Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:12]=1[CH2:13][N:14]1[C:26]2[CH:25]=[N:24][C:23]([CH2:27][NH2:28])=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.COCCOC.C(N(CC)CC)C>ClCCCl>[Cl:10][C:11]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:12]=1[CH2:13][N:14]1[C:26]2[CH:25]=[N:24][C:23]([CH2:27][NH:28][C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:8])=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: ClCCCl
Product: Cc1cc(C(=O)NCc2cc3c4ccccc4n(Cc4cc(Cl)ccc4Cl)c3cn2)no1
Reaction time: 8 h

Procedure:
A solution of 5-methylisoxazole-3-carbonyl chloride in DCE (0.25M) was treated with a solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine in DME (0.25M, 1 equiv), followed by a solution of triethylamine in DME (1.0M, 1 equiv). The mixture was agitated, and allowed to stand overnight. The solvent was evaporated and the residue purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6) δ9.5 (br t, 1H), 9.40 (s, 1H), 8.74 (s, 1H), 8.60 (d,J=7.8 Hz, 1H) 7.78 (m, 1H), 7.66-7.60 (m, overlap, 2H), 7.50-7.41 (m, overlap, 2H), 6.69 (s, 1H), 6.65 (s, 1H), 5.97 (s, 1H), 4.96 (d, J=5.4Hz, 2H), 2.49 (s, overlap with DMSO peak). A peak at 13.7 ppm in the 13C NMR spectrum is consistent with the methyl group, which presumably overlaps with the solvent in the 1H NMR spectrum. Monoisotopic mass calcd for C24H18Cl2N4O2: 464.1, (M+H) found 465.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH2:25])[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1.[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]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>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH:25][C:35](=[O:36])[C:34]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:32]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:33]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
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: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N3-[1-(6-amino-pyrimidin-4-yl)-1H-benzoimidazol-2-yl]-4-methyl-benzene-1,3-diamine (10.0 mg, 0.030 mmol), 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid (10 mg, 0.036 mmol), and DIEA (21 μL, 0.12 mmol) in DMF (2 mL) is added HATU (13 mg, 0.033 m mol). After stirring for 1 hour at room temperature, the solvent is removed under vacuum. The residue is dissolved in DMSO (1 mL). The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[N:6][C:7]=1[I:8].[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].Cl.C(Cl)Cl>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([I:8])=[N:6][CH:5]=1
Reactant: O=Cc1cnc(I)c(Cl)c1
Reactant: COC(OC)OC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1cnc(I)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A mixture of 5-chloro-6-iodo-3-pyridinecarbaldehyde (260 mg, 0.972 mmol), trimethyl orthoformate (1.064 ml, 9.72 mmol), HCl (3M in MeOH) (0.778 ml, 2.333 mmol), DCM (1.5 ml) and MeOH (1.5 ml) was stirred at 50° C. for 3 h. TLC showed full conversion. The solution was cooled to room temperature and concentrated under vacuum. The residue was diluted with sat. NaHCO3 and EtOAc. Extraction, drying (MgSO4), filtration, and concentration afforded 271.5 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 5-[bis(methyloxy)methyl]-3-chloro-2-iodopyridine (239.9 mg, 79%) as a yellow oil. It will be used in the next step without further purification.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[OH2:9].[CH3:10][C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[C:14]([CH:22]=[CH2:23])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:10][C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[C:14]([CH:22]([OH:5])[CH2:23][OH:9])[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O
Reactant: C=Cc1cccc2cc(C)c(C)nc12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cc2cccc(C(O)CO)c2nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
1.17 g (10 mmol) of N-methylmorpholine N-oxide, 10 ml of water and 30 ml of acetone are placed in a 100 ml three-necked flask. 0.4 mol of a solution containing 1% by mass of osmium tetroxide in tert-butanol is added dropwise, followed by addition of a solution of 1.4 g (7.6 mmol) of 2,3-dimethyl-8-vinyl-quinoline in 10 ml of acetone. The reaction mixture is stirred for 2 hours at room temperature. 50 ml of water are added and the resulting mixture is extracted with ethyl acetate (3×100 ml). The organic phases are combined, washed with 100 ml of 1% sodium bisulphite solution and 100 ml of 1% sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a column of silica (elution solvent: 30% ethyl acetate in cyclohexane). 1.34 g (yield: 81%) of 2,3-dimethyl-8-(1,2-dihydroxyethyl)quinoline are obtained in the form of a white solid. m.p. =120° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29])(C)(C)C.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([C:24]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 150 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A mixture of anthranilamide (0.15 g, 1.10 mmol), 4-[2(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.340 g, 1.101 mmol), sodium hydrogensulfite (0.126 g, 1.101 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The solid was collected by filtration, washed with water (10 mL×3) and dried under high vacuum to provide desired compound (328 mg, 70%), as a white solid. A solution of the above described compound (0.316 g, 0.745 mmol) in THF (3 mL) was cooled to 0° C. under nitrogen and TBAF (1.5 mL, 1.49 mmol) was added, followed by stirring at room temperature for 1 h. The reaction mixture was diluted with cold water (30 mL), the white precipitate was filtered off, washed with water (15 mL×3) and MeOH (20 mL×3) and dried under high vacuum, to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (150 mg, 65%), as a white solid. Selected data: MS (ES) m/z: 311.04; MP 260-261° C.
Reaction SMILES: [C:1](=[C:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)=C1CCOC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)C1CCOC1=O
Yield: 90.9 %

Procedure:
In a 250 mL autoclave a mixture of 2-isopropylidene-γ-butyrolactone (10.5 g) and Pd-catalyst (10 wt. % Pd on carbon, 0.050 g) in ethanol (10 mL) was treated with hydrogen (6 bar) at 60° C. for 18 h. Upon completion of the hydrogenation, the mixture was filtered and concentrated on a rotary evaporator to give 9.70 g (91%) of the title compound.
Reaction SMILES: [C:1]1([C:7]23[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17](=[O:25])(=[O:24])[CH2:16][C:10]4([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:8]2[O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[H][H]>[Pd].C(Cl)Cl>[OH:9][C@@H:8]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:16][S:17](=[O:25])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=S1(=O)CC2(CCCCC2)C2OC2(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of ethanol,10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2[NH:13][N:14]=[CH:15][C:16]1=2)[CH3:2]
Reactant: CCc1ccccc1C=O
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2CC)c2cn[nH]c2N1

Procedure:
The title compound was prepared from 2-ethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1coc2c(OC)cccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1coc2c(O)cccc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Methyl (7-methoxybenzofuran-3-yl)acetate (12.37 g) was dissolved in dichloromethane (50 ml) and the solution was cooled to −78° C. To this solution, boron tribromide (1.0 M, 120 ml) was added dropwise for 50 minutes. Thereafter, the temperature was raised to room temperature and the reaction solution was stirred at this temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to −78° C. and methanol (100 ml) was added thereto. After neutralizing the reaction mixture by adding sodium hydrogen carbonate, the resulting solution was filtered. The filtrate was concentrated and poured into water layer (300 ml) and the resultant was extracted twice with ether (150 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (10.53 g, yield: 91%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 108.2 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in dioxane/water (300 mL:200 mL) was purged with nitrogen for 1 hour. [1,-bis(Diphenylphosphino) ferrocene]dichloropalladium [II] (4.5 g, 5.5 mmol) was added. The reaction mixture was heated to 100° C. with vigorous stirring for 3.5 hours, then cooled and filtered through Celite® (Celite Corp., Santa Barbara, Calif.). The cake was washed with ethyl acetate (500 mL). The combined organic phases were washed with 1N sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium carbonate, and concentrated in vacuo to afford a dark oil (28.6 g). Purification by flash chromatography using 2% ethyl acetate in hexanes as solvent provided the title compound (24.7 g, 93%) as a pale yellow oil. MS [(+)ESI, m/z]: 241 [M+H]+ HRMS [(+)ESI, m/z]: 241.12205 [M+H]+. Calcd for C16H17O2: 241.12286 Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.67; H, 6.61.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[C:6]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=[S:8])[NH2:7]>C(Cl)(Cl)Cl>[CH3:4][C:3]1[N:7]=[C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:8][CH:2]=1
Reactant: NC(=S)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: Cc1csc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Yield: 53.5 %

Procedure:
Part A. Chloroacetone (36 mg, 0.37 mmol) was added to a solution of benzyl (S)-2-thiocarbamoyl-pyrrolidine-1-carboxylate (90 mg, 0.34 mmol) in dry chloroform (2 mL). The resulting solution was heated to reflux for 24 h then purified by preparative HPLC yielding benzyl (S)-2-(4-methylthiazol-2-yl)-pyrrolidine-1-carboxylate as a colorless oil (55 mg, 54% yield): HPLC (method 1) tR=3.11 min, Purity 100%; LCMS (method 4) tR=1.57 min, m/z 303 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:23]#[CH:22]
Reactant: CC(=CCOc1ccc(C(=O)O)cc1)CCC(C)=C(C)C
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC(C)=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,6,7-trimethylocta-2,6-dienyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,6,7-trimethylocta-2,6-dienyl)oxy]benzoic acid propargyl ester; nD24 = 1.5349.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:31][C@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][C@H:23]2[OH:32])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:5]=[CH:6][C:7]=1F.ClC1C=C(C2SC(C(O)=O)=NC=2C2C=CC=C(Cl)C=2)C=C(F)C=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:13]2[S:12][C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[N:10][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: O=C1CN(C(=O)c2nc(-c3ccc(F)c(Cl)c3)c(-c3cc(F)cc(Cl)c3)s2)CN1
Agent: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Product: O=C1CN(C(=O)c2nc(-c3cccc(Cl)c3)c(-c3cc(F)cc(Cl)c3)s2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with the compound from Example 10A. 40.0 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Cl.[C-:11]#[N:12].[Na+].O>CN(C=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:11]#[N:12])=[C:2]([F:1])[CH:7]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
2-Fluoro-4-bromo-chloromethylbenzene (25.0 g, 112 mmol) and NaCN (6.32 g, 129 mmol) were dissolved in DMF (70 mL) and the solution was stirred under a N2 atmosphere for 18 hrs at ambient temperature. The solution was poured into water (300 mL), and was extracted with EtOAc (1×1 L, 4×300 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure, yielding the title compound (22.5 g, 105 mmol, 93%) as a yellow oil that contained some traces of DMF. 1H-NMR (CDCl3, 300 MHz): 3.75 (s, 2H); 7.20-7.4 (m, 3H)
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([NH:9][C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[SH:4][CH2:5][CH:6]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)NC(C)(C)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)C(CS)Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
Benzyl 2-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]isobutyrate (0.45 g) is dissolved in a mixture of methanol (5 ml) and water (3 ml) under nitrogen, and thereto is added triethylamine (0.22 g), and the mixture is stirred at room temperature for 5 hours. After the reaction, the reaction mixture is acidified with saturated aqueous citric acid solution, and methanol is distilled off under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform) to give the title compound (0.35 g).
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (100 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol) and then Tf2O (186 mg, 0.66 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [U:1](F)(F)(F)(F)(F)F.[F-].[U+2:9](=O)=[O:10].[F-].[OH-:13].[NH4+:14]>O>[NH4+:14].[NH4+:14].[O-2:10].[O-2:13].[O-2:10].[O-2:10].[O-2:10].[O-2:10].[O-2:10].[U:1].[U:9]
Reactant: [OH-]
Reactant: F[U](F)(F)(F)(F)F
Reactant: O=[U+2]=O
Agent: [F-]
Agent: [NH4+]
Solvent: O
Product: [O-2]
Product: [U]

Procedure:
Namely, solid uranium hexafluoride (UF6) is heated to vaporize, the UF6 gas is hydrolyzed with deionized water to uranyl fluoride (UO2F2) solution. The UO2F2 solution is added with ammonium hydroxide to form ammonium diuranate (ADU) precipitate. This slurry is filtered, then there is obtained a cake. The cake is washed, dried and milled. The obtained ADU powder is supplied to a calcining and reducing kiln to manufacture uranium dioxide powder. The uranium dioxide powder manufactured by this process has generally a particle size of about 0.1-3 μm and an example of the particle size distribution thereof is illustrated in FIG. 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][N:25]([CH3:26])[CH3:24])[CH2:11][CH2:10]2)[CH3:23])=[N:6][CH:7]=1
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 125 mg (corresponding to 0.30 mmol) of crude trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 3 ml of methanol was cooled (0° C.), treated with 0.54 ml (3 mmol) of Dimethylamine (33% in EtOH 5.6M) and stirred for 20 h at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 97.5:2.5) gave 65 mg (62%) of pure trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-amine, mp: 83–84° C., dec.; MS: 351 (MH+, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20](O)=[O:21])=[C:11]2[C:10]([C:28]([O:30][CH3:31])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:23]1([C@@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]=23)[C:20]([NH:46][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45]2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CCCC3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C3CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopentylacetic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C27H38N4O5, 499; found, 499.6.