Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.[Na+].[I-].C(N(CC)CC)C>S(Cl)(Cl)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@@H:13]1[CH3:12])[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-1-indanol (1.0 g, 4.7 mmol) of Step A was dissolved in thionyl chloride (10 mL). After stirring at room temperature for 2 hrs, the solution was concentrated under vacuum. The residue was taken up in DMF (10 mL). To the mixture were added tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.94 g, 4.7 mmol), NaI (2 g, 13 mmol) and triethylamine (1.5 mL, 10 mmol). The resulting solution was stirred at 70° C. overnight. After cooling to room temperature, water was added. The solution was extracted with EtOAc twice. The combined EtOAc layers were washed with brine, dried over MgSO4 and concentrated. Column chromatography on silica (50% EtOAc in hexane) provided two isomers. Isomer 1 (fast moving isomer): 0.36 g; MS calculated for C19H27BrN2O2 (M+H)+ 395; found 395.1, 397.0. Isomer 2 (slow moving isomer): 0.33 g; MS found 395.1, 397.0.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:17]#[CH:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:18]=[C:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Reactant: C#CC(O)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1cc(C(O)(C(F)(F)F)C(F)(F)F)on1
Yield: 46.7 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (109 mg, 0.5 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol from step 1 (about 1 mmol) was added a solution of triethylamine (60 mg, 0.6 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes: EtOAc, 5:1) to afford the title compound as a white solid (87.2 mg). 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 7.60 (d, 2H), 8.14 (d, 2H), 9.92 (s, 1H); ESIMS: m/z 372 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:10]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:9][C:8]=1[Cl:26])[CH3:2].C(O)(=O)C>C(O)C.[Fe]>[CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:10]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:9][C:8]=1[Cl:26])[CH3:2]
Reactant: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc(N)cc1

Procedure:
A mixture of 0.5 g of 3-[2-butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]propenoic acid ethyl ester (E isomer) prepared from Part B of Example 227, 1 g of iron and 2 mL of glacial acetic acid in 30 mL of absolute ethanol was refluxed for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in 50 mL of H2O. The aqueous solution was adjusted to pH 8 by K2CO3 and was extracted with ethyl acetate. The crude product obtained upon concentration of the ethyl acetate extract was purified by flash silica gel column chromatography (hexane:ethyl acetate=1:1 elution). The desired compound was obtained as a thick colorless oil, 0.35 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[O:16][CH3:17]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(F)c(F)cc1CCl
Reactant: OCCCCl
Product: COc1cc(F)c(F)cc1COCCCCl

Procedure:
In an analogous manner to that described in (δ) 1-chloromethyl-4,5-difluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene as a colorless liquid; MS: 250 (M)+.
Reaction SMILES: CO[C:3](OC)([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)[CH:4]([OH:6])C.CN(C)[CH:21]=[O:22].S(Cl)(Cl)(=O)=O.[C:29]1(C)C=CC=CC=1>>[C:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:3]([CH3:29])[C:4]([O:22][CH3:21])=[O:6])=[CH:12][CH:11]=1)(=[O:16])[CH3:15]
Reactant: COC(OC)(c1ccc(OC(C)=O)cc1)C(C)O
Reactant: Cc1ccccc1
Reactant: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)C(C)c1ccc(OC(C)=O)cc1
Temperature: -50 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
In this example, 2.54 g of α-hydroxy-p-acetoxypropiophenone dimethylacetal was dissolved in a mixed solvent of 2 ml of N,N-dimethylformamide and 20 ml of toluene and the solution was cooled to -50° C. Then, 1.75 ml of sulfuryl chloride was added thereto. The mixture was stirred at the same temperature for 3 hours. After completion of the reaction, post-treatment was performed in a manner similar to Example 1 to obtain 1.78 g of methyl 2-(p-acetoxyphenyl)propionate (yield 80%). The product was heated in 20 ml of an aqueous 1N sodium hydroxide solution at 50° C. for 1 hour. Thereafter, the pH was adjusted to 3 with conc. hydrochloric acid. The solution was extracted with 50 ml of chloroform. The extract was concentrated under reduced pressure to obtain 1.2 g of 2-(p-hydroxyphenyl)propionic acid (yield 90%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[H][H].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19](=[O:33])[C:20]([S:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([CH3:22])[CH3:21]>CS(C)=O.CCCCCC>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1([C:20]([S:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)([CH3:22])[CH3:21])[CH2:4][O:33]1
Reactant: C[S+](C)(C)=O
Reactant: [H][H]
Reactant: COc1ccc(CSC(C)(C)C(=O)c2ccc(F)cc2F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Temperature: 0 °C
Yield: 67988.1 %

Procedure:
In 900 ml of dimethyl sulfoxide was suspended 41.2 g (1.0 mol) of 60% sodium hydride having been washed with hexane, and 226.7 g (1.0 mol) of trimethyloxosulfonium iodide was added to the suspension in divided portions with stirring under cooling with ice. After the evolution of hydrogen gas ceased, stirring was continued at room temperature for an additional 2-hour period. A solution of 193.0 g (0.57 mmol) of 1-(2,4-difluorophenyl)-2-((4-methoxyphenyl)methylthio)-2-methylpropan-1-one in 110 ml of dimethyl sulfoxide was added thereto, followed by stirring for 12 hours. The reaction mixture was poured into ice-water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography and eluted with a mixed solvent of hexane and ethyl acetate (10:1). The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of diethyl ether and hexane to obtain 135.8 g (68%) of (±)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane as a colorless crystal.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=O)[CH3:2].[C:8]([C:10]1[CH:38]=[CH:37][CH:36]=[CH:35][C:11]=1[O:12][C:13]1[C:27]([O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:16]2[NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:19][C:15]=2[CH:14]=1)#[N:9].[N:39]1C=CC=CC=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]2[C:13]([O:12][C:11]3[CH:35]=[CH:36][CH:37]=[CH:38][C:10]=3[C:8]3[N:39]=[C:1]([CH3:2])[O:4][N:9]=3)=[CH:14][C:15]3[NH:19][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[N:17][C:16]=3[CH:26]=2)[CH:30]=1
Reactant: N#Cc1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccccc2Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.3 ml of acetic anhydride was added to a pyridine (0.5 ml) solution of 20 mg of 5-(2-(N-hydroxycarbaminidoyl)-phenoxy)-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in the same manner as in Example 61 but using 5-(2-cyano-phenoxy)-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in Example 5, and the reaction liquid was stirred overnight at 60° C. The solvent was evaporated away under reduced pressure, and this was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]2=[N:10][C:9]=1[CH3:23].C(Cl)Cl.C1C(=O)N([Br:34])C(=O)C1>CCOCC>[Br:34][C:5]1[S:4][C:3]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(C)c3C)c(C)nc12
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(C)c3C)c(C)nc12
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 3-(3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.41 g, 1.25 mmol) and CH2Cl2 (30 mL) is added NBS (0.23 g, 1.32 mmol). The solution is stirred for 1 hour, diluted with Et2O (100 mL), washed with water (3×100 mL), brine (100 mL), dried (MgSO4) filtered and concentrated to furnish the title compound (0.41 g, 1.01 mmol, 80%). 1H NMR (CDCl3) δ 0.86 (t, J=7.4 Hz, 6H), 1.72-1.94 (m, 4H), 2.02 (s, 3H), 2.18 (s, 3H), 2.43 (s, 3H), 2.49 (s, 3H), 3.27-3.36 (m, 1H), 6.67 (s, 1H). LC/MS (m/z): calcd. for C19H24BrN3S (M+H)+: 407.4; found: 407.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:26])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)C1CCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C1CCCC1
Yield: 60.7 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with cyclopentanecarbonyl chloride (1.04 g, 7.83 mmol) to provide 1.67 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopentanecarboxamide as a solid, m.p. 207.8-208.9° C. Analysis: Calculated for C20H25N5O: % C, 68.35; % H, 7.17; % N, 19.93. Found: % C, 68.09; % H, 7.19; % N, 20.09.
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)OCC[O:18]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCCCCCC.CCOCC>C1COCC1>[CH:2]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(CCC1CCCCC1)OCCCCC1(c2ccccc2)OCCO1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)OCCCCC(=O)c1ccccc1
Yield: 59.6 %

Procedure:
This compound was synthesised as described under 1.e) with 2.0 ml of a 1N solution of HCl, 4.12 g (11.4 mmol) of 4-(2-phenyl-1,3-dioxolan-2-yl)butyl 3-cyclohexylpropionate obtained under a) in 20 ml of THF for 19 h. Column chromatography (SiO2, heptane/ether 3:2) afforded 2.15 g (60%) of a yellow oil containing small amounts of impurities, which can be distilled off (Kugelrohr, 150° C./1×102 Pa).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[N:12]=1
Reactant: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12

Procedure:
256 g of 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are refluxed in 1 liter of phosphorus oxychloride for 24 hours. The excess phosphorus oxychloride is decomposed by pouring the solution on ice and the crystallized 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4', 3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester is filtered off, yield 245 g (91%); m.p. 170°-172° (butyl alcohol).
Reaction SMILES: FC1C=C([C@H]2CC[C@H](CCCCC)CC2)C=C(F)C=1O.C([O-])([O-])=O.[K+].[K+].C(I)CCCCC.[F:34][C:35]1[CH:40]=[C:39]([C@H:41]2[CH2:46][CH2:45][C@H:44]([CH2:47][CH2:48][CH2:49]CC)[CH2:43][CH2:42]2)[CH:38]=[C:37]([F:52])[C:36]=1[O:53][CH2:54]CCCCC>CN(C)C=O>[F:34][C:35]1[CH:40]=[C:39]([C@H:41]2[CH2:42][CH2:43][C@H:44]([CH2:47][CH2:48][CH3:49])[CH2:45][CH2:46]2)[CH:38]=[C:37]([F:52])[C:36]=1[O:53][CH3:54]
Reactant: CCCCCCOc1c(F)cc([C@H]2CC[C@H](CCCCC)CC2)cc1F
Agent: CCCCC[C@H]1CC[C@H](c2cc(F)c(O)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCI
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H](c2cc(F)c(OC)c(F)c2)CC1

Procedure:
A mixture of 28.2 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol, 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of dimethylformamide is heated at 80° for 16 hours, while stirring, and is then cooled and worked up in the usual manner. This gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-1-hexoxybenzene.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:21]([CH:22]=O)=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CO>[Cl:12][C:13]1[C:21]([CH:22]=[N:5][O:4][CH2:2][CH3:3])=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
1.63 g (0.017 mol) of ethoxyamine hydrochloride and 1.15 g (0.0085 mol) of finely pulverulent potassium carbonate were stirred for 1 hour in 60 ml of dry methanol. 4.00 g (0.015 mol) of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid in 40 ml of methanol were subsequently added. After the mixture was stirred for 12 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate, and the organic phase was washed four times with water. After the mixture had been dried and the solvent distilled off, 3.60 g of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoic acid were obtained (78% yield).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H][H]>C(O)C.O.[C].[Pd]>[CH3:2][N:3]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCNCC1
Yield: 70.1 %

Procedure:
60 ml of concentrated hydrochloric acid and 13.3 g of 10% palladium-carbon were added to a solution of 266 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine in 1 liter of ethanol and 500 ml of water. The mixture was stirred at a hydrogen pressure of 1 atm. at 60° C. for 5 hours. 10% palladium-carbon was removed by filtration and then washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was added to ice water. The mixture was made alkaline with a 25% aqueous sodium hydroxide solution and then extracted with methylene chloride. The extract was water-washed and then concentrated under reduced pressure. The residue was subjected to vacuum distillation to obtain 131.9 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4])#[N:2].S(=O)(=O)(O)O.[CH3:19]O>>[C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])[CH3:4])#[N:2]
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)C#N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-(1-cyanoethyl)benzoic acid (2.0 g, 11 mmol) in methanol (20 mL) was added conc. sulfuric acid (0.2 mL), and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (1.9 g, 89%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1Br)[CH2:6][CH3:7])[CH3:2].[CH3:29][N:30](C)C=O>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[C:29]#[N:30])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N

Procedure:
A 10 g of ethyl-α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy)phenoxy]butyrate was dissolved in 20 ml of dimethylformamide.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:28]2=[N:29][CH:30]=[CH:31][N:27]2[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:28]4=[N:29][CH:30]=[CH:31][N:27]4[N:26]=[CH:25][N:24]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnn2ccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnn2ccnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Yield: 78.7 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.106 g, 0.32 mmol), 4-chloroimidazo[2,1-f][1,2,4]triazine (WO2010/014930) (0.050 g, 0.32 mmol) and diisopropylethylamine (0.222 mL, 1.28 mmol) in isopropanol (2 mL) was heated to 60° C. in a sealed tube for 0.5 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and washed with water (2 mL) The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 321 as a pale pink solid, (94 mg, 78%). LCMS (Method C): RT 4.31 min [M+H]+ 374.01. 1H NMR δ (ppm) (DMSO-d): 9.15 (1H, d, J=7.24 Hz), 8.02 (1H, d, J=1.09 Hz), 7.95 (1H, s), 7.71 (1H, dd, J=8.81, 4.85 Hz), 7.57-7.54 (3H, m), 7.48-7.39 (3H, m), 7.10 (1H, td, J=9.33, 2.51 Hz), 6.83 (1H, dd, J=8.91, 2.52 Hz), 5.57 (1H, dq, J=7.00 Hz), 1.61 (3H, d, J=6.88 Hz)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:23])[CH3:13]>C(O)C.O.[Na]>[CH2:12]([O:14][C:15]1[C:16]2[O:23][C:2]([C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)=[O:4])=[CH:18][C:17]=2[CH:20]=[CH:21][CH:22]=1)[CH3:13]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOc1cccc(C=O)c1O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOc1cccc2cc(C(=O)c3ccc(Cl)cc3)oc12

Procedure:
23.3 g of ω-bromo-p-chloroacetophenone are added to 17 g of 3-ethoxysalicylaldehyde in 800 ml of ethanol and 4 g of sodium hydrate. After heating the mixture for one hour under reflux, it is allowed to cool, the product which separates is filtered off, and is crystallised from ethanol: M.P. 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:11])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[C:3]=1[Cl:13].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:11])[N:7]([C@@H:30]3[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]3[O:32][C:33](=[O:35])[CH3:34])[C:6]=2[CH:5]=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1nc2c(Br)c(Cl)c(Cl)cc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Cl)nc2c(Br)c(Cl)c(Cl)cc21
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a suspension of 4-bromo-2,5,6-trichloro-1H-benzimidazole (0.30 g, 1 mmol), in acetonitrile (5 mL) was added N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1 mmol). The resulting mixture was allowed to stir at 65° C. for 15 min., followed by the addition of 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The mixture was allowed to stir at 65° C. for 20 min and was then allowed to cool to RT. The mixture was diluted with ethyl acetate and was washed with a saturated NaHCO3/NaCl solution, dried over MgSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using chloroform as eluent followed by recrystallization from methanol to provide 0.28 g (55%) of the title compound as white crystals; m.p. 138-141° C.; 1H NMR (DMSO-d6) δ: 8.18 (s, 1H), 6.19 (d, 1H), 5.61 (dd, 1H), 5.25 (dd, 1H), 4.24 (m, 1H), 2.14 (s, 3H), 2.02 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.[NH2:17][C:18]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:28]=1)=[O:21].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1>CS(C)=O>[NH2:17][C:18]1[N:39]=[C:38]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH:37]=[CH:36][C:19]=1[C:20](=[O:21])[NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCC(=O)O
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: Nc1nc(NCC(=O)O)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 190 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
Glycine (610 mg, 8.13 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (405 μl, 2.71 mmol) were added to 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (195 mg, 0.542 mmol) under nitrogen atmosphere, and the solution was stirred at 190° C. for 4 hours. Dimethylsulfoxide (5 mL) was added to the reaction mixture, which was then filtered with a polytetrafluoroethylene membrane filter (Whatman Inc), the filtrate was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), title compound (55.36 mg, 0.108 mmol, 20%) was obtained.