Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:35]2[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Product: COc1ncccc1-c1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c(Cl)n1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:11][CH2:12]OS(C)(=O)=O)[C:7]1=[O:26].[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:32]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH2:12][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:51][CH2:50]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]1=[O:26]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccccc1CN1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4ccccc4OC)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 18.5 using 1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.76 g, 2.65 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (1.15 g, 2.65 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.38 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=3)=[C:9]([F:29])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C[CH2:43][CH2:42][CH2:41]1.C(I)C=C.[NH4+].[Cl-]>CN(C=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:43][CH:42]=[CH2:41])[N:16]=3)=[C:9]([F:29])[CH:8]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cc3ccccc3)nc2s1
Reactant: C1CCOC1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=CCC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reaction time: 0.03 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-benzylthiazolo[5,4-b]pyridine (2.28 g, 5.6 mmol) in 40 mL DMF under argon was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (7.0 mL, 7.0 mmol). A very deep blue solution resulted. After 2 min, allyl iodide (0.77 mL, 8.4 mmol) was added via syringe and the reaction became brown. After 5 min, sat'd aq. NH4Cl was added and the reaction partitioned between water and EA. The organic was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was sonicated in MTBE, filtered, and dried to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylbut-3-enyl)thiazolo[5,4-b]pyridine as a yellow solid. MS (ESI) m/z: Calculated: 446.2; Observed: 447.1 (M++1).
Reaction SMILES: C([Mg]Br)CCC.[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:17][CH2:18]/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH3:23])(=O)C.ClC(O)CCCCC>[Cu].[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[CH2:18]([OH:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12]
Reactant: C/C=C/C=C/COC(C)=O
Reactant: CCCCCCBr
Agent: [Cu+2]
Agent: [Cu]
Agent: CCCCCC(O)Cl
Product: CC=CC=CCCCCCCCO

Procedure:
The copper catalyzed coupling reaction of a Grignard reagent with an organic halide, which is commonly referred to as a halide displacement reaction, was first reported in 1971 by Kochi and Tamura (J. Am. Chem. Soc. 1971, 93, 1487, Synthesis 1971, 303, J. Organomet. Chem. 1972, 42, 205). In the Synthesis paper the authors reported the coupling reaction of n-butylmagnesium bromide with n-hexyl bromide in the presence of dilithiumtetrachlorocuprate (Li2CuCl4). Since that report the use of Li2CuCl4 in coupling reactions has been quite extensive and is prominent in the synthesis of pheromones as well as in the synthesis of α,ω-olefins. One of the more interesting uses of this copper catalyzed coupling reaction may be found in U.S. Pat. No. 4,912,253 where sorbyl acetate was coupled with the Grignard prepared from the magnesium salt of chlorohexanol to form the codling moth (Laspeyresia pomonella) sex pheromone 8,10-dodecadien-1-ol on a metric ton scale. α,ω-olefins have been formed by coupling 4-pentenylmagnesium bromide with the bis-tosylate of 1,5-pentanediol to form 1,14-pentadecadiene in 81% yield (Tetrahedron 1991, 47, 6287-6292). 1,9-Decadiene has been prepared by the Li2CuCl4 catalyzed coupling reaction of 1,4-dibromobutane with allylmagnesium bromide at 25° C. in 38% yield (Synthetic Communications 1994, 24, 459-463).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:17]([O:21][C:22]([N:24]1[C@@H:29]([C@@H:30]([OH:41])[C@@H:31]([NH2:40])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH:29]([C@@H:30]([OH:41])[C@@H:31]([NH:40][C:1](=[O:3])[CH3:2])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:19])([CH3:18])[CH3:20]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 34.7 %

Procedure:
Add acetic anhydride (320 μL, 3.4 mmol) and N,N-diisopropylethylamine (590 μL, 3.4 mmol) to a solution of 5-(R)-[2-(S)-amino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (770 mg, 1.70 mmol). Stir for 2.5 hours. Dilute with ethyl acetate, wash with 1 N hydrochloric acid (twice), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 25:75 ethyl acetate:hexanes) to give the desired compound (292 mg).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:51]([CH2:53][NH2:54])[OH:52]>ClCCl.O>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:54][CH2:53][CH2:51][OH:52])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reactant: NCCO
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCO)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reaction time: 14 h

Procedure:
ylethyl)ureido]benzoic acid (obtained in Example 45) dissolved in dichloromethane are introduced into a 100 mL flask under an argon atmosphere, then HOBt (27 mg, 1.2 eq.), EDC (37 mg, 1.2 eq.), and ethanolamine (12 mg, 1 eq.) are added to the medium. After reacting for 14 hours, the mixture is neutralised with water, then with a saturated NaHCO3 solution and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with brine, then, dried over MgSO4 and concentrated. The crude product thus obtained is purified by silica column chromatography (eluent: CH2Cl2/MeOH 99/1 to 96/4). The desired amide, 3-[3-(3,3-diphenylpropyl)-3-(2-morpholin-4-ylethyl)ureido]-N-(2-hydroxyethyl)benzamide, is obtained in a yield of 52%. This procedure is hereinafter called method “J”, route 2.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30]CC)=[O:29])[CH2:23]3)[C@@H:17]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[C@@H:17]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:41])([F:1])[F:40])[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C[C@@H]2CC[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccc(F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O[C@H]1CC[C@@H](CN2CCC[C@@H](C(=O)O)C2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
To a solution of 10.14 g (17.2 mmole) of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-3-ethoxycarbonylpiperidin-1-yl)methyl)cyclopentane from Step B in 100 mL of methanol was added 17.2 mL (86 mmole) of 5N sodium hydroxide. The reaction was stirred at rt for 20 hours and was then most of the methanol was removed in vacuo. The residue was diluted with water and the pH was adjusted to 7 with 2N hydrochloric acid. The mixture was extracted 3 times with methylene chloride and each organic layer was washed with a portion of brine. The organic layers were dried over sodium sulfate and evaporated to afford 9.0 g of crude title compound as a white foam. NMR (CDCl3)δ: 1.37 (d, J=6 Hz, 3H), 1-8-2.0 (m, 2H), 2.0-2.7 (m, 12H), 2.7-3.1 (m, 2H), 3.2-3.4 (1H), 3.4-3.6 (m, 2H), 3.69 (m, 1H), 4.48 (q, J=6 Hz, 1H), 6.96 (m, 1H), 7.11 (m, 1H), 7.40 (s, 2H), 7.69 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:14][CH3:15])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (10.5 g, 31.9 mmol) in DCM (100 mL) was added 2,6-lutidine (4.8 mL, 41.4 mmol) followed by TMSOTf (7.5 mL, 41.4 mmol). The resulting solution was stirred at RT for 30 min. The solvent was removed and the remaining residue was dried under vacuum to give (S)-1-(tert-butyldimethylsilyloxy)-N-methylpent-4-en-2-amine, which was used without further purification. LRMS (M+H+) m/z 230.2.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][C:2]#[CH:3])[CH3:9])[CH3:6]
Reactant: C#CCO
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C#CCOC(C)OCC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 20 g (0.36 mol) of 2-propyn-1-ol in 637 ml (6.66 mol) of ethyl vinyl ether was treated at 0° under argon with 1.27 ml (16.7 mmol) of trifluoroacetic acid and the mixture was subsequently stirred at room temperature for 65 hours. 1.3 g of sodium carbonate were added, the reaction mixture was stirred at room temperature for a further 30 minutes and concentrated on a rotary evaporator. Distillation of the residue under reduced pressure yielded 1-(1-ethoxyethoxy)-2-propyne of boiling point 55°/30 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: COc1ccc(B(O)O)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1ccc(-c2cc(OC)nc(-n3ccc(C(F)(F)F)n3)n2)cc1
Yield: 55 %

Procedure:
4-Methoxy-6-(4-methoxy-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307d was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methoxy-phenyl)-boronic acid 306d (819 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a beige solid in 55% yield. MS (ESI, EI+) m/z=351 (MH+).
Reaction SMILES: I[C:2]1[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Br:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.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.O>[Br:24][C:25]1[C:30]([C:2]2[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]=2[CH3:8])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1c(I)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2cccnc2Br)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cccnc2Br)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 20.9 %

Procedure:
5-Iodo-3-isopropyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 85) (600 mg) and 2-bromo-3-pyridine boronic acid pinacol ester (878 mg) were dissolved in 1,2-dimethoxyethane (30 ml). Thereto were added under nitrogen atmosphere water (6 ml), sodium carbonate (290 mg), 2-(dicyclohexylphosphino)biphenyl (57.6 mg) and tetrakis(triphenylphosphine)palladium (316 mg) and the resulting mixture was stirred with heating under reflux for four and a half hours. The reaction solution was concentrated under reduced pressure and to the residue was added water, and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(2-bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (134 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14][Br:16])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reaction time: 8 h

Procedure:
2-Methyl-4-nitro-benzoic acid ethyl ester (6.0 g, 28.7 mmol), N-bromosuccinimide (5.4 g, 30.3 mmol), and benzoyl peroxide (0.695 g, 2.87 mmol) were combined in CCl4 (250 mL). The reaction was heated to reflux and stirred under a halogen lamp overnight. After aqueous work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:17]([OH:20])[C:18]#[CH:19].C(OCC)(=O)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:20][CH2:17][C:18]#[C:19][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)COc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
The compound (1.00 g, 3.00 mmol) of Example 22-1 was dissolved in triethylamine (30 ml) under an atmosphere of nitrogen. Thereto were added propargyl alcohol (0.35 ml, 6.00 mmol), copper(I) iodide (6.00 mg, 30.0 μmol) and dichlorobis(triphenylphosphine)palladium (II) (42.0 mg, 60.0 μmol) and the mixture was stirred for 1 hour at 70° C. The mixture was cooled and thereto was added ethyl acetate. The mixture was washed with 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order and dried over sodium sulfate. The solvent was removed and purified with silica gel chromatography (hexane:ethyl acetate, 3:1–2:1) to give the subject compound as a yellow oil(537 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH2:28][C:29]1[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:28][C:29]2[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1ncccc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C)c1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), 3-amino-2-(dimethylamino)pyridine (commercially available, CAS RN 5028-25-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=403.072 [M+H]+.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1.CS(O[CH2:25][CH2:26][C@H:27]1[C:32]2[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][C@H:27]4[C:32]5[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=5[CH2:30][CH2:29][O:28]4)[C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21
Temperature: 25 °C

Procedure:
(3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-methylpiperazine (0.138 g, 0.55 mmol), 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate (0.15 g, 0.50 mmol), potassium carbonate (0.138 g, 1.0 mmol), potassium iodide (0.083 g, 1.0 mmol) and acetonitrile (50 mL) were heated under reflux for 1 day with stirring under nitrogen. After cooling to room temperature, the inorganics were filtered off and the solvent evaporated in vacuo. The crude product was purified by preparative LC-MS to give the title compound. M+H=456.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15](=[O:27])[C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([Br:24])[C:17]=1[O:25]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>CCO>[ClH:28].[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15](=[O:27])[C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([Br:24])[C:17]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(OC)c1C(=O)NCC1CCCN1Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Br)c(O)c1C(=O)NCC1CCCN1Cc1ccccc1
Yield: 55 %

Procedure:
The title compound was prepared from (-)-N-benzyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 55%. M.p. (HCl) 207°-209° C. (EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)[CH:5]=[CH:6][C:7]=1[OH:8].C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: Oc1ccc2cc(-c3ccc(O)c(Cl)c3)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(3-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (346 mg, 2.59 mmol) in THF (37 mL) according to method A to yield 380 mg (68%) of yellowish solid: mp 174-175° C.; 1H NMR (DMDO-d6): δ 7.09 (1H, d, 8.47 Hz), 7.31 (1H, d, J=8.89 Hz), 7.60 (1H, dd, J=8.20 Hz, J=2.26 Hz), 7.78 (1H, d, J=2.22 Hz), 7.84 (1H, d, J=8.99 Hz), 7.88 (1H, dd, J=9.00 Hz, J=1.80 Hz), 8.05 (1H, d, J=8.86 Hz), 8.14 (1H, d, J=1.60 Hz), 10.37 (1H, s), 10.49 (1H, s);MS (ESI) m/z303/305/307 (M−H)−.
Reaction SMILES: [NH2-].[Na+].CCOC(C(P(OCC)(OCC)=O)C)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=C(C(=O)C)N=C2)C=CC=CC=1.[CH3:45]/[C:46](=[C:52](\[C:54]1[N:55]=[CH:56][N:57]([C:59]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:58]=1)/[CH3:53])/[C:47]([O:49][CH2:50][CH3:51])=[O:48]>O1CCCC1.C(OCC)C>[CH3:45]/[C:46](=[C:52](/[C:54]1[N:55]=[CH:56][N:57]([C:59]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:58]=1)\[CH3:53])/[C:47]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: CCOC(=O)/C(C)=C(\C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [NH2-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C(/C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 2 h

Procedure:
11.7 g (0.3 mol) sodium amide are suspended in 300 ml tetrahydrofurane under nitrogene. 71.47 g (0.3 mol) triethyl 2-phosphonopropionate are dropped to the stirred mixture which is kept at ambient temperature for 2 hours subsequently. 30.5 g (86.5 mmol) 1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanone are added and the mixture is held under reflux for 16 hours. Evaporation and dissolving in 1 l chloroform/2-propanol (3:1) is follwed by washing 3 times with water. Drying with sodium sulphate and evaporation result an oil which mainly consists of E-ethyl 2-methyl-3-(1-triphenylmethyl-1H-imidazol-4-yl)2-butenate. Treating this residue with diethyl ether affords 10.9 g of a solid material mainly consisting of the Z-isomer. Purification via column chromatography (silicagel 63-200 μm, eluent: petrol ether/diethyl ether [2:2]) leads to 5.6 g (14.8%) of the title compound as a white solid. An analytical sample was recrystallized from diethyl ether/ethanol resulting colourless crystals, melting point 166°-168° C.