2:6][C@@H:5]([CH3:7])[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[CH3:22]
Reactant: C[C@H]1[C@@H](O)C[C@@H](C[Si](C)(C)C)N1C(=O)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](O)[C@H](C)N1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 65.1 %

Procedure:
To a solution (12 mL) of benzyl (2S,3S,5S)-3-hydroxy-2-methyl-5-[(trimethylsilyl)methyl]pyrrolidine-1-carboxylate (222 mg) synthesized according to the method described in Journal of Organic Chemistry, vol. 59, pages 1958-1960 (1994), potassium tert-butoxide (130 mg) and 18-crown-6-ether (53 mg) in DMSO was added water (0.6 mL), and the mixture was stirred at 100° C. for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as colorless oil (yield: 112 mg, yield: 65%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([C@@H:11]([CH2:19][CH3:20])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([NH2:18])=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[N+:1]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:11]([CH2:19][CH3:20])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([NH2:18])=[N:14]2)=[CH:10][CH:9]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC[C@@H](C[C@H]1COC(N)=N1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H](C[C@H]1COC(N)=N1)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
To stirred nitric acid (9.5 ml, 65% conc.) at room temperature was added (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine (1.5 g, CAS 1043495-96-0) and the mixture was then heated at 60° C. for 3 hours. The mixture was then cooled in an ice-bath before being made basic by careful addition of 30% aq. sodium hydroxide solution. The resulting mixture was diluted with ethyl acetate/THF (1:1) and the phases were separated. The organic phase was washed with saturated brine, dried over sodium sulphate and concentrated in vacuo to give (S)-4-[(S)-2-(4-nitro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine (1.89 g, quant.) as a yellow solid. MS (ISP): 264.2 ([M+H]+).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[CH:9]=[C:8]([OH:15])[C:7]2=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:9]1[C:10]([C:12]2[C:6]([C:7](=[O:16])[C:8]=1[OH:15])=[CH:5][C:4]([F:3])=[CH:14][CH:13]=2)=[O:11]
Reactant: O=C1C=C(O)C(=O)c2cc(F)ccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(O)=C(Br)C(=O)c2ccc(F)cc21
Reaction time: 4 h

Procedure:
A solution of bromine (12.5 g), in chloroform (50 ml) was added to a stirred suspension of 6-fluoro-3-hydroxynaphtho-1,4-quinone (12.5 g; 0.065 mole) in chloroform (50 ml) over 15 mins. During the addition the mixture became a clear dark red solution. Stirring was continued for a further 4 hours and a yellow solid which had been deposited as crystals was filtered off, washed with ice-cold chloroform and dried. Yield 13.95 g (80%), mp 183° C. (CHCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
2,6-Dibromo-pyridine (1.2 g, 0.508 mmol), phenylboronic acid (0.620 g, 0.508 mmol) and sodium carbonate (2 M aq., 30 mL) were dissolved in MeOH (10 mL) and toluene (30 mL) and the solution was degassed with bubbling N2 (g). Tetrakis(triphenylphosphine)palladium(0) (0.172 g, 0.149 mmol) was added and the reaction was heated to 100° C. overnight. After cooling the reaction was submitted to standard aqueous workup and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:33]([SH:36])[CH:34]=[CH2:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:33]([S:36][C@:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:2][CH:3]=2)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]1)[CH:34]=[CH2:35]
Reactant: C=CCS
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 20 h
Yield: 22.1 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (3236 mg, 7.5 mmol) and prop-2-ene-1-thiol (834 mg, 9.00 mmol) in Acetonitrile (40 mL) was added Scandium(III) trifluoromethanesulfonate (369 mg, 0.750 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 20 h. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by Biotage column, eluted with 5%˜50% EtOAc-Hexane to afford a mixture of the diasteromers (2.88 g, 79%) and the starting material (0.600 g, 18%). This mixture of the diasteromers was purified by Biotage column again, eluted with 2%˜8% EtOAc-Toluene to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (900 mg, 1.661 mmol, 22.15% yield) as the second peak collected from the column as a viscous oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.59-2.76 (m, 1 H) 2.78-2.93 (m, 3 H) 3.60 (s, 1.5 H) 3.77 (s, 1.5 H) 3.92 (d, J=11.60 Hz, 1 H) 4.17-4.31 (m, 1 H) 4.34-4.49 (m, 1 H) 4.92-5.07 (m, 2 H) 5.08-5.34 (m, 2 H) 5.53-5.72 (m, 1 H) 7.23-7.41 (m, 6 H) 7.45 (t, J=7.63 Hz, 3 H) 7.48-7.67 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-methoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 2.54 (t, J=4.80 Hz, 4H), 3.37 (t, J=4.80 Hz, 4H), 3.88 (s, 3H), 7.01 (dt, J=1.50 Hz, 3.90 Hz, 2H), 7.73 (dt, J=1.50 Hz, 3.60 Hz, 2H); MS (ES) m/z 269.8 (MH+); HRMS for C12H15NO4S: 269.0722; Anal. Calcd. for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.35; H, 5.60; N, 5.15.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:24][CH3:25])=[N:12][N:13]2COCC[Si](C)(C)C)=[CH:9][CH:8]=1)=O.Cl.[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([NH:42]N)[CH:39]=[CH:40][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([N:42]2[C:5]([C:7]3[CH:15]=[C:14]4[C:10]([C:11]([CH2:24][CH3:25])=[N:12][NH:13]4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:39]=[CH:40][CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NNc1cccc(OCc2ccccc2)c1
Reactant: CCc1nn(COCC[Si](C)(C)C)c2cc(C(=O)/C=C/N(C)C)ccc12
Agent: Cl
Solvent: CCO
Product: CCc1n[nH]c2cc(-c3ccnn3-c3cccc(OCc4ccccc4)c3)ccc12
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
(2E)-3-(dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one (256 mg, 0.685 mmol) and 3-benzyloxyphenylhydrazine hydrochloride (270 mg, 1.1 mmol) were dissolved in ethanol (4 mL) in a 10 mL sealed tube. The mixture was subjected to microwave radiation (300 watts, 160° C.) for 5 minutes. The solvent was removed and the residue was extracted with ethyl acetate, then washed with water and brine. Removal of volatiles provided a tan solid, which was purified by column chromatography on silica gel, eluting with a 10-50% hexane/ethyl acetate gradient over 10 minutes (flow rate 20 mL/min), to give 160 mg (59%) of 6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole. 1 H NMR (CDCl3) δ 1.4 (t, 3H), 3.0 (q, 2H), 5.0 (s, 2H), 6.6 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.1 (m, 2H), 7.2 (t, 1H), 7.3, (m, 5H), 7.6 (d, 1H), 7.8 (m, 1H), 9.7 (br s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:11]#[CH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ncccc1OC(C)=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1ncccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-ethynylpyridin-3-yl acetate (5.0 g, 31 mmol) in ethanol (50 mL) was added PtO2 (0.50 g, 2.2 mmol). The mixture was degassed with nitrogen and placed under a double-layer balloon of hydrogen. The reaction was stirred at ambient temperature for 30 minutes. The mixture was filtered and concentrated in vacuo to give 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) that was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[N:22]1(O)C2C=CC=CC=2N=[N:23]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:22]([C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[NH2:23]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.60 g), 1H-1,2,3-benzotriazol-1-ol (0.28 g) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.40 g) at room temperature. The mixture was stirred for 10 min and hydrazine monohydrate (0.28 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.28 g, yield 44%) as colorless crystals. melting point>276° C. (decomposition).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][CH3:28])[C:22](OCC)=[O:23])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][Si:2]([CH3:29])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][CH3:28])[CH:22]=[O:23])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCOC(=O)C(CC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -55 °C
Yield: 90.2 %

Procedure:
A solution of ethyl 2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanoate (1.0 g, 2.3 mmol) in toluene (10 mL, 90 mmol) was cooled at −78° C. 1.0 M of Diisobutylaluminum hydride in toluene (2.8 mL, 2.8 mmol) was added dropwise over 10 minutes. Another 1.0 M of diisobutylaluminum hydride in toluene (3.0 mL, 3.0 mmol) was added. The mixture was warmed to −55° C. After quenching with 2.8 M of sodium hydroxide in water (10 mL, 30 mmol), the mixture formed an emulsion. Ethyl acetate was then added, and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with 2.8 M of sodium hydroxide in water, water, saturated NH4Cl, and saturated NaCl. The organic phase was dried and the solvent was evaporated by rotary evaporation at 35° C. to give an orange oil. The orange oil was then twice redissolved in toluene and then the solvent was removed by rotary evaporation to give 0.8 g orange oil (90% yield). LCMS: 386.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (199 mg).
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].O>CCOCC>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:20])([CH3:8])[CH3:7]
Reactant: CC(C)c1ccccc1Br
Reactant: CCN(CC)C(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
n-Butyllithium (2.5M, 100 mL) was added with stirring under nitrogen at 0°-5° C. during ten minutes to a solution of 2-isopropylbromobenzene in anhydrous ether (500 mL). The mixture was allowed to warm to room temperature, stirred at room temperature for six hours, and cooled to -60° C. A solution of diethylcarbamyl chloride (34 g) in anhydrous ether (50 mL) was added during 20 minutes while maintaining the temperature below -50° C. The temperature was allowed to rise to room temperature during one hour. Water (100 mL) was added. The ether layer was washed with saturated aqueous solution chloride (200 mL), dried over magnesium sulfate and stripped of ether. Distillation of the residue (80°-90° C./0.1 mm Hg) gave 2-isopropyl-N,N-diethylbenzamide (44 g, 80% yield).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:40][C@@H:41]([C@H:43]3[CH2:47][NH:46][C:45](=[O:48])[CH2:44]3)[CH3:42])[C:34]3[N:35]([N:37]=[CH:38][CH:39]=3)[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:40][C@@H:41]([C@H:43]3[CH2:47][NH:46][C:45](=[O:48])[CH2:44]3)[CH3:42])[C:34]3[N:35]([N:37]=[CH:38][CH:39]=3)[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:29][CH2:30]1
Reactant: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(S(C)(=O)=O)CC1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Methanesulfonic anhydride (9.5 mg, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.48 (22.4 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dichloromethane (1.8 mL). After two hours, reaction mixture was loaded directly onto silica and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(3-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.50 (19 mg).
Reaction SMILES: ClS(O)(=O)=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.Cl[CH:13](Cl)[C:14](O)=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:18]1([S:24]([C:14]2[CH:13]=[CH:20][CH:19]=[CH:18][CH:23]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)C(Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=S(=O)(O)Cl
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Into a mixture of 6.6 ml of chlorosulfonic acid, 12.6 ml of antimony pentachloride and 10 ml of dichloroacetic acid, was added 8.9 ml of benzene at 25° C., and the mixture was stirred for 5 hours. The reaction mixture was transferred into ice water and the precipitated product was extracted with benzene. From the results of analysis, it was confirmed that benzene-sulfonyl chloride and diphenylsulfone were formed in yields of 60% and 30%, respectively, based on benzene.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:4]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)=[O:27])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CSc1cc(Oc2ccc(N)cc2)ncn1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CSc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of 4-(6-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine (1.3 g, 5.5 mmol) in THF (24 ml) is cooled to 0° C. A solution of 3-(trifluoromethyl)phenyl isocyanate (790 μl, 5.5 mmol) in THF (24 ml) is added and stirring is continued overnight at r.t. The solvent is evaporated and the crude product is purified by silica gel chromatography using an ethyl acetate/heptane eluent (1:1) to give 1.76 g (75%) of a white powder.