Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([N:9]=[C:10]=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH3:30])[C:16]=1[C:17]([OH:19])=O>C(OCC)C>[CH2:28]([O:27][C:25]([C:21]1[C:20]([CH3:30])=[C:16]2[C:15](=[CH:23][C:22]=1[CH3:24])[NH:14][C:10](=[O:11])[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:12])[F:13])[C:17]2=[O:19])=[O:26])[CH3:29]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Solvent: CCOCC
Product: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
α,α,α-Trifluoro-o-tolyl isocyanate (434 mg) was added to a solution of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid (500 mg) in diethyl ether (22 ml), and the mixture was stirred overnight. The resulting precipitate was filtered off and dissolved in ethanol (15 ml). Then, hydrogen chloride (1 g) was introduced into the solution. The reaction mixture was refluxed for 3 hours and the solvent was evaporated off. The residue was recrystallized from diethyl ether to give 6-ethoxycarbonyl-5,7-dimethyl-3-[2-(trifluoromethyl)phenyl]-2,4-(1H,3H)-quinazolinedione (575 mg, 67%) melting at 175°-176° C. MS: m/e, 406(M+), 377, 361, 357, 337, 332, 314, 309. NMR: δ(ppm, CDCl3) 1.40 (3H, t), 2.30 (3H, s), 2.68 (3H, s), 4.44 (2H, q), 6.70 (1H, b), 7.2-8.0 (4H, m), 10.25 (1H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[C:8]([S:10][CH3:11])[C:7]([S:12][CH3:13])=[CH:6][C:4]=1[NH2:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:5][C:4]1[CH:6]=[C:7]([S:12][CH3:13])[C:8]([S:10][CH3:11])=[CH:9][C:3]=1[S:2][CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1cc(SC)c(SC)cc1N
Product: CSc1cc(SC)c(SC)cc1NC(C)=O
Yield: 62 %

Procedure:
N-Acetyl 2,4,5 trimethylthioaniline was prepared by dissolving 2,4,5 trimethylthioaniline (33 g, 0.143 mol) in 200 mL of acetic anhydride at room temperature. Ligroin (800 mL) was added and the mixture was stirred and cooled until the product precipitated. The solid was collected and dried (24 g, 62% yield), mp 87-89° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:22]=2)[C:27]([OH:28])=[C:18]([C:16]([NH:15][CH2:14][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:38])=[O:5])=[O:17])[N:19]=1)#[N:37]
Reactant: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 2-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-2-propyl-pentanoic acid tert-butyl ester (180 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (150 mg). LC MS ESI+: 462 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:45][C:44]5[CH:43]=[CH:42][C:41]([N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:47][CH:46]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 4-(4-methylpiperazin-1-yl)aniline with yield 82 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s., 4 H) 1.73 (br. s., 2 H) 1.99 (br. s., 2 H) 2.22 (s, 3 H) 2.45 (br. s., 4 H) 3.09 (br. s., 4 H) 3.94 (s, 3 H) 4.08 (t, J=13.89 Hz, 2 H) 4.84 (br. s., 1 H) 6.91 (d, J=8.84 Hz, 2 H) 7.26 (d, J=6.32 Hz, 1 H) 7.56 (d, J=8.59 Hz, 2 H) 8.08 (s, 1 H) 8.18-8.41 (m, 2 H) 9.91 (br. s., 1 H). [M+H] calc'd for C32H37F3N8O3, 639; found 639.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:18]1[N:17]=[C:16]([NH2:15])[CH:21]=[N:20][CH:19]=1
Reactant: Nc1cncc(Cl)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cncc(N)n1
Yield: 34 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-amino-6-chloropyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 47 mg, 34%) which was obtained as a brown solid. MS: m/e=277.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and p-anisoyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as a white powder (58.2 mg, 69%). HPLC, Rt: 3.19 min. (purity 97.0%).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([OH:36])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[C:38]([O:36][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]=1)([CH3:45])[CH3:44])[CH3:43]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A mixture of 3-phenethyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.3 Hz, 2H), 7.64 (t, J=8.3 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.26-7.17 (m, 2H), 7.13 (dd, J=12.3, 7.3 Hz, 3H), 4.24-4.19 (m, 4H), 2.98 (t, J=6.6 Hz, 2H), 2.81 (s, 4H), 2.32 (s, 3H), 1.48 (s, 6H), 1.27 (t, J=7.1 Hz, 3H), MS (ES) m/e 590 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:22]>CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][C:8]=1[CH:9]=[O:22])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1N1CCCCC1
Reactant: O=[Se]=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1N1CCCCC1
Reaction time: 1.5 h

Procedure:
27 g of 5-cyano-6-methyl-2-piperidinyl-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) and 12.2 g selenium dioxide (0.11 mol) are refluxed together in diethyleneglycoldimethyl ether with stirring for 1.5 hours. The solvent is distilled off in vacuo and the oily residue crystallized with diethyl ether. Yield 19 g (66%); m.p. 62°-64° C. (ether).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCC=CCc1ccccc1
Agent: [Pd]
Product: O=C(O)CCCCCCCCCCCc1ccccc1
Yield: 97.2 %

Procedure:
This compound was synthesized from 12-phenyl-10-dodecenoic acid (1.92 g, 7 mmol) by a hydrogenation reaction using Pd/C (190 mg). Crystallization (petroleum ether) afforded the product (1.88 g, 97%) as white crystals (mp 47-48° C.). IR: 3400-2500, 1700 cm-1 ; 1H-NMR: 1.30 (m, 14H), 1.60 (m, 4H), 2.32 (t, 2H), 2.57 (t, 2H), 7.20 (m, 5H), 10.20 (bs, 1H). Anal. Calcd. for C18H28O2 : C, 78.21, H, 10.21%;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:26]1[CH:27]=[C:28]2[C:23]([CH:22]=[CH:21][NH:20]2)=[CH:24][CH:25]=1)=[O:30]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1H-indole-6-carboxylic acid. MS: 403.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[C:27]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:29])=[N:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCc1ncccc1NC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of (4-Aminobutyl)-carbamic acid tert-butyl ester and (2-formylpyridin-3-yl)carbamic acid tert-butyl ester in MeOH with NaBH4 gave {2-[(4-tert-butoxycarbonylamino-butylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a clear residue. 1H NMR (CDCl3): δ 1.44 (s, 9H), 1.53 (s, 9H), 1.55 (m, 4H), 2.67 (m, 2H), 3.13 (m, 2H), 4.07 (s, 2H), 4.53 (m, 1H), 7.15 (dd, 1H, J=6, 3 Hz), 8.11 (dd, 1H, J=6, 3 Hz), 8.33 (d, 1H, J=9 Hz), 10.09 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][O:7][CH2:6]1.C([Mg]Cl)(C)C.CN([CH:23]=[O:24])C>C1COCC1>[F:14][C:12]1[CH:11]=[CH:10][C:3]([O:4][CH:5]2[CH2:9][CH2:8][O:7][CH2:6]2)=[C:2]([CH:13]=1)[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Fc1ccc(OC2CCOC2)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1OC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of 3-(2-bromo-4-fluorophenoxy)tetrahydrofuran (50.0 g, 191 mmol) in 400 ml of dry THF at −78° C., isopropyl magnesium chloride (2M in THF) (240 ml, 479 mmol) was added drop wise, stirred the reaction mixture at room temperature for 4 h, again cooled the reaction mixture at −78° C., DMF (22.1 ml, 287 mmol) was added, stirred the reaction mixture at room temperature for 1 h, quenched with NH4Cl solution (400 ml), diluted with EtOAc (1.0 L), washed with water and brine solution, dried over sodium sulfate and concentrated to dryness to afford the title product 38.0 g (crude).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.7 %

Procedure:
2.4 ml of aqueous 2.5 N sodium hydroxide solution was added to a solution of 0.44 g of ethyl 5-fluoropyridine-2-carboxylate in 5 ml of tetrahydrofuran and 2 ml of methanol, and stirred at room temperature for 15 minutes. This was neutralized with aqueous 10% citric acid solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure to obtain 0.41 g of the entitled compound as a white crystal.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])([CH3:26])[C:34]([F:37])([F:36])[F:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)(O)C(F)(F)F)C1=O
Reaction time: 2 h

Procedure:
A solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (30 mg, 0.065 mmol; Example 149, Step B) and trimethyl(trifluoromethyl)silane (48.5 μL, 0.327 mmol) in THF (0.5 mL) was treated with 1 M tetrabutylammonium fluoride solution in THF (196 μL, 0.196 mmol) at 0° C. After being stirred for 2 h, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by the flash chromatography on silica gel (eluent: 10 to 20% EtOAc/Hexane, gradient elution) to provide the title compound as the major product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16]
Reactant: Cc1cccc(C=CCBr)c1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(OC2(CC=Cc3cccc(C)c3)C=CC=CC2C=NO)n1
Yield: 64.1 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.2 g of 3-methylcinnamyl bromide were dissolved in 30 ml of acetonitrile containing 2.7 g of anhydrous potassium carbonate, and the solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetonitrile was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate:4:1) to obtain 5.2 g of 0-(3-methylcinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as crystals.
Reaction SMILES: C([N:3](CC)CC)C.FC(F)(F)S(O[C@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)=O>ClCCl>[NH2:3][C@H:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:22]
Reactant: CCN(CC)CC
Reactant: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-nitrophenylalanine, ethylester, hydrochloride (2.3 g) in dichloromethane (10 ml), add triethylamine (2.55 ml) and then t-butyl 2(R)-(trifluoromethanesulfonyloxy)propionate (2.80 g) (see Preparation 4) in dichloromethane (10 ml). Stir the resulting solution at room temperature for 20 hours. Concentrate the reaction mixture, add diethyl ether and extract with salt solution. Dry over magnesium sulfate and concentrate the ether solution in vacuo to give an oil. Place the oil on a column of silica gel (100 ml, 60-200 mesh) and elute with diethyl ether:hexane 60:40 to give N-[1(S)-ethoxycarbonyl)-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl.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>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C#Cc1cc(CO)nc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
C2 (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL, 68 mmol), bis(triphenylphosphine)palladium dichloride (1.02 g, 1.46 mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl3/40 mL THF under N2. TEA (21 mL, 151 mmol) is added, and the reaction is stirred 3 h at rt and is diluted with 200 mL CHCl3. The mixture is washed with 2×150 mL 5% HCl and the combined aqueous layers are extracted with 2×50 mL CHCl3. The combined organic layer is washed with 100 mL 50% saturated NaCl, is dried over anhydrous MgSO4, and is concentrated in vacuo to an amber oil. The crude material is chromatographed over 350 g silica gel (230–400 mesh), eluting with 35% EtOAc/hexane. The fractions with the desired compound are combined and concentrated to afford 2-chloro-6-(hydroxymethyl)-4-[(trimethylsilyl)ethynyl]-3-pyridinol (C3) as a golden solid (92% yield). MS (EI) for C11H14ClNO2Si, m/z: 255(M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19]OS(C)(=O)=O)[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1.[Na+].[I-].[CH3:27][NH:28][CH3:29]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19][N:28]([CH3:29])[CH3:27])[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)c1ncc(Br)cn1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CC#C[C@H]1CC[C@H](CN(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 323 mg (corresponding to 0.49 mmol) of trans-Methanesulfonic acid 3-(4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester in 5 ml of methanol was cooled (0° C.), treated with a catalytic amount of NaI, 0.88 ml (4.94 mmol) of Dimethylamine (33% in EtOH 5.6M) and stirred for 16 h at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 40:1) gave 137 mg (76%) of pure trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexylmethyl]-methyl-amine, mp: 71–72° C.; MS: 365 (MH+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:13])[CH3:14])=[C:7]([O:15][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH:6]=1)[CH3:2]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC(C)C)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.5 g (6.69 mmol) of 3-Hydroxy-4-isopropoxy-benzoic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 1.4 g (7.36 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 6.7 g (equivalent to 20 mmol PPh3) of triphenylphosphine derivatized polystyrene and 3.5 g (20 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/6).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].C(O)(=O)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=[CH2:34])[N:28]=1>C(O)C>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH2:34][CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:36])([F:25])[F:35])[N:28]=4)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: C=Cc1cccc(C(F)(F)F)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4cccc(C(F)(F)F)n4)CC3)c2o1
Temperature: 73 °C

Procedure:
N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.09 g, 0.33 mmol) (Example 39d) was dissolved in ethanol (0.95 mL), and acetic acid (0.015 mL, 0.26 mmol) was added, followed by 2-(trifluoromethyl)-6-vinylpyridine (0.10 g, 0.58 mmol) (volatile) dissolved in ethanol (1.40 mL). The mixture was heated at 73° C. for 14 h in the microwave and then heated for another 48 h at 86° C. in an oilbath, and finally it was heated in the microwave for 15 min at 100° C. More 2-(trifluoromethyl)-6-vinylpyridine (0.10 g, 0.58 mmol) and ethanol (0.95 mL) were added and the mixture was heated in a oil bath for 7 days at 86° C. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-7%) and then by preparative HPLC to give the title compound. Yield: 0.075 g (51%).