Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](F)=[CH:13][C:12](Br)=[CH:11][C:10]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li:22])CCC.CCCCCC.COB(OC)OC>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Li:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(F)c1OCc1ccccc1
Reactant: [Li]CCCC
Agent: COB(OC)OC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-benzyloxy-3,5-difluoro-bromobenzene (9.87 g, 0.033 mole) in ether (100 ml) under an atmosphere of argon was cooled to less than 31 70° C. in a dry ice-acetone bath. To this solution was slowly added a solution of butyllithium in hexane (1.5M, 22 ml, 0.033 moles). Stirring was continued for 30 minutes after the addition was complete. In a separate apparatus, a stirred solution of trimethylborate (3.1 g, 0.033 mole) in ether (50 ml) under an atmosphere of argon was cooled to less than -70° C. The freshly prepared benzyloxyphenyllithium formed in the first reaction solution was slowly transferred to the trimethylborate/ether solution by way of a double-tipped stainless steel needle. The addition was at such a rate that the reaction temperature was maintained at less than -66° C. After the addition was complete, the temperature was allowed to rise to room temperature. At this point, 10 percent hydrochloric acid (25 ml) was carefully added. After stirring an additional 15 minutes, the aqueous phase was separated and discarded. The organic phase was treated with 10 percent hydrogen peroxide (20 ml) and the resulting mixture stirred and heated at reflux for 24 hours. After cooling, the aqueous phase was separated and discarded. The organic layer was washed with 10 percent ferrous ammonium sulfate (25 ml), then with water (50 ml). After drying (MgSO4), the ether was evaporated to yield a brown oil (7.1 g, 91 percent) which solidified upon standing. G.C. showed that this material was approximately 92 percent pure. The proton and fluorine NMR spectra were consistent with the desired structure. Recrystallization of this material from hexane/ether gave a partially purified sample: m.p.=42°-44° C. It was used without additional purification.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccccn3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 2-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 160° C., R=0.4 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].[C:19]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:24][C:25]=2[CH3:30])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 46 c], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester was reacted with 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-methoxy-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:34]([NH:42][NH2:43])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C>[C:34]([NH:42][NH:43][C:16]([C:12]1[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:14][C:13]=1[CH3:15])=[O:18])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 13.6 %

Procedure:
To a solution of 2-benzamido-4-methylthiazole-5-carboxylic acid (0.30 g, 1.14 mmol) in tertahydrofuran (28 mL) was added N-methylmorpholine (0.23 mL, 0.21 g, 2.09 mmol) under nitrogen atmosphere, followed by the addition of isobutyl chloroformate (0.2 mL, 0.21 g, 1.54 mmol) dropwise at ambient temperature. The mixture was stirred at ambient temperature for 7 hours. Benzhydrazide (0.23 g, 1.71 mmol) and 4-methylmorpholine (0.15 mL, 0.14 g, 1.36 mmol) were added to the reaction mixture. After being stirred at ambient temperature for 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3×10 mL). The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes (20/80 to 30/70) to afford the title compound as a white solid (0.059 g, 14% yield); m.p. 258-260° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.90 (br, 1H), 10.46 (s, 1H), 10.10 (s, 1H), 8.09 (d, J=7.4 Hz, 2H), 7.93 (d, J=6.9 Hz, 2H), 7.65-7.47 (m, 6H), 2.56 (s, 3H); MS (ES+) m/z 381.4 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:27][CH2:28][CH:29]([O:32][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:30][CH2:31]2)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Reactant: CCCCC1CCC(C2CCC(O)CC2)CC1
Solvent: C1CCOC1
Product: CCCCC1CCC(C2CCC(OC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 7.5 g (35 mmol) was dissolved in 75 ml of THF, 4.6 g (19 mmol) of 4-(4-butyl-cyclohexyl)cyclohexanol was added thereto, they were refluxed for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off, the residue was subjected twice to recrystallization by using heptane to give 1.5 g (4.5 mmol) of trifluoroacetic acid 4-(4-butylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-butylcyclohexyl)cyclohexanol was 24%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29]([O:31]CC)=[O:30])[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29]([OH:31])=[O:30])[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(C)CC3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (220 mg, 0.464 mmol) in EtOH (5 mL) was added 1N NaOH (0.464 mL, 0.464 mmol) and the resulting mixture was stirred at room temp for 4 h. A this point LCMS indicated completion of reaction. Solvents were then removed under reduced pressure and the residue was diluted with water (3 mL), acidified with 1N HCl, extracted with ethyl acetate (25 mL), washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to afford (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (180 mg, 0.403 mmol, 87% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 5.95 (s, 1H), 4.31-4.16 (m, 2H), 2.66 (s, 3H), 1.82-1.60 (m, 4H), 1.60-1.46 (m, 4H), 1.28-1.22 (m, 12H), 1.14 (s, 6H). LCMS (M+H)=447.4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:4]2[C:8](=[C:9]([CH:11]=[CH2:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2>CCOC(C)=O.[Pd]>[CH2:11]([C:9]1[CH:10]=[C:2]([CH3:1])[C:3]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2)[CH3:12]
Reactant: C=Cc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C

Procedure:
To a solution of 2-((5-methyl-7-vinyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (11 mg, 0.035 mmol) in EtOAc (0.7 mL) was added Pd/C (5%, 3.75 mg) and the reaction was stirred at room temperature under hydrogen. After 10 minutes the reaction was filtered through Celite®, rinsing with EtOAc, and concentrated. The resulting residue was purified directly by RP-HPLC (HC-A) to provide the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.97 (br. s., 1H) 7.98 (s, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.53 (d, J=8.34 Hz, 1H) 7.23 (t, J=2.78 Hz, 1H) 6.79 (s, 1H) 6.45 (dd, J=3.16, 1.89 Hz, 1H) 4.46 (s, 2H) 2.81 (q, J=7.58 Hz, 2H) 2.37 (s, 3H) 1.25 (t, J=7.45 Hz, 3H). HRMS calcd. for C20H18N4 (M+H)+ 315.1604. found 315.1609.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([Br:28])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCCCCNc1ncnc2occ(-c3ccc(OC)cc3)c12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C

Procedure:
Dissolve 4.1 g (11.1 mmol) 6-{[5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester at room temperature in 150 ml carbon tetrachloride and add 2.2 g (12.2 mmol) N-bromosuccinimide. Stir the mixture under reflux for three hours, then filter after cooling to room temperature and concentrate the filtrate by vacuum evaporation. 4.8 g (96% of theor.) of the title compound is obtained.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[N:11]1[C:15](=[O:16])[CH:14]([N+:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH:23][C:24](=[O:54])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:53])[CH:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH2:34][CH3:35])[CH:26]=2)=[N:12]1.[H][H]>C(O)(=O)C.[Ni]>[Cl:10][C:5]1[CH:6]=[C:7]([Cl:9])[CH:8]=[C:3]([Cl:2])[C:4]=1[N:11]1[C:15](=[O:16])[CH:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:13]([NH:23][C:24](=[O:54])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:53])[CH:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH2:34][CH3:35])[CH:26]=2)=[N:12]1
Reactant: [H][H]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2[n+]2ccccc2)c1
Agent: [Ni]
Agent: [Br-]
Solvent: CC(=O)O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2N2CCCCC2)c1
Temperature: 80 °C

Procedure:
15 Grams of 1-(2,4,6-trichlorophenyl)-3-[3-{α-(2,4-di-tert-amylphenoxy)butyramido}benzamido]-4-(1-pyridinio)-5-oxo-2-pyrazoline bromide (Compound 1-2; m.p: 260° - 262° C.) was dissolved in 300 ml of acetic acid, with 10 g of Raney nickel being added thereto. The resulting mixture was maintained at 80° C. and vigorously stirred for 24 hours in a stream of hydrogen. Then, the reaction product was treated in the same manner as described in Example 1. Upon recrystallizing from a chloroform-ethyl acetateacetonitrile mixed solvent (1:1:10 by volume), 8.5 g of Compound 2-2 having a melting point of 186° - 190° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: NC(=O)c1c(N)ncn1CCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CN(CC(=O)Nc1ncn(CCc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.84 g (7.99 mmol) of 4-amino-1-(2-phenylethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 56 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.03 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(2-phenylethyl)-5-imidazolecarboxamide (yield 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)#[N:17]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[C:18]([C:16]#[N:17])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: N#Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-cyanophenyl)boronic acid. MS (ESI): mass calcd. for C17H11FN4, 290.10; m/z found, 291.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.05-7.98 (m, 3H), 7.83 (m, 1H), 7.71 (d, J=7.6, 1H), 7.66-7.47 (m, 3H), 6.77 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:14](=O)[CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15]
Reactant: CC(=O)c1ccc(OCC(F)(F)F)cc1Cl
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cc1Cl
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:15][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCNCC1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 150.1 %

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 5.58 mmole, Astatech) and triethylamine (3.2 mL, 22.95 mmole) in dichloromethane (70 mL) at 0° C. was added methanesulfonyl chloride (724 mg, 6.287 mmole, Aldrich). The mixture was allowed to stir for 30 min before washed successively with aqueous sodium bicarbonate and water and concentrated to dryness. The residue was taken up in dichloromethane (20 mL), treated with trifluoroacetic acid (20 mL) and allowed to stir for 3 h before it was concentrated to dryness. The residue was dissolved in dichloromethane, washes with aqueous sodium bicarbonate and concentrated to give N-methyl-N-piperidin-4-yl-methanesulfonamide (1.61 g) which was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].Cl[CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.O>CN(C)C=O.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[CH2:14][N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[N:7][C:3]1=2
Reactant: c1cnc2c(c1)OCCN2
Reactant: ClCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1cnc2c(c1)OCCN2CC1OCCO1
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (0.4 g) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% oil suspension; 0.24 g) in portions. After a few minutes, a solution of 2-chloromethyl-1,3-dioxolane (0.43 g) in N,N-dimethylformamide (2 ml) was added dropwise to the mixture. After stirring for 2 hours, the mixture was poured into a mixed solvent of water and ethyl acetate. The organic layer was separated, washed with water twice, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of ethyl acetate and hexane (1:1) as an eluent to give 3,4-dihydro-4-[(1,3-dioxolan-2-yl)methyl]-2H-pyrido[3,2-b]-1,4-oxazine (0.28 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:46])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])=[O:35].[CH3:47]I.O>CN(C=O)C>[CH3:3][C:4]1([CH3:46])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:47])[C:17](=[O:19])[CH3:18])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])=[O:35]
Reactant: CI
Reactant: CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Temperature: 23 °C
Yield: 72 %

Procedure:
NaH (to 60%) (6 mg, 0.16 mmole) is added under argon to a solution of N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]-nonyl}imidazolidin-1-yl)-2 (trifluoromethyl)phenyl]acetamide (100 mg, 0.15 mmole) (prepared according to Example 18) in anhydrous DMF (2 ml). A release of gas accompanies the change in colour of the reaction medium. Stirring is maintained for 1 hour at 23° C. before adding methyl iodide (10 μl, 0.16 mmole). After reaction for 1 hour the same quantity of sodium hydride and methyl iodide as previously are added, then the reaction mixture is again stirred for 3 hours at 23° C. The reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: CH2Cl2/MeOH: 95/5 to 90/10). The expected compound is obtained in the form of a colourless oil with a yield of 72% (72 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][N:40]([CH2:12][CH:13]4[O:14][C:15]5[C:16](=[CH:17][CH:18]=[C:19]6[N:20]=[C:21]([CH3:24])[O:22][C:23]6=5)[O:25][CH2:26]4)[CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4cc(F)ccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen. After completion, the reaction was cooled to room temperature and diluted with 400 mL of ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/methylene chloride to give 0.52 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 188-190° C.) after evaporation of the solvent.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22]1([CH:28]=[C:29]2[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]2=[O:38])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:22]1([C@H:28]([CH:29]2[C:34](=[O:35])[O:33][C:32]([CH3:36])([CH3:37])[O:31][C:30]2=[O:38])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)OC(=O)C(=CC2CCCCC2)C(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(=O)C([C@H](C#Cc2ccccc2)C2CCCCC2)C(=O)O1
Temperature: 0 °C
Yield: 81.1 %

Procedure:
A solution of copper (II) acetate monohydrate (5.0 mg, 0.025 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (10 mg, 0.050 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylaminol]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 16.5 mg, 0.025 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(cyclohexylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (59 mg, 0.25 mmol). The reaction mixture was-stirred vigorously at 0° C. for 13 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1) to give 69 mg of the pure title compound as a white solid. (yield: 81%)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Product: Cc1ccc(CNc2ccc3c(Nc4cccnc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 3-bromopyridine as described in example 1 step B.