Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>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>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C=Cc2ccc(CC(=O)OC)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-7% EtOAc-hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](/[CH:9]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96 %

Procedure:
A solution of 10.3 g (50 mmol) of 4,5-dichloro-2-nitrotoluene (Helv. Chim. Acta 1936, 19, 434-439) in a mixture of 11.9 g (100 mmol) N,N-dimethylformamide dimethylacetal in DMF (25 ml) was heated at 100° C. for 16 h. The dark reaction mixture was concentrated in vacuo, the residue diluted with methylene chloride and washed twice with water. The organic solution was dried over MgSO4, concentrated in vacuo affording 12.6 g (48 mmol, yield 96.5%) of the title compound as dark red to crude crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([F:14])[CH:8]=1)([CH3:6])[CH3:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:17]=[O:19])=[C:9]([F:14])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)c1ccc(N)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, 2-(4-amino-3-fluoro-phenyl)-2-methyl-propionic acid methyl ester (Chung, Jae-Uk; Kim, Su Yeon; Lim, Ju-Ok; Choi, Hyun-Kyung; Kang, Sang-Uk; Yoon, Hae-Seok; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Kang, Bomi; Choi, Sun; Toth, Attila; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Lundberg, Daniel J.; Blumberg, Peter M. Bioorganic & Medicinal Chemistry (2007), 15(18), 6043-6053) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 16 h to give the title compound as brown oil which was used in the next step without further purification. MS: m/e=255.4 [M+NH4+].
Reaction SMILES: C(OP([CH2:9][C:10](=[O:15])[N:11]([O:13][CH3:14])[CH3:12])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH:24]1([O:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[O:38][CH3:39])[CH:33]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.O>[CH3:14][O:13][N:11]([CH3:12])[C:10](=[O:15])[CH:9]=[CH:33][C:32]1[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:31]=1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a stirred solution of diethyl(N-methoxy-N-methyl-carbamoylmethyl)phosphonate (2.60 g, 10.90 mmol) in dry tetrahydrofuran (50 ml) at -78° C. was added lithium diisopropylamide (1.5M solution in cyclohexane, 7.33 ml, 11 mmol) dropwise over 3 minutes. The resulting solution was stirred at -78° C. for 30 minutes, after which time 3-cyclopentyloxy-4-methoxybenzaldehyde (1.5 g, 6.81 mmol) in dry tetrahydrofuran (5 ml) was added in one portion. The reaction was allowed to warm to room temperature and stirring continued overnight. After which time the reaction mixture was diluted with water (25 ml) and the tetrahydrofuran removed in vacuo. The aqueous residue was diluted with brine (25 ml) and extracted with methylene chloride (3×60 ml). The organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellow liquid. The liquid was purified by flash chromatography (SiO2 ; hexane/ethyl acetate (65:35)) to afford the title compound as a pale yellow liquid (1.986 g).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:11][C@@H:9]2[CH2:10][C@H:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-fluorobenzaldehyde (0.18 mL, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (3% MeOH/CH2Cl2) affording 0.18 g of N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine [Rf=0.5 (5% MeOH/CH2Cl2), colorless oil, 49% yield].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: C[Si](C)(C)C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide (20 mg, 0.045 mmol), potassium carbonate (20 mg, 0.14 mmol) and methanol (1 mL) was stirred at room temperature for 2 h, and then was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-ethynylphenyl)benzoxazole-4-carboxamide (14 mg, 84%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.49 (d, J=7.0 Hz, 1H), 8.22-8.18 (m, 3H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.48 (t, J=8.0 Hz, 1H), 4.35-4.31 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.30 (s, 1H), 3.15-2.82 (m, 5H), 2.20-2.03 (m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 372 (M+H); HPLC>99% (AUC), tR=12.77 min.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[C:33]2[NH:40][NH2:41]>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[C:33]2[N:40]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:41]1
Reactant: NNc1ccnc2ccc(Cl)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@H:36]([O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:35]([CH2:46][O:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:34][C@H:33]([O:56][C@H:57]3[C@@H:70]([O:71][CH2:72][C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C@H:69]([O:79][CH2:80][C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[C@@H:68]([CH2:87][O:88][CH2:89][C:90]4[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=4)[O:67][C@@H:58]3[O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:32]2[O:96][C:97](=[O:104])[C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C@H:6]1[O:105][C:106](=[O:113])[C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)C=C>CO.ClCCCl.Cl[Pd]Cl>[C:106]([O:105][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@H:36]([O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:35]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:34][C@H:33]([O:56][C@H:57]2[C@@H:70]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=3)[C@H:69]([O:79][CH2:80][C:81]3[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=3)[C@@H:68]([CH2:87][O:88][CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[O:67][C@@H:58]2[O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C@H:32]1[O:96][C:97](=[O:104])[C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=1)(=[O:113])[C:107]1[CH:108]=[CH:109][CH:110]=[CH:111][CH:112]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@@H](OCc4ccccc4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@@H](OCc4ccccc4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 88.3 %

Procedure:
PdCl2 (40 mg) was added to a solution of the allyl ether (26) (394 mg, 241 μmol) in MeOH (10 mL) and 1,2-DCE (10 mL) and the combined mixture was heated (70°, 60 min). After the time, the solvents were evaporated and the residue subjected to FC (20-30% EtOAc/hexanes) to yield the alcohol (27) as a colourless oil (317 mg, 84%). 1H NMR (CDCl3) δ 3.67-3.82, 3.91-3.99, 4.01-4.21, 4.29-4.71 (4 m, 21 H; H-2I,-3I,-4I,-5I,-6aI,-6bI,-3II,-5II,-6aI,-6bII,-3III,-5III,-6aIII,-6bIII, CH2Ph), 4.83 (d, 1 H, JA,B 10.9 Hz; A of AB quartet), 5.03-5.05 (m, 2 H; H-1I,-2II), 5.25-5.28 (m, 2 H; H-1II,-1III), 5.63 (dd, 1 H, J3,4=J4,5 9.9 Hz; H-4II), 5.77 (dd, 1 H, J1,2 2.0, J2,3 3.1 Hz; H-2″), 5.92 (dd, 1 H, J3,4 9.7, J4,5 9.9 Hz; H-4III), 6.99-7.62, 7.80-8.16 (2 m, 50 H; Ar).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccccn2)cc1

Procedure:
Thionyl chloride (10 mL) was added to 4-(pyridin-2-yl)benzoic acid (1.8 g, 9 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give crude 4-(pyridin-2-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (1 g, 6 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) were added the crude 4-(pyridin-2-yl)benzoyl chloride (1.3 g, 6 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.6 g, yield 76%). LC-MS (ESI) m/z: 349 (M+1)+. (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6]([O:8][N:9]=[C:10]([NH2:12])[CH3:11])=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:9]=[C:10]([CH3:11])[N:12]=2)[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)ON=C(C)N)cc([N+](=O)[O-])c1OC
Solvent: CC(=O)O
Product: COc1cc(-c2nc(C)no2)cc([N+](=O)[O-])c1OC

Procedure:
2.0 g of N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy] acetamidine are held at reflux temperature for 1 hour in 20 ml of glacial acetic acid. After distillation of the acetic acid, the crystalline residue is recrystallized from ether/hexane. There is obtained 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole in the form of colorless crystals of m.p. 111°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.OS(O)(=O)=O.[CH2:27](O)[CH3:28]>>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([O:13][CH2:27][CH3:28])=[O:12]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (7.21 mmol, 2.2 g), H2SO4 (36 mmol, 1.92 ml) in ethanol (25 ml) was stirred at 100° C. for 16 hours. The solvent was evaporated, water was added, pH was taken to 6 and extracted with CHCl3. The crude mixture was purified by chromatography over SiO2 eluting with DCM/MeOH mixtures and affording 0.69 g (yield 41%) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][N:12]([CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:20])[CH3:11])=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(S)cc1
Reactant: COC(=O)C=CC=CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.15 g, 5.6 mmol) and 4-dimethylamino-benzenethiol (0.86 g, 5.6 mmol) in tetrahydrofuran (30 mL) was added dropwise triethylamine (1.6 mL, 11.4 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for 30 minutes, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (100 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (50 mL), demineralised water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 7:3 60-80° C. petroleum ether:diethyl ether, all eluant containing 1% triethylamine by volume). The solid was recrystallised from diethyl ether/petroleum ether to give the title compound (1.0 g, 64%) as a white solid, mp 68-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[NH2:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28]>>[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(C(F)(F)F)cc1
Reactant: NCC(O)CO
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step A of Example 2-2-38 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[C:10](O)(=[O:14])[C:11]([CH3:13])=O>>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:11]([CH3:13])[C:10]1=[O:14]
Reactant: CNc1ccccc1N
Reactant: CC(=O)C(=O)O
Product: Cc1nc2ccccc2n(C)c1=O

Procedure:
Reaction between N-methyl-1,2-phenylene-diamine and pyruvic acid gave after recrystallisation (EtOH) the title compound;
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[CH:33]=[N:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccc(C#N)nc2)c1
Yield: 45 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 6-cyano-3-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13](=[O:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:12][CH2:11][CH2:10]1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH:13]([OH:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1C1(C(O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Yield: 59.7 %

Procedure:
1-[1-(2-Methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (15 mg) was dissolved in 2 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (5 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanol (9 mg, 60%). Data for this mixture of diastereomeric amino alcohols: MS 464 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), the 53.09 singlet for the starting material was absent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:18])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(CO)ccc1C(C)(C)C
Solvent: ClCCl
Product: CC(C)c1cc(CCl)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
Alcohol 26.4 (77.0 mg, 0.37 mmol) was dissolved in anhydrous DCM (5.0 mL). Thionyl chloride (0.041 mL, 0.56 mmol) was added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was then removed under vacuo to give a white solid (80 mg). The crude product (26.5) was used in the next step without further purification.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([F:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:30])[CH:21]=1.[C:31]([NH:35][C:36](=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([F:29])=[CH:27][C:23]([C:24]([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][C:39]3[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:50])[CH2:49][CH2:48]2)=[O:26])=[C:22]([F:30])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (2.91 g, 9.2 mmol, 2.73 mL) was added dropwise to a solution of 4-amino-2,5-difluorobenzoic acid (792.9 mg, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.3878 g, 5 mmol) and triethylamine (1.39 g, 13.9 mmol, 1.91 mL) in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.52 g). MS (ESI) m/z 431.9 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8](=[O:35])[C:9]([C:20]([C:22]2[CH:26]=[C:25]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[S:24][C:23]=2Cl)=[O:21])=[CH:10][NH:11][CH2:12][CH2:13]N2CCOCC2)=[CH:4][CH:3]=1.[C:38]([O-:41])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:9]2[C:20](=[O:21])[C:22]3[CH:26]=[C:25]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[S:24][C:23]=3[N:11]([CH2:12][CH2:13][CH:6]3[NH:7][CH2:8][CH2:38][O:41][CH2:5]3)[CH:10]=2)=[O:35])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)C(=CNCCN1CCOCC1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCC2COCCN2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-((2-chloro-5-(morpholin-4-ylmethyl)thien-3-yl)carbonyl)-3-((2-morpholin-4-ylethyl)amino)acrylamide (Preparation 6, 4.3 g) and K2CO3 (1.6 g) in DMF (75 mL) is stirred at 100° C. for 5 h. The mixture is allowed to cool to room temperature and is concentrated in vacuo. The crude product is triturated with EtOAc and filtered to afford 1.4 g of the title compound as a yellow solid Physical characteristics. 1H NMR (300 MHz, DMSO-d6) δ 10.57, 8.71, 7.42-7.32, 4.55, 4.37, 3.74, 3.59, 3.50, 2.73, 2.44; MS (ESI+) m/z 531 (M+H)+.