Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:21])=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[C:10](=O)[CH2:9][CH:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:21])=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[C:10](=[N:25][OH:26])[CH2:9][CH:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=NO)CC1C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
A stirred solution of 6-fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (940 mg, 2.8 mmol), hydroxylamine hydrochloride (215 mg, 3.1 mmol), and sodium acetate (254 mg, 3.1 mmol) in ethanol (20 mL) was heated at reflux for 3 h. Water (25 mL) was added, and the volatiles were removed in vacuo. Ethyl acetate (100 mL) was added, and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (937 mg, ca. 100%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 2.73 (dd, 1H), 3.09 (d, 1H), 5.0-5.1 (m, 2H), 7.68 (d, 1H), 7.88 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:26]([OH:28])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)C>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:26]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:25])[F:23])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][CH3:30])=[O:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxy-indoline-2(S)-carboxylic acid (0.432 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.271 g, 2 mmol) were dissolved in dried dichloromethane (20 ml) under nitrogen at 0° C., and triethylamine (0.7 ml, 5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.509 g, 2 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 8:2 dichloromethane: diethyl ether as eluent to provide an off-white solid as the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5](O)[CH3:6].C[O-:9].[Na+].N#N.[OH:13][CH:14]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=O>C1COCC1.O>[OH:9][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([OH:13])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CC(O)NCCN
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OCC
Reactant: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(O)CCCCCCCCCCC(=O)NCCNCCO
Yield: 737.2 %

Procedure:
A 30-ml two-necked flask equipped with a stirrer and dropping funnel was charged with 2.08 g (20 mmol) of aminoethylaminoethanol and 0.054 g (1 mmol) of sodium methoxide. While heating and stirring the contents at 80° C. in an N2 atmosphere, a solution of 3.29 g (10 mmol) of ethyl 12-hydroxystearate in 10 ml of THF was added dropwise over 2 hours. The resultant mixture was stirred further for 13 hours at 80° C. under reduced pressure. After completion of the reaction, the reaction mixture was poured into 500 ml of water, and precipitate formed was purified by flash column chromatography on silica gel, thereby obtaining 2.85 g (yield: 74%) of the title compound (IIf-1).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35]>CO>[NH3:8].[F:30][C:28]([F:31])([F:29])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][NH:37][CH:34]([CH3:36])[CH3:35])=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: CC(C)N
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: CO
Product: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Product: N
Temperature: 140 °C
Yield: 154.2 %
Yield: 2 %

Procedure:
To a 20 mL of microwave vial was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (1.0 g, 1.9 mmol, Intermediate B), isopropylamine (2.5 mL, 28 mmol, Aldrich, St. Louis, Mo.), and MeOH (10.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (80 g of silica gel, 100% CH2Cl2 first then 2 to 5% 2M NH3 in MeOH/CH2Cl2) to afford 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.720 g) as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH3:12]
Reactant: CCBr
Reactant: Oc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cccc2cc[nH]c12
Reaction time: 18 h

Procedure:
7-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].B(Br)(Br)Br.N#N>C(Cl)Cl>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2cc(OC)ccc21
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: CCC1CCNc2cc(O)ccc21
Temperature: 0 °C
Yield: 97.5 %

Procedure:
In a flame dried 100 mL rb flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline (21 mg, 109.9 μmol) in CH2Cl2 (4 mL). The solution was cooled to 0° C. and a 1.0M solution of BBr3 in CH2Cl2 (0.33 mL, 320 μmol, 2.75 equiv) was added slowly by syringe. The solution was warmed to rt and stirred under a blanket of N2 for 9 h. The reaction was quenched by addition of sat. NaHCO3 solution (5 mL), extracted with CH2 Cl2 (3×25 mL), washed with brine (2×20 mL), dried (Na2SO4) and concentrated in vacuo to give 19 mg (99%) of the desired phenolic amine as a clear yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 6.85 (d, J=8.1, 1H), 6.11 (dd, J=2.4, 8.3, 1H), 5.98 (d, J=2.4, 1H), 3.25 (m, 2H), 2.57 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 0.940 (t, J=7.4, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:22]([NH2:24])=[O:23])=[C:13]([NH:15]C2C=NC=CC=2)[N:14]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([CH3:35])[CH:33]=[CH:34][C:27]=12.BrC1C=NC=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:22]([NH2:24])=[O:23])=[C:13]([NH:15][C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[N:32]([CH3:35])[CH:33]=[CH:34][C:27]=23)[N:14]=1
Reactant: Cn1ccc2c(Cl)ccnc21
Reactant: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccnc1
Solvent: Brc1cccnc1
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)ccnc21

Procedure:
The title compound was prepared in the same procedure as described in Example 3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide. Here, 4-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine was utilized as the coupling partner instead of 3-bromopyridine. MS found for C18H23N9O as (M+H)+ 382.4. UV: λ=213, 263 nm. Proton NMR: (CD3OD) δ 8.78 (1H, br), 8.28 (1H, br) 7.46 (1H, d, J=3.6 Hz), 6.76 (1H, m), 4.82 (1H, m), 3.93 (3H, s), 3.73 (1H, br), 2.01-1.60 (8H, m) ppm.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][N:34]([CH3:39])[S:35]([NH2:38])(=[O:37])=[O:36])(C(C)(C)C)(C)C.C(O)C.Cl>O1CCCC1.O>[C@@H:24]1([NH:23][C:22]2[C:17]3[CH:16]=[CH:15][N:14]([C@@H:12]4[CH2:11][C@@H:10]([CH2:33][N:34]([CH3:39])[S:35]([NH2:38])(=[O:37])=[O:36])[C@@H:9]([OH:8])[CH2:13]4)[C:18]=3[N:19]=[CH:20][N:21]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CN(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C)S(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[((1S,2S,4R)-2-[tert-Butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]-N-methylsulfamide (25.0 mg, 0.0000438 mol) was dissolved in tetrahydrofuran (2.0 mL), ethanol (2.0 mL) and 1.00 M of hydrochloric acid in water (2.0 mL). The mixture was stirred overnight at room temperature. The solution was evaporated to dryness, and the residue was dissolved in methanol and treated with a 7.00 M solution of ammonia in methanol (0.1 mL). Solvents were again evaporated, and the residue was purified by silica gel chromatography, eluting with 2 to 10% methanol in dichloromethane to yield the product, 9.8 mg (49%). 1H-NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, 1H, J=3.6 Hz), 5.84 (t, J=7.7 Hz, 1H), 5.43 (ddd, J=4.5 Hz, 8.6 Hz, 12.8 Hz, 1H), 4.43 (t, J=3.7 Hz, 1H), 3.25 (dd, J=8.1 Hz, 13.7 Hz, 1H), 3.14 (dd, J=7.2 Hz, 13.7 Hz, 1H), 3.05 (ddd, J=3.3 Hz, 8.8 Hz, 15.8 Hz, 1H), 2.91 (m, 1H), 2.74 (m, 1H, 2.63 (m, 1H), 2.34 (ddd, J=1.1 Hz, 7.8 Hz, 13.6 Hz, 1H), 2.20 (m, 2H, 1.99 (m, 2H). LC/MS: Rt=1.51 min, ES+ 457 (AA standard).
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[N+:10]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH:16]=[CH:17][CH:18]=[N:19][NH:20][C:21]([NH2:23])=[S:22])([O-])=O>[H][H].[S]>[NH2:10][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH:16]=[CH:17][CH:18]=[N:19][NH:20][C:21]([NH2:23])=[S:22]
Reactant: NC(=S)NN=CC=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [S]
Solvent: CCO
Product: NC(=S)NN=CC=Cc1cccc(N)c1
Temperature: 50 °C
Yield: 67.9 %

Procedure:
A solution of 10 mL ethanol and 2 mL sodium carbonate 2N is saturated in hydrogen sulfur. 500 mg (2 mmoles) 3-nitrocinnamaldehyde thiosemicarbazone prepared in step 2A are added. The solution is heated 10 minutes at 50° C., then 3 minutes at 75° C. The solution is cooled in a ice bath. The crystals formed are filtered, washed with ethanol. 299 mg of 3-aminocinnamaldehyde thiosemicarbazone is obtained. Yield 68%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=1)=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of 5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (85 mg, 0.2004 mmol) in methylene chloride (5 ml) were added 4-trifluoromethylaniline (48 mg, 0.2981 mmol), triethylamine (41 mg, 0.4059 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (102 mg, 0.6035 mmol) followed by stirring at room temperature for 3 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (60 mg, 0.1060 mmol, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCOCC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 105 °C
Yield: 21 %

Procedure:
To a sealed tube was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (900 mg, 1.91 mmol), ethanol (12 mL), piperidine (0.23 mL, 2.29 mmol) and 2-methyl-2-morpholino-propanal (0.49 mL, 2.86 mmol). The tube was sealed and heated to 105° C. for 24 hrs. The mixture was then cooled, concentrated and then dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (100 ml) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (column size 100 g. Solvent system 4%-8% MeOH/EtOAc) to obtain 245 mg (21% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1cccc(C#CCCCCO)c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cccc(CCCCCCO)c1)(c1ccccc1)c1ccccc1
Reaction time: 17 h
Yield: 660.4 %

Procedure:
To a solution of 6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hex-5-ynol (880 mg, 2 mmol) in ethyl acetate (10 mL) is added Pd on Carbon (120 mg, 10% Pd by wt.). The mixture is stirred under a hydrogen atmosphere for 17 h, purged with argon filtered through celite concentrated to give the title compound (5.9 g) as an oil. MS (EI) 389 (M−tBu)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[CH3:26][NH:27][CH:28](O)[CH3:29].[O:31]1CCOCC1>>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([N:27]([CH3:26])[CH2:28][CH2:29][OH:31])=[N:3][CH:4]=1
Reactant: CNC(C)O
Reactant: C1COCCO1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Product: CN(CCO)c1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 75 %

Procedure:
A 1,4-dioxane (2.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and methylaminoethanol (200 μl) was stirred at 110° C. for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (164 mg, 75%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>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.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 g, 0.0006 mol), Cu(I)I (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 0.013 mol). Next, TEA (5.19 g, 0.05 mol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M−H)−=314.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.CN([CH:21]=[O:22])C.C(O)(=O)C.[S:27](S([O-])=O)([O-:30])(=[O:29])=[O:28].[Na+:34].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:21]([OH:22])[S:27]([O-:30])(=[O:29])=[O:28])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1.[Na+:34]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)([O-])C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-Chloro-4-fluoro-benzotrifluoride (5.0 g, 25.18 mmol) in THF (40 ml) was added at −78° C. n-BuLi (1.6 M in hexanes, 16.53 ml, 26.45 mmol, 1.05 equiv.) over a period of ca. 20 min. The clear yellow solution was stirred for 15 min at −78° C. and then transferred dropwise via cannula to a pre-cooled (−78° C.) solution of DMF (2.14 ml, 27.7 mmol, 1.1 equiv.) in THF (100 ml) such as that the internal temperature stayed below −65° C. The light yellow reaction mixture was stirred for 2 h at −78° C., was then warmed to 0° C. and quenched upon addition of a acetic acid (4.32 g, 75.54 mmol, 3.0 equiv.) and water (50 ml) keeping the temperature below 5° C. The turbid light yellow suspension was stirred for 2 h, the precipitate was filtered off with suction on a funnel with a fritted disk and the filter cake was washed with TBME (30 ml). The organic phase was separated and washed with water (50 ml), whereas the aqueous phase was washed with TBME (50 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvents were removed under vacuum and the residue was treated with toluene (40 ml) and a solution of sodium pyrosulfite (5.42 g, 27.95 mmol, 1.11 equiv.) in water (12 ml) was added, whereupon a white suspension was formed. The suspension was stirred overnight (ca. 15 h), the precipitate was filtered off, washed with toluene (20 ml) and dried under vacuum to yield the title compound as a light yellow crystalline compound (7.82 g, 93.9% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:29][C:30]#[N:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cccc(C(=O)c2ccc(OC)c(OC)c2)c1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2ccc(OC)c(OC)c2)c1
Yield: 91.7 %

Procedure:
(3,4-Dimethoxyphenyl)-(3-methoxyphenyl)methanone (CC-15126, 5193-25-B, 2.00 g, 7.35 mmol), cyanomethylphosphonic acid diethyl ester (2.31 ml, 14.69 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 14.69 ml, 14.69 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile as a pink oil (1.99 g, 92%): 1HNMR (DMSO-d6) δ 7.46-7.30 (m, 2H, Ar), 7.14-7.04 (m, 4H, Ar), 6.98-6.84 (m, 7H, Ar), 6.72-6.68 (m, 1H, Ar), 6.32 (s, 0.85H, double bond proton of one isomer), 6.20 (s, 0.97H, double bond proton of the other isomer), 3.83-3.73 (multiple singlets, 18H, 6OCH3); 13C NMR (CDCl3) δ 162.8, 162.7, 159.7, 159.6, 151.3, 150.8, 149.0, 148.8, 140.9, 138.6, 131.5, 129.7, 129., 129.5, 123.4, 122.3, 122.2, 121.3, 118.4, 118.2, 116.0, 115.9, 115.0, 114.5, 112.8, 111.2, 110.9, 110.9, 93.8, 93.3, 56.2, 56.1, 56.1, 55.5; Anal. Calcd. For C18H17NO3: C, 72.20; H, 6.09; N, 4.43 (+0.04H2O). Found: C, 72.33; H, 6.10; N, 4.60.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6]1)([CH3:4])(C)C.[CH3:11][CH2:12][O:13][CH2:14][CH3:15].[C:16]([CH:20]1[C:24](=O)[CH:23]=[CH:22][CH2:21]1)([CH3:19])(C)C.CCOCC.[C:31]([CH:35]1C(C(C)(C)C)C(=O)[CH:37]=[CH:36]1)(C)(C)[CH3:32].CCOCC>>[CH2:1]([CH:5]1[CH:9]([CH2:24][C:20]2[CH:16]=[CH:19][CH:23]=[CH:22][CH:21]=2)[C:8](=[O:10])[CH:7]=[CH:6]1)[C:4]1[CH:37]=[CH:36][CH:35]=[CH:31][CH:32]=1.[CH3:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: CC(C)(C)C1C=CC(=O)C1C(C)(C)C
Reactant: CC(C)(C)C1CC=CC1=O
Reactant: CC(C)(C)C1C=CC(=O)C1
Solvent: CCOCC
Product: O=C1C=CC(Cc2ccccc2)C1Cc1ccccc1

Procedure:
Structures of 4-t-butylcyclopentenone ether, 5-t-butylcyclopentenone ether and 4,5-di-t-butylcyclopentenone ether were confirmed by NMR as described in Referential Example 1-(21). The results are shown below.