Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](Cl)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a dry 25 mL round bottom flask, fitted with a reflux condenser, was added the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2H-pyridazin-3-one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and anhydrous dimethylformamide (11 mL). The reaction flask was placed in a 68° C. oil bath and the reaction was stirred for 12 hours. The reaction flask was removed from the oil bath and allowed to cool. The mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with water (25 mL, 5×). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.3 g of crude product. Column chromatography [silica gel; eluent hexanes-ethyl acetate (9:1)] provided the desired product (594 mg, 89%). 1H(CDCl3) δ(ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C(CDCl3) δ(ppm): 18.57, 26.19, 27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23, 132.38, 143.72, 154.02, 159.30.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[NH2:19].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:25]1([NH:19][C:18]2[CH:17]=[C:16]([F:15])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1cc(NC2CCCC2)cc(F)c1F
Reaction time: 3.5 h

Procedure:
Under ice-cooling, 11.5 g of sodium triacetoxyborohydride was added in small portions to a solution of 4.0 g of 3,4,5-trifluoroaniline and 3.6 ml cyclopentanone in 150 ml dichloroethane and 3.1 ml acetic acid, and, after rising to room temperature, stirred for 3.5 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and subsequent drying over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of N-cyclopentyl-3,4,5-trifluoroaniline.
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])[Cl:5])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][C:14](=[C:16]([CH3:18])[CH3:17])[CH3:15].C1(OC)C=CC=CC=1>>[C:14]([Si:4]([CH:6]([CH3:8])[CH3:7])([CH:1]([CH3:3])[CH3:2])[Cl:5])([CH:16]([CH3:18])[CH3:17])([CH3:15])[CH3:13]
Reactant: CC(C)=C(C)C
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 30.1 g (0.2 mol) of diisopropylchlorosilane and 2.7 g (0.02 mol) of aluminum chloride and heated at 50° C. Once the internal temperature became constant, 16.8 g (0.2 mol) of 2,3-dimethyl-2-butene was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for one hour at 50° C. The aluminum chloride was deactivated by adding 4.3 g (0.04 mol) of anisole. The reaction solution was distilled, collecting 28.3 g of a boiling point 79° C./133 Pa fraction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH3:8])[CH:2]=1.[O-][CH2:18]C.[Na+].CI>C(O)C>[CH3:18][S:15][C:12]1[NH:11][C:10](=[O:16])[C:9]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:8])=[CH:14][N:13]=1
Reactant: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1ncc(C(C)c2cccnc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 113 %

Procedure:
5-[1-(3-Pyridyl)ethyl]-2-thiouracil (3.4 g) was added to a solution of sodium ethoxide (from 0.74 g sodium) in ethanol (35 ml). Methyl iodide (2.42 g) was added over 0.5 hour at 0°. After standing for a further 2 hours at 0° the solution was evaporated to dryness. The residue was taken up in water and the pH adjusted to 7.0 and the mixture was allowed to stand at 0° overnight. The solid was filtered off to give 2-methylthio-5-[1-(3-pyridyl)ethyl]-4-pyrimidone (3.04 g) m.p. 201°-204° (from ethanol).
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[N+]([O-])([O-])=[O:8].[Na+]>>[Si:2]([O-:8])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
An aqueous solution (c-2) of silica particles was prepared in accordance the paragraphs [0012] to [0031] of the description of JP 06-16414 A. To be specific, sodium water glass JIS No. 3 was dissolved in an aqueous sodium nitrate solution, thereby producing an aqueous sodium silicate solution. The aqueous sodium silicate solution was passed through a hydrogen-type cation exchange resin column, a hydroxyl group-type anion exchange resin column, and again, the hydrogen-type cation exchange resin column in the stated order. Thereafter, an aqueous sodium hydroxide solution was added, thereby obtaining an aqueous silicic acid solution. Subsequently, the aqueous silicic acid solution in an amount equivalent to 20% was subjected to vacuum distillation for removing evaporated water, and simultaneously, the remaining aqueous silicic acid solution was continuously and gradually supplied for successively performing the vacuum distillation, thereby producing a colloidal silica sol. The colloidal silica sol was passed through a hydrogen-type cation exchange resin column, a hydroxyl group-type anion exchange resin column, and again, the hydrogen-type cation exchange resin column in the stated order. Immediately thereafter, a special grade aqueous ammonia was added, thereby obtaining an aqueous silica sol (c-2) in which the pH was 9, the average particle diameter was 4 nm, and the concentration of each of various metal oxides was lower than 500 ppm (reactive functional group: silanol group; proportion: 100 mol %).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:26]([O:28]C)=[O:27])=[C:12]([CH2:14][N:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[S:24][CH3:25])[S:13][C:7]=2[N:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]1=[O:34].CO.Cl>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:26]([O-:28])=[O:27])=[C:12]([CH2:14][N:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[S:24][CH3:25])[S:13][C:7]=2[N:6]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:5]1=[O:34].[Na+:2]
Reactant: COC(=O)c1c(Cn2c(SC)nc3ncccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1nc2ncccc2n1Cc1sc2c(c1C(=O)[O-])c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (0.8 ml, 1M) was added to a solution of the product of example 37 part b) (190 mg) in tetrahydrofuran under nitrogen. Methanol was added to solubilise the solution and the reaction mixture was stirred at room temperature for 3 hours. HCl (0.4 ml, 2M) was added to neutralise the solution and the mixture was concentrated in vacuo to give the title-compound. MS(ES) 460 [M+H]+
Reaction SMILES: [N:1]1[NH:2][C:3](=[S:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16][O-].[Na+].CO.CI>CO>[CH3:16][S:15][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1
Reactant: C[O-]
Reactant: S=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nnc2n1C=Cc1ccccc1C2
Reaction time: 0.33 h

Procedure:
To 3 ml of methanol was added 0.215 g of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepine-3-thione and, under stirring, 0.6 ml of 2N-sodium methoxide/methanol was added. Then, 0.07 ml of methyl iodide was added dropwise. After 20 minutes, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with ether. In this manner, 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine were obtained as crystals. Recrystallization from methanol yielded colorless needles melting at 168°-169° C. This was identical with the products obtained in Examples 1 and 2.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]=1>[Pd].CO>[NH2:20][C:18]1[CH:17]=[CH:16][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]=2)=[C:2]([F:1])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Yield: 64.9 %

Procedure:
A solution of 2.90 g (9.41 mmol) 3-[4-(2-fluoro-4-nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in a mixture of 50 ml TH/methanol 1:1 was hydrogenated over 500 mg 10% Pd/C for 10 h. The catalyst was filtered off and the filtrate evaporated. The obtained oil was dissolved in ethyl acetate and purified by chromatography on silica (dichloromethane/methanol 94:6) to give 1.70 g (65%) of 3-[4-(4-amino-2-fluoro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([Cl:28])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([Cl:28])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[C:9]([C:11]1[CH:12]=[C:13]([F:37])[C:14]([NH:28][C@H:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:30]([NH2:32])=[O:31])=[N:15][C:16]=1[NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)#[N:10].[Cl-].[Na+]>C(OCC)(=O)C.O.C(O)C>[NH2:32][C:30](=[O:31])[C@H:29]([NH:28][C:14]1[C:13]([F:37])=[CH:12][C:11]([C:9]([NH2:10])=[O:2])=[C:16]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:15]=1)[CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)C[C@@H](Nc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F)C(N)=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C[C@@H](Nc1nc(Nc2ccc3ncccc3c2)c(C(N)=O)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
Potassium carbonate (35 mg) and a 30% hydrogen peroxide solution (29 μl) were added to an ethanol (1 ml) solution containing (2R)-2-(5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-ylamino)-4-methylpentanamide (20 mg), followed by stirring at room temperature for 1 hour. A 30% hydrogen peroxide solution (29 μl) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Water, sodium chloride, and ethyl acetate were added to the reaction mixture. The organic layer was collected and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was dissolved in ethyl acetate, and diisopropylether was added. Solid matter was collected by filtration and washed with diisopropylether, and a yellow solid of 6-((2R)-1-amino-4-methyl-1-oxopentan-2-ylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide (8 mg) was thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=4[C:36]([F:37])([F:38])[F:39])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(C(F)(F)F)c1
Yield: 6.1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-methoxy-2-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 110 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-methoxy-2′-trifluoromethyl-biphenyl-2-carboxylic acid (8 mg, 6%). 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.26 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8](=[O:10])[CH3:9]>CC(O)=O>[Br:1][CH2:9][C:8]([C:4]1[S:3][CH:7]=[CH:6][N:5]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1nccs1
Solvent: CC(=O)O
Product: O=C(CBr)c1nccs1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Bromine (70 μL, 1 mmol) was added to a mixture of 1-(1,3-thiazol-2-yl)ethanone (200 mg, 2 mmol) in AcOH (5 mL). The reaction mixture was stirred at 100° C. for 30 min. and was concentrated under reduced pressure to give 2-bromo-1-(1,3-thiazol-2-yl)ethanone as an oil (100%) used as crude.
Reaction SMILES: [C:1]([C@@H:3]([NH:21][C:22]([C:24]1([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:30][C:24]1([C:22]([NH:21][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CCOCC1
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)C1(N)CCOCC1
Temperature: 50 °C
Yield: 38.1 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4′-(trifluoromethyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (v(i)), 650 mg) was added formic acid (3 mL) and the mixture heated to 50° C. for 10 min. The mixture was evaporated to dryness, dissolved in methanol (6 mL) and purified on reverse phase HPLC eluting with 25 to 95% methanol in 0.1% TFA on a Waters SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in dichloromethane (20 mL) and shaking with saturated sodium bicarbonate solution (20 mL). The dichloromethane was dried and to evaporated to afford the titled compound as a solid (200 mg).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[NH2:37].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[C:8]([NH:37][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][N:31]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cnccn1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 160 mg, 0.47 mmol) in methylene chloride (10 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 281 μL, 0.56 mmol) and stirred at 0° C. for 15 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 30 min. After this time, the reaction mixture was then concentrated in vacuo to ˜1 mL volume and an additional amount of methylene chloride (3 mL) was added. One half of this solution of prepared acid chloride (2 mL, 0.23 mmol) was added dropwise to a separate reaction flask containing a mixture of pyrazin-2-ylamine (33 mg, 0.35 mmol) and 2,6-lutidine (52 μL, 0.47 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (12 g silica gel column, 25-75% ethyl acetate/hexanes and then a 4 g silica gel column, 40-60% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide (39 mg, 40%) as a white foam: [α]28D=−65.0° (c=0.10, methylene chloride); HR-ES(+) m/e calcd for C21H21N4O2F3 [M+H]+ 419.1690, observed 416.1688; 1H NMR (300 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 9.26 (s, 1H), 8.34-8.49 (m, 2H), 8.02 (t, J=8.45 Hz, 2H), 7.67-7.84 (m, 1H), 5.23 (dd, J=4.98, 10.41 Hz, 1H), 5.06 (d, J=18.41 Hz, 1H), 4.67-4.85 (m, 1H), 1.02-2.21 (m, 11H).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1>C(O)C.O>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N+:33]=[N-:34])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
3.0 g of the cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)methane prepared in (2), was put into a flask, and 100 mL of ethanol was added thereto, followed by stirring. Further, to this solution, 8.0 g of a 5 wt % ethanol solution of sodium hydroxide was added, followed by stirring. This reaction solution was cooled to from -5° C. to -10° C., and 35 mL of pure water was added thereto. Then, 10 mL of the ethanol solution containing 2.0 g of p-toluenesulfonylazide obtained in Reference Example 2, was dropwise added thereto over a period of 5 minutes, and the mixture was stirred for 3 hours and left to stand overnight. Then, the precipitate was collected by filtration to obtain crude crystals. The crude crystals were re-crystallized from ethanol to obtain cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)diazomethane.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
Next, the above 2-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-1-(3,4-difluorophenyl)ethene (10 g ) was dissolved in ethyl acetate (100 ml), followed by subjecting the solution to catalytic hydrogenation at 20° C. by means of 5%-Pd/C catalyst (0.5 g) till absorption of hydrogen ceased, removing the catalyst after completion of the reaction, distilling off ethyl acetate and recrystallizing a remaining oily substance from ethanol to obtain the objective 2-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-1-(3,4-difluorophenyl)ethane (8 g). This product had a broad mesomorphic range, and C-S point: 18.4° C., S-N point: 49.5° C. and N-I point: 118.3° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:44]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C(O)(C(F)(F)F)=O>CS(C)=O.ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]([CH2:51][N:44]5[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]5)[CH:38]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (50 mg, 0.086 mmol) was added 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (34.4 mg, 0.172 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic conditions) and solvent evaporated using a GeneVac EZ-2 evaporator. To this material was added TFA (0.198 mL, 2.57 mmol) in dichloromethane (0.2 mL) and the mixture was placed in a Glas-Col evaporator overnight. The resultant residue was then redissolved in MeOH/DMSO and purified using a Gilson HPLC (acidic condition), and the product fractions were combined and the solvent evaporated by GeneVac EZ-2 evaporator. Each compound was redissolved in MeOH/DCM (1/1) and an amine cartridge was used to neutralize the mixture to afford 8.4 mg (14%) of the title compound. LC-MS m/z 667 (M+H)+.