Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: BrCc1ccccn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccccn1

Procedure:
The title compound, MS: m/e=309.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: C(N)CC.[C:5]1([O:11][C:12]([N:14]2[CH:27]([C:28]#[CH:29])[C:26]3[CH2:25][CH2:24][CH2:23][CH:22]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:21]=3[C:20]3[CH:19]=[CH:18][C:17]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N+:46]([O-:48])=[O:47])=[CH:16][C:15]2=3)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:49]1C=C[CH:52]=[CH:51][CH:50]=1>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.[Cu]I>[C:5]1([O:11][C:12]([N:14]2[CH:27]([C:28]#[C:29]/[CH:49]=[CH:50]\[C:51]#[C:52][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:26]3[CH2:25][CH2:24][CH2:23][CH:22]([O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[C:21]=3[C:20]3[CH:19]=[CH:18][C:17]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N+:46]([O-:48])=[O:47])=[CH:16][C:15]2=3)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: C#CC1C2=C(c3ccc(OCc4ccccc4[N+](=O)[O-])cc3N1C(=O)Oc1ccccc1)C(O[Si](C)(C)C(C)(C)C)CCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: CC(C)(C)[Si](C)(C)OC1CCCC2=C1c1ccc(OCc3ccccc3[N+](=O)[O-])cc1N(C(=O)Oc1ccccc1)C2C#C/C=C\C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A mixture of Pd(PPh3)4 (1.12 g, 0.97 mmol), 1-chloro-4-(trimethylsilyl)-but-1-3n-3-yne (4.60 g, 28.98 mmol), and n-propylamine (2.38 mL, 28.98 mmol) in degassed benzene (100 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 143b (79:21, mixture of diastereomers, 11.80 g, 19.32 mmol) and CuI (0.74 g, 3.86 mmol) in degassed benzene (300 mL) via a syringe followed by stirring at 25° C. for five hours. The reaction was quenched with saturated aqueous NH4Cl, extracted with ethyl ether (500 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, 20 percent ethyl ether in petroleum ether) gave Compound 232 (12.3 g, 87 percent): amorphous solid; Rf =0.51 (silica, 25 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2957, 2932, 1716, 1613, 1506, 1495, 1384, 1344, 1306, 1253, 1200, 1093, 1025, 858, 844 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 8.1 Hz, 1 H, aromatic), 7.97 (d, J=7.7 Hz, 1 H, aromatic), 7.80-7.17 (m, 9 H, H1, H4 and aromatic), 6.93-6.84 (m, 1 H, H2), 5.96 (br s, 0.79 H, H6), 5.93 (br s, 0.21 H, H6), 5.88-5.77 (m, 2 H, olefinic), 5.58 (s, 2 H, benzylic), 5.03 (br s, 0.79 H, H10), 4.73 (br s, 0.21 H, H10), 2.67-2.50 (m, 1 H, H7), 2.39-2.26 (m, 1 H, H7), 2.16-1.91 (m, 3 H, H8 and H9), 1.84-1.70 (m, 1 H, H 8 or H9), 1.02 (s, 1.89 H, SiC(CH3)3), 0.90 (s, 7.11 H, SiC(CH3)3), 0.27 (s, 9 H, Si(CH3)3), 0.18 (s, 3 H, SiCH3), 0.16 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 865 (M+Cs, 72), 732 (42), 675 (82), 639 (28), 585 (100), 450 (34), 330 (39), 279 (52), 198 (42); HRMS for C42H48N2O6Si2Cs (M+Cs), calcd 865.2105, found 865.2111.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:5]=2[S:4](=[O:19])[CH2:3]1
Reactant: CN1CS(=O)c2cc(C(=O)c3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CS(=O)c2cc(C(O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
0.02 mol of 3-methyl-6-benzoylbenzothiazolinone prepared in Example 2 are dissolved, with magnetic stirring, in 200 cm3 of methanol in a 250 cm3 flask 0.04 mol of sodium borohydride is added very slowly, with agitation. The agitation is maintained for 4 hours at ambient temperature. The reaction medium is evaporated under vacuum on a water bath The residue is taken up in water, and the precipitate formed is drained and dried.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:44][N:45]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:46]1[N:51]=[C:50]([NH2:52])[N:49]=[C:48]([C:53]2[N:57]=[C:56]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[O:55][N:54]=2)[N:47]=1>CN(C=O)C.O>[NH2:52][C:50]1[N:51]=[C:46]([N:45]([CH3:44])[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[N:47]=[C:48]([C:53]2[N:57]=[C:56]([CH:58]3[CH2:63][CH2:62][N:61]([C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])[CH2:60][CH2:59]3)[O:55][N:54]=2)[N:49]=1
Reactant: CC(C)C(=O)O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)CC1
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To 2-methylpropanoic acid (27.0 μL, 0.299 mmol) in DMF (5 mL) was added DIPEA (109 μL, 0.624 mmol) at room temperature and the mixture was stirred for 5 min. (1H-Benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (0.121 g, 0.274 mmol) was added to the reaction mixture and stirred for 5 min. 2-N-Methyl-2-N-phenyl-6-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 105, 0.100 g, 0.249 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water, extracted with EtOAc and the organic layer washed with brine. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (DCM:MeOH 90:10) to afford the title compound (96 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O>C1COCC1.[Ni]>[O:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 154A (12.5, 59.5 mmol) in THF (150 mL) was added to Ra-Ni 2800, water slurry (12.5 g, 212 mmol) in a 500 mL SS pressure bottle. The mixture was pressurized (H2, 30 psi) and stirred for 2 hours at room temperature. The mixture was filtered and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([B:25]4[O:29]C(C)(C)C(C)(C)[O:26]4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:3]1.COCCN(S(F)(F)[F:44])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([F:44])[CH2:3][C@H:4]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:29])[OH:26])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1c1ncc(-c2ccc(B(O)O)cc2)[nH]1
Temperature: -78 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 1-2c (1.5 g, 3.3 mmol) was added as a solid to a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.91 mL, 5.0 mmol) in 15 mL CH2Cl2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH2Cl2. Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown oil. The oil was chromatographed on silica gel with 5% MeOH/CH2Cl2 to yield 4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenylboronic acid as a tan solid (0.46 g, 37%). LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, tR=1.46 min, Anal. Calcd. for C18H23B1F1N3O4 375.18. found 376.12 (M+H)+ JG-22 is synthesized from JG-20 and JG-21 as described in Example 28 step c.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.[OH-].[Na+]>ClCCCl.C(OCC)(=O)C>[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[CH2:6][CH2:7]2)[CH2:18][CH2:17]1
Reactant: O=C1CCN(CCc2ccccc2F)CC1
Reactant: Brc1ccc2c(c1)NCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccccc1CCN1CCC(N2CCc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Triacetoxylated sodium borohydride (15.0 g) was added under ice cooling to a liquid mixture of 6-bromoindoline (9.0 g), 1-(2-fluorophenethyl)piperidin-4-one (11.0 g) and acetic acid (12.5 ml) in 1,2-dichloroethane (140 ml). Then the reaction mixtures were stirred at room temperature overnight. The reaction mixtures were diluted with ethyl acetate (400 ml) and then an 8 N aqueous solution (70 ml) of sodium hydroxide was added thereto. The organic layer was separated, extracted with 5 N hydrochloric acid (100 ml) and then basified with an 8 N aqueous solution of sodium hydroxide. Then it was extracted with ethyl acetate and washed successively with water and brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated distilled off under reduced pressure to give the title compound (12.2 g) as a pale yellow solid (yield: 66.6%). 2.10(2H,dt,J=7.6,2.8 Hz), 2.48-2.53(2H,m), 2.77(2H,t, J=8.4 Hz), 2.83(2H,t,J=8.4 Hz), 2.96-3.03(2H,br-d), 3.37(2H,t,J=8.4 Hz), 3.34-3.43(1H,m), 6.57(1H,d,J=1.2 Hz), 6.61(1H,dd,J=7.6,1.2 Hz), 6.90(1H,d,J=7.6 Hz), 7.10-7.16(2H,m), 7.21-7.28(1H,m), 7.33(1H,dt,J=7.6,1.2 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.O>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1(CCO)CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCC1(CCOCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (881 mg) in N,N-dimethylformamide (20 mL) was added 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (2.92 g) under ice cooling. To the solution was further added benzyl bromide (2.83 mL) under ice cooling, and it was stirred at room temperature for 63 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=6:4) to give the title compound (2.93 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[Br:17]Br.N>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Br:17])[C:3]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: Brc1c(NC2=NCCN2)ccc2nc[nH]c12
Reactant: BrBr
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CC(=O)O
Product: Brc1cc2nc[nH]c2c(Br)c1NC1=NCCN1
Yield: 86 %

Procedure:
To a solution of 4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.2 g, 0.7 mmol) in 10 ml AcOH was added 200 mg of Hg(OAc)2 and few drops of Br2. Reaction mixture was concentrated in vacuo, yielding a dark oily residue, which was subjected to silica gel column chromatography (NH3 sat'd 30% MeOH/EtOAc) to provide 210 mg (0.58 mmol, 86%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from EtOH to afford 0.051 g (14%) of the product as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1OCCO1.[CH:9](/[CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:10]\[CH2:11][CH3:12].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Br:1][CH2:2][CH2:3][CH:4]1[O:17][CH2:16][CH:13](/[CH:9]=[CH:10]/[CH2:11][CH3:12])[CH2:14][O:15]1
Reactant: BrCCC1OCCO1
Reactant: CC/C=C/C(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC/C=C/C1COC(CCBr)OC1

Procedure:
A solution of 14.4 ml of 2-(2-bromoethyl)-dioxolane and 20.6 g of (E)-2-but-1-enyl-1,3-propanediol in 200 ml of toluene was heated to slight boiling overnight with 2.7 ml of 10% aqueous sulfuric acid (v/v) and 8 ml of water. The mixture was treated with 6 ml of triethylamine and the aqueous phase was separated. The organic phase was washed with semi-conc. sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting orange oil (31.3 g) was chromatographed on 400 g of silica gel with hexane/ethyl acetate 2.5% (v/v). 23.4 g of (E)-2-(2-bromoethyl)-5-but-1-enyl-1,3-dioxane (GC purity 97.5%, trans/cis ratio 73:27) were obtained as a yellowish oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CCCC)CCCC)CCC.Cl[CH2:20][C:21](Cl)=[O:22].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[NH2:4][C:3]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C:21](=[O:22])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: N#CC1=C(N)N(c2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.4 g of malononitrile were dissolved in 150 ml of DMF and cooled to 0° C. While cooling, 148 g of tributylamine and 45 g of chloracetyl chloride were simultaneously added dropwise to this, and the mixture was stirred at room temperature for 30 minutes. 42 g of aniline were then added to the mixture, which was stirred at 80° C. for 15 hours and then 200 g of water were added. After cooling to room temperature, the organic phase was separated off and digested with dichloromethane. The precipitate was filtered off with suction, washed and dried. 37.4 g (46% of theory) of the compound of the formula ##STR28## of melting point 285° to 290° C. were obtained. The IR, NMR, UV and mass spectra and the elemental analysis are consistent with the structural formula
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:43]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[OH:43][C@H:10]([CH3:11])[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:8]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1ccc2ccccc2c1
Yield: 78 %

Procedure:
Compound 10i was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(naphthalen-2-yl)prop-1-enyloxy)dimethylsilane, (9i, 4.7 g, 0.016 mol), AD-mix-β (22.0 g), and CH3SO2NH2 (1.55 g, 0.016 mol) in tert-butyl alcohol-water (60 mL:60 mL). The reaction was quenched with sodium sulfite (15.7 g). After purification by column chromatography on silica gel, 2.5 g (80%) of the desired product was isolated: [α]20D +115° (c 0.7, CHCl3); 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.01-7.86-8.00 (m, 4H), 7.69-7.54 (m, 2H), 5.37-5.27 (m, 1H), 3.86 (d, 1H, J=6.5 Hz), 1.52 (d, 3H, J=7.0 Hz); 13C NMR (CDCl3) δ 202.3, 136.0, 132.4, 130.7, 130.5, 129.7, 129.0, 128.8, 127.9, 127.1, 124.0, 69.4, 22.5. C13H12O2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C1[C:40]2(C[NH:42][CH2:41]2)CO1.C(N(CC)CC)C>C1COCC1>[CH2:41]([NH:42][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)[CH3:40]
Reactant: C1NCC12COC2
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1nc(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)cc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and 2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.) in THF (0.20M) was added triethylamine (3.5 equiv.) and the allowed to stir at 75° C. for 48 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(3-(2-(ethylamino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 21% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 1.28 (t, J=7.24 Hz, 3H) 2.38 (s, 3H) 3.52 (q, J=6.65 Hz, 2H) 3.80 (br. s., 6H) 4.05 (br. s., 2H) 6.50 (s, 1H) 7.41 (d, J=8.61 Hz, 1H) 7.66 (dd, J=8.22, 2.35 Hz, 1H) 7.72-7.78 (m, 1H) 7.91 (d, J=7.83 Hz, 1H) 7.96 (d, J=2.35 Hz, 1H) 8.21 (d, J=7.83 Hz, 1H) 8.26 (s, 1H). LCMS (m/z) (M+H)=486.3, Rt=0.86 min.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN([C@@H]1c2ccccc2C[C@H]1O[Si](C)(C)C(C)(C)C)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN([C@@H]1c2ccccc2C[C@H]1O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-N-methyl-methanesulphonamide (0.53 g) is dissolved in 5 mL THF, combined with Bu4NF (5 mL of a 1 N solution in THF) and stirred for 2 h at RT. After the reaction is complete the reaction mixture is freed from the solvent. After the addition of CH2Cl2 it is extracted with HCl (aqu., 1 N). The organic phase is dried on MgSO4. After elimination of the solvent the mixture is purified by normal phase chromatography (CH2Cl2, MeOH). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][OH:15].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
47.6 g (0.25 mol) of 4-toluenesulphonyl chloride were dissolved in 100 ml of chloroform, 35 g (0.3 mol) of 2,2-dimethyl-1-hydroxy-butan-3-one were added and 40 ml (0.5 mol) of pyridine were introduced dropwise at 0° to 5° C. The reaction mixture was then stirred for 15 hours at room temperature and was poured onto 200 g of ice and 70 ml of concentrated hydrochloric acid, and the organic phase was separated off, washed with three times 200 ml of water, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of petroleum ether, whereupon the end product crystallized out. 46 g (71% of theory) of 2,2-dimethyl-1-tosyloxy-butan-3-one were obtained as colorless crystals of melting point 49°-52° C. ##STR11##
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:24])([F:23])[CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([C:16]([F:24])([F:23])[F:15])[CH2:18]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)C1CCCNC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(N2CCCC(C(F)(F)F)C2)c(-c2ccccc2)n1
Yield: 7.8 %

Procedure:
5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (50 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethyl)piperidine (0.40 g, 2.58 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:8][O:7][CH2:6][CH:5]1[O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:13]#N)[CH3:2].[OH-:20].[K+].[OH2:22]>OCC(CO)O>[CH2:1]([O:3][CH:4]1[CH2:8][O:7][CH2:6][CH:5]1[O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:13]([OH:22])=[O:20])[CH3:2]
Reactant: O
Reactant: [OH-]
Reactant: CCOC1COCC1Oc1cc(C#N)ccc1OC
Agent: [K+]
Solvent: OCC(O)CO
Product: CCOC1COCC1Oc1cc(C(=O)O)ccc1OC
Reaction time: 1 h

Procedure:
1.46 g (5.5 mmol) of 3-(4-ethoxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A7) and 3.0 g (55.0 mmol) of potassium hydroxide are heated at 140° C. for 3 h in 15 ml of glycerol. The mixture is treated with 50 ml of water, washed with 2×25 ml of ethyl acetate and the aqueous phase is acidified by dropwise addition of 30 ml of 2 N hydrochloric acid with ice-cooling. The mixture is subsequently stirred for 1 h, filtered and the precipitate is washed with ice water. 1.49 g of the title compound of m.p. 135-138° C. are obtained.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=O>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH:22]=[C:23]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCCc2c(F)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1=CCCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (5.00 g) in toluene (250 ml) was added dropwise ethyl diethylphosphonoacetate (23.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Then, a solution of 5-fluoro-3,4-dihydro-2H-naphthalen-1-one (18.0 g) in toluene (50 ml) was added dropwise, and the mixture was stirred at 80° C. for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl (5-fluoro-3,4-dihydronaphthalen-1-yl)acetate (17.4 g).