Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1F.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[CH2:36]([O:43][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=1)[C:20]1[N:21]=[CH:22][C:23]([Br:26])=[CH:24][N:25]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OCc1ccccc1
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.1 g) is dissolved in tetrahydrofuran (20 ml), and thereto are added benzyl alcohol (6 ml) and sodium hydride (60%) (2.32 g), and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3→9:1) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (12.9 g). MS (m/z): 664/666 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CO
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: Cl
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
p-Methoxycinnamic acid was dissolved in refluxing methanol containing a catalytic amount of hydrogen chloride to form methyl p-methoxycinnamate. The yield of purified ester was 85%, m.p. 88°-89° (lit. 90°; Dictionary of Organic Compounds, II, Sir Ian Heilbron, ed., p. 600 (1946)): λmaxCCl4 3.32, 3.38 and 3.52 (CH1 -OCH3), 5.81 (C=O), 6.1 and 10.15 (CH=CH, trans), 7.95 and 8.5-8.6 (ester)μ. The NMR (δ) supported the expected structure: 6.13-7.78 (series of multiples, aromatic and vinyl), 3.86 (--CO2CH3), and 3.78 (AR--O--CH3).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)=[N:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3cc(Br)ccc23)cc1Cl
Reactant: F[B-](F)(F)CN1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc(-c3cccnc3)nc3cc(CN4CCCCC4)ccc23)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 22.3 %

Procedure:
A dry 15 mL sealed tube was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), potassium 1-trifluoroboratomethylpiperidine (52.5 mg, 0.256 mmol), cesium carbonate (227.5 mg, 0.698 mmol), Pd(OAc)2 (1.6 mg, 3 mol %) and XPhos (6.7 mmol, 6 mol %) in THF/water (10:1, 3.3 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered through a pad of Celite and solvent was removed in vacuo. The crude product was purified by ISCO (silica, 12 g column, 97% dichloromethane-3% methanol-0.1% NH4OH) to yield the desired compound as a yellow solid (23.3 mg, 22%). LCMS m/z=448.0 (M+1) (Method C) (retention time=1.95 min). 1H NMR (300 MHz, CD3OD) δ 9.40 (d, J=1.4 Hz, 1H), 8.70-8.62 (m, 1H), 8.56 (dd, J=4.9, 1.6 Hz, 1H), 8.18-8.09 (m, 2H), 7.69 (ddd, J=6.8, 4.1, 2.1 Hz, 2H), 7.54-7.45 (m, 2H), 7.23 (t, J=9.0 Hz, 1H), 3.61 (s, 2H), 2.47 (s, 4H), 1.64 (dd, J=13.9, 8.9 Hz, 5H), 1.49 (d, J=4.1 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH2:6]2.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:7]12[CH2:8][CH2:9][C:2](=[O:1])[CH:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: OC1CCC2CCCC12
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C1CCC2CCCC12
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxyoct-1-enyl]-6-hydroxybicyclo[3,3,0]octane (430 mg prepared as described in Reference Example 25 and predominantly in the 2β-configuration) in dry dichloromethane (15 ml) was treated with potassium acetate (127 mg), potassium carbonate (110 mg) and pyridinium chlorochromate (561 mg), and the mixture was stirred for 150 minutes at 20° C. A further quantity of pyridinium chlorochromate (120 mg) was then added and the mixture was stirred for a further period of 1 hour. The mixture was then concentrated in vacuo and subjected to chromatography on a silica gel column, using a mixture of ethyl acetate and hexane (1:4 v/v) as eluant, to give (E)-2-[(mixture of 3α and 3β)-tertbutyldimethylsilyloxyoct-1-enyl]bicyclo[3,3,0]octan-6-one (330 mg), predominantly in the 2β-configuration.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C:15](=[C:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][C:31]([Cl:36])([CH2:35][CH:27]2[CH2:28]4)[CH2:32]3)[O:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][CH:14]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:9]1[CH:10]=[C:11]([C:15](=[C:26]2[CH:27]3[CH2:28][CH:29]4[CH2:30][C:31]([Cl:36])([CH2:32][CH:33]2[CH2:34]4)[CH2:35]3)[O:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC2CC(Cl)(C4)C3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC2CC(Cl)(C4)C3)c1
Reaction time: 2 h

Procedure:
To a solution of 4.9 parts of alkene (64) in 75 mL of THF was added 5.0 parts of 70% mixture of tetra-n-butylammonium fluoride in 25 mL of THF over a period of 15 minutes. The reaction mixture was stirred for two hours. TLC on silica gel plate showed the formation of new product. The solvent was evaporated under reduced pressure and the oily material was dissolved in 150 mL of ethyl acetate and washed with two times with 200 mL of water. After drying over anhydrous sodium sulfate, the solvent was evaporated and the oily product was purified on silica gel column. TLC on silica gel plate of the fractions were checked and the combined organic solvent was evaporated, yield 2.5 parts. The structure of the product was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:30])[CH3:29]>>[CH:28]([O:27][CH2:26][CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:30])[CH3:29]
Reactant: CC(C)OCCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCOC(C)C)cn1
Yield: 74 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-aminoethyl isopropylether instead of methylamine, to the title compound (190 mg, 74%) which was obtained as a white solid. MS: m/e=454.1 [M+OAc]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[F:17])=[C:5]([OH:20])[CH:4]=1)[CH3:2].[C:21]([NH:28][CH2:29][C:30](O)=[O:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][C:30](=[O:31])[CH2:29][NH:28][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[C:9]([F:17])[CH:10]=1)(=[O:16])[CH3:15]
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(O)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (0.37 mmol; 100 mg) in dry THF (2 mL) cooled to 0° C. were added, N-Boc-glycine (0.37 mmol; 64 mg), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro phosphate (0.37 mmol; 190 mg) and triethylamine (1.09 mmol; 153 μL). The reaction was stirred at 0° C. for 3 hours and overnight at room temperature. The mixture was concentrated, treated with saturated NH4Cl and extracted with dichloromethane. Combined organic phases were washed with water, dried over Na2SO4 and concentrated in vacuo. The title compound (91 mg; 58%) was obtained as clear oil after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: Cl.[C:2]([O:21][CH:22]1[CH2:25][NH:24][CH2:23]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CS(C)=O.C(OCC)(=O)C.O>[Cl:38][CH2:37][CH2:36][CH2:35][N:24]1[CH2:23][CH:22]([O:21][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:25]1
Reactant: c1ccc(C(OC2CNC2)(c2ccccc2)c2ccccc2)cc1
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: ClCCCN1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 5 mL of dimethyl sulfoxide was dissolved 0.50 g of 3-(trityloxy)azetidine hydrochloride, and to the solution were added 0.49 g of potassium carbonate, 0.35 g of potassium iodide and 0.22 mL of 1-bromo-3-chloropropane, after which the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 15 mL of water and 10 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-(3-chloropropyl)-3-(trityloxy)azetidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9]([N:12]=[C:13]=[O:14])[CH:10]=[CH2:11]>CN(C)C=O>[CH2:9]([NH:12][C:13]([N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14])[CH:10]=[CH2:11]
Reactant: O=c1ncc(Br)c[nH]1
Reactant: C=CCN=C=O
Solvent: CN(C)C=O
Product: C=CCNC(=O)n1cc(Br)cnc1=O
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (2 mmol) and allylisocyanate (3 mmol) in dimethyl formamide (2 ml) was stirred together at room temperature until a clear solution resulted (ca. 3 h) before the solvent was distilled off at 1 mmHg, the residue triturated with ether and then with water; the residue was the title compound, yield 59%. MS (70 eV) m/e: 257/255 (M,O), 176 (31), 174 (33), 148 (9), 106 (8), 104 (8), 95 (60), 83 (20), 56 (100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.[Li+].[OH-]>O.C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
To a solution of methyl 4-(4-chloro-2,5-difluorophenyl)nicotinate (400 mg, 1.41 mmol) in water:THF (1:1, 8 mL) was added LiOH (67.5 mg, 2.82 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (5 mL) and washed with ethyl acetate (2×5 mL). The aqueous layer was separated and acidified with 1.5N HCl and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)nicotinic acid (180 mg, 0.541 mmol, 38% yield) as a solid. LC/MS (ESI) m/e 270 [(M+H)+, calcd for C12H7ClF2NO2 270]; LC/MS retention time (method B): tR=1.48 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(Br)c3)CC2)cc1
Yield: 65.5 %

Procedure:
0.38 g (0.001.41 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.49 ml (0.0035 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.23 ml (0.00176 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.358 g (65%) of 1-(3-bromo-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:9]#[C:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccncc1
Reactant: N#Cc1ccccc1
Product: C(#Cc1ccncc1)c1ccccc1
Reaction time: 20 h
Yield: 44 %

Procedure:
The procedure was identical to Example 2, with the exception that 4-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 0.88 mmol (44% yield) of 4-(phenylethynyl)pyridine, and no remaining 4-cyanopyridine in the reaction mixture.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[CH2:20](OCC)[CH3:21]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:15]([C:14]1[CH:13]=[C:12]([OH:11])[CH:19]=[CH:18][CH:17]=1)=[CH:20][CH3:21]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=Cc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of (ethyl)triphenylphosphonium bromide (35 g, 94.3 mmol) in THF (95 mL) was added potassium bis (trimethylsilyl)amide (180 ml, 0.5M in toluene, 90.2 mmol) dropwise. The reaction was stirred at 0° C. for 30 min, then a solution of 3-hydroxy-benzaldehyde (5 g, 41.0 mmol) in THF (5 mL) was added dropwise. After addition the reaction was stirred at 0° C. for 1 h. Ethyl ether (200 mL) was added to dilute the reaction. The organic layer was washed with water (50 mL×2), brine (50 mL×2) and dried over magnesium sulfate. Purification was performed by flash chromatography on 600 g silica gel, loaded and eluted with 10% ethyl acetate in hexane. Pure fractions were combined and evaporated to give the title compound (5.1 g, 93%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[O:11].[CH:12](Cl)([CH3:14])[CH3:13]>C(=S)=S>[CH:12]([C:8]1[CH:7]=[C:6]([CH:10]=[O:11])[O:5][CH:9]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Cl
Reactant: O=Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)c1coc(C=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension containing aluminium chloride (24 g, 180 mmol) in 100 mL of CS2 was added 2-furaldehyde (9.8 mL, 156 mmol). To this mixture was added dropwise isopropyl chloride (14.3 mL, 156 mmol), and the resulting mixture stirred at rt for 24 h. The dark mixture was carefully poured into a vigorously stirred 250 g of ice, and then extracted with ether (5×100 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered through a pad of silica gel, and concentrated. The residue was purified by flash chromatography (0-5% EtOAc in heptane) to give 4-isopropylfuran-2-carbaldehyde as an orange oil: Yield 3.5 g (16%). 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (d, J=6.88 Hz, 6H), 2.80-2.91 (m, 1H), 7.16-7.18 (m, 1H), 7.47 (q, J=0.91 Hz, 1H), 9.61 (d, J=0.59 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a mixture of 4-chloro-2-fluoronitrobenzene (175 mg, 1.00 mmol) and K2CO3 (139 mg, 1.00 mmol) in toluene (2 mL), morpholine (87 μL, 1.0 mmol) was added at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction mixture was concentrated and the product was isolated by flash chromatography on silica (20% EtOAc/hexane) to obtain 4-(5-Chloro-2-nitro-phenyl)-morpholine (205 mg, 67%). This compound (243 mg, 1.00 mmol) was dissolved in 1-methylpiperazine (1 mL) and the resulting mixture was heated at 130° C. overnight. The reaction mixture was diluted with water and the product was extracted with DCM (3×10 mL). The DCM layers were combined, dried (Na2SO4) and concentrated to obtain the title compound (177 mg, 58%). 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.4 Hz), 6.46 (dd, 1H, J=9.4, 2.6 Hz), 6.31 (d, 1H, =2.6 Hz), 3.89 (m, 4H), 3.40 (m, 4H), 3.07 (m, 4H), 2.50 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.[F:31][C:32]1([F:43])[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33]1>C(#N)C>[F:43][C:32]1([F:31])[CH2:36][CH2:35][N:34]([CH:37]2[CH2:38][CH2:39][N:40]([CH2:2][C:3]3[C:4]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[N:5][C:6]4[C:11]([C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=4)[CH2:41][CH2:42]2)[CH2:33]1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: FC1(F)CCN(C2CCNCC2)C1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCC(F)(F)C3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
To a suspension of methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.05 g, 2.090 mmol) in acetonitrile (13.94 mL) was added 4-(3,3-difluoro-1-pyrrolidinyl)piperidine (0.517 g, 2.72 mmol). After 15 h, additional 4-(3,3-difluoro-1-pyrrolidinyl)piperidine (0.188 g, 0.988 mmol, 0.47 equiv.) was added. The mixture was stirred at room temperature for 4 days. The solvent was removed, and the residue was absorbed onto florisil and purified via column chromatography (ISCO 0.5-3% methanol/methylene chloride) to give methyl 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.976 g, 73% yield) as a yellow foam. MS (m/z) 612.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(#N)N(C)C>[Br:20][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:19])=[O:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)cc1
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Yield: 78.3 %

Procedure:
4 g of N-methoxy-N-methyl-4'-methyl-4-biphenylcarboxamide, 3.34 g of N-bromosuccinimide and 0.02 g of azaisobutyronitrile in 50 mL of carbon tetrachloride were heated to boiling under reflux for 18 hours. The reaction mixture was diluted with 50 mL of methylene chloride and washed twice with 50 mL of water each time and once with 50 mL of saturated sodium chloride solution. The organic phases were dried over magnesium sulphate and concentrated. The residue was recrystallized from ethyl acetate. There was obtained 4.1 g (78%) of 4'-bromomethyl-N-methoxy-N-methyl-4-biphenylcarboxamide as a solid with a m.p. of 105°-106° C.