Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](CC#N)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:2][C:1]([OH:4])=[O:3])=[CH:9][C:8]=1[C:16]([F:17])([F:18])[F:19]
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
According to a method similar to Example (17-1), using [4-chloro-3-(trifluoromethyl)phenyl]methanol (2.00 g, 5.59 mmol) as a starting material, [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile was obtained. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile and the mixture was stirred at 100° C. for 2 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude [4-chloro-3-(trifluoromethyl)phenyl]acetic acid. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the crude product obtained in the above and the mixture was stirred at 50° C. for 1 hour. The temperature of the reaction mixture was returned to room temperature and the solvent was removed under reduced pressure. After ethyl acetate was added thereto, the organic layer was successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1) to give methyl[4-chloro-3-(trifluoromethyl)phenyl]acetate (1.08 g, two-step total yield: 45%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[Cl:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:14][CH2:13]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:26])[CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC1CCN(c2ncccc2Cl)CC1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: O=C(NC1CCN(c2ncccc2Cl)CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 1-(3-chloropyridin-2-yl)piperidin-4-amine (57 mg, 0.27 mmol). Yield: 50 mg (40%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>ClCCl>[CH2:1]([NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11])[CH2:2][CH3:3]
Reactant: CCCCN=C=O
Reactant: CCCN
Solvent: ClCCl
Product: CCCCNC(=O)NCCC
Reaction time: 8 h
Yield: 92.5 %

Procedure:
205.8 Grams (3.48 moles) of n-propylamine and 250 ml of dichloromethane were charged to a round bottom flask equipped with stirrer, thermometer, reflux condenser and dropping funnel. 313.7 Grams (3.16 moles) of butyl isocyanate were added to the dropping funnel and then metered into the flask with stirring and strong external cooling (solid CO2 bath) at a rate slow enough to maintain the contents generally below 0° C. except for brief excursions to higher temperatures. The resulting mixture was left to stand overnight and then freed of solvent and lights under vacuum with a rotary evaporator leaving 462.3 g of crude product (92.6% crude yield). After further drying of a portion under vacuum a 97.6 area % purity was recorded by gas chromatography. The product contained substantially only one compound by gas chromatography. It melted at 70°-72° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.[N:27]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH2:32][CH2:31][CH:30](OS(C)(=O)=O)[CH2:29][CH2:28]1>>[N:27]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH2:32][CH2:31][CH:30]([O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:29][CH2:28]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: CS(=O)(=O)OC1CCN(c2ccccn2)CC1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OC3CCN(c4ccccn4)CC3)cc12

Procedure:
6-(3,4,5,6-Tetrahydro-2H[1,2′]bipyridinyl-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime was prepared in 6% overall yield using the method described in example 169, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and methanesulfonic acid 3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl ester (example 170A).
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][N:4]([CH2:22][O:23][CH3:24])[N:3]=1.[BH4-].[Na+].O>CO>[I:1][C:2]1[C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:5][N:4]([CH2:22][O:23][CH3:24])[N:3]=1
Reactant: COCn1cc(C=NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCn1cc(CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Reaction time: 3 h
Yield: 19.3 %

Procedure:
N-((3-Iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methylene)-4-(trifluoromethyl)benzenesulfonamide (41) (7.41 g, 15.66 mmol) was suspended in MeOH (20 mL). NaBH4 was added portionwise and the reaction was stirred for 3 hr until TLC monitoring revealed the disappearance of starting material. Water (20 mL) was added and MeOH was removed in vacuo. The residue was taken up in EtOAc (100 mL) and washed with sat. aq. NaHCO3 (100 mL) and dried over Na2SO4. The reaction was concentrated in vacuo. The resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield N-((3-iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (42) (1.44 g, 37% over two steps) as a clear oil that solidified upon standing.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].Cl>O1CCOCC1>[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCCC1CCN
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NCCC2CCCN2C)cc1

Procedure:
The title compound was prepared as in Example 81 with 4-toluenesulfonyl chloride replacing 2-naphthalenesulfonyl chloride and with 2-(1-methyl-pyrrolidin-2-yl)-ethylamine replacing 2-pyrrolidin-1-yl-ethylamine. The hydrochloride salt was prepared by treatment with hydrogen chloride in 1,4-dioxan. 1H NMR (DMSO-d6) 7.62 (2H, d, 8.1), 7.47 (1H, t, 5.1), 7.37 (2H, d, 8.1), 2.86-2.70 (3H, m), 2.37 (3H, s), 2.09 (3H, s), 1.98-1.93 (2H, m), 1.7-1.49 (4H, m) 1.29-1.16 (2H, m). Microanalysis found C 52.52 H 7.30 N 8.53. C14H23ClN2O2S requires C 52.73 H 7.27 N 8.79.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][CH2:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:46](=[O:47])[CH2:45][O:44][CH2:43][CH2:42][O:41][CH3:40])[CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: COCCOCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Yield: 33.6 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylene chloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 519; melting point 110 to 111° C.
Reaction SMILES: C[N:2](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]([F:20])[CH:15]=2)[N:8]=1)=O.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH:31]N)=[CH:30][C:25]=2[O:24][CH2:23]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([N:31]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(F)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCO2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-fluoro-phenyl)-1H-pyridazin-4-one (A-13) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[C:29]([CH3:36])[N:28]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methylpyridin-3-yl)boronic acid (233 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 2 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→1:4) to give the title compound as a colorless oil (yield 400 mg, 87%).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C@:14]2([CH3:21])[CH2:19][CH2:18][O:17][C:16]([NH2:20])=[N:15]2)[CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C@:14]3([CH3:21])[CH2:19][CH2:18][O:17][C:16]([NH2:20])=[N:15]3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: C[C@@]1(c2cc(N)ccc2F)CCOC(N)=N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(NC3CCCC3)ccc2F)CCOC(N)=N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.4 %

Procedure:
A solution of cyclopentanone (26.2 μl, 296 μmol) and (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (60 mg, 269 μmol) in dichloromethane (2 ml) was treated with acetic acid (30.8 μl, 538 μmol) followed by sodium triacetoxyborohydride (85.4 mg, 403 μmol). The reaction mixture was stirred at room temperature for 2.5 hours. For the workup, the reaction mixture was quenched with a saturated solution of sodium hydrogencarbonate, then extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on a silica-NH2 phase using a gradient of n-hexane/ethyl acetate=50:50 to 0:100 as the eluent to yield the (S)-4-(5-cyclopentylamino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (5 mg, 6% yield). MS (ISP): m/z=292.1 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([OH:38])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][OH:16])=[CH:35][CH:36]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28° C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55° C. The reaction mixture is stirred at 60° C. for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HCl and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50%).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1
Reactant: OC1CNCc2occc21
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Product: FC(F)(F)c1cc(Br)ccc1OC1CNCc2occc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 5-bromo-2-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:37])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:22]([O:24][C:25](=[O:37])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH2:2][C:3]3[C:4]([CH:19]4[CH2:21][CH2:20]4)=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:23]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)ccc21

Procedure:
In analogy to the procedure described in example 1 h], 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine was reacted with (5-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) in the presence of cesium carbonate to give {5-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester, which was subsequently treated with lithium hydroxide in analogy to the procedure described in example 1 i] to yield {5-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>C(#N)C.C(N(CC)CC)C>[F:20][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][N:3]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][N:8]=[CH:9]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reactant: BrCCOCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (0.92 g, 0.0029 mmol) in acetonitrile (150 mL) and triethylamine (3.2 mL) was added 2-bromoethyl ether (0.839 mL, 0.0067 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in vacuo and the residue was dissolved in EtOAc which was washed twice with 1M HCl (100 mL). The HCl layers were combined and adjusted to pH=9 with solid Na2CO3 and extraxcted 3 times with EtOAc. The EtOAc layers were combined and dried with brine and MgSO4. Removal of the EtOAc in vacuo yielded the title compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)O1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([O:35][C:34]([NH:33][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:11]([Cl:15])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=2)=[CH:29][CH:28]=1)([CH3:32])[CH3:31])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Yield: 81.7 %

Procedure:
2M aqueous Na2CO3 (4.7 ml, 9.4 mmol) was added to a solution of 2,4,5-trichloropyrimidine [Chesterfield, J.; McOmie, J. F. W.; Sayer, E. R.; J. Chem. Soc. (1955) 3478-3481] (1.18 g, 6.44 mmol), tert-butyl N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]1-methylethyl}carbamate (1.55 g, 4.29 mmol) and tetrakis(triphenylphosphine)palladium (O) (150 mg, 0.13 mmol) in ethyleneglycol dimethylether (20 ml) under N2 and the mixture heated to reflux for 6 h. The reaction was diluted with H2O (30 ml) and extracted with ethyl acetate (3×50 ml), the combined ethyl acetate extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 15% ethyl acetate in hexane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine as a white solid (1.34 g). δH (d6DMSO) 8.62 (1H, s), 7.90 (2H, d, J 8.6 Hz), 7.54 (2H, dt, J 8.7, 2.1 Hz), 5.02 (1H, bs), 1.65 (6H, s) and 1.37 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[OH-].[Na+].O>CO>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl-3-Iodo-4-methylbenzoate (3 g, 109 mmol, 1 eq) dissolved in MeOH (30 ml) was added sodium hydroxide (1.3 g, 327 mmol, 3 eq) followed by the addition of water (15 ml). The above solution was stirred at room temperature for 14 h. The solution was concentrated under vacuum, and then added water. The pH of the reaction was bought to 3 using Conc.HCl. The solid obtained was filtered and dried under vacuum. Yield: 2.7 g (96%). 1HNMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H), 7.45 (d, J=8.00 Hz, 1H), 7.85 (d, J=3.18 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([CH2:12][P+](CCCC)(CCCC)CCCC)[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[CH:28]([C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=O>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10](/[CH:12]=[CH:28]/[C:30]3[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=3)[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(=O)Nc1cc(C)cc(C=O)n1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1nc2cc(Br)cnc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)cc(/C=C/c2nc3cc(Br)cnc3[nH]2)n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 6-brom-3H-imidazo[4,5-b]pyridin-2-yl-methyl}-tributyl-phosphonium-chlorid (compound A5) are suspended in 50 ml of tetrahydrofuran and added to a suspension of sodium hydride (60% strength) in 50 ml tetrahydrofuran at room temperature. After vigorously stirring for 10 min, 1.43 g of N-(6-formyl-4-methyl-pyridin-2-yl)-acetamide (compound B11) is added in portions (10 min). Subsequently, the suspension is heated at 90° C. for 22 h. Thereafter, the mixture is filtered with suction and the remaining residue is rinsed with tetrahydrofuran. The pure title compound is obtained by evaporating the filtrate to dryness to afford 1.88 g of an amorphous solid. M.p.>350° C. ESI-MS: 372.1/374.1 (MH+; 99%/100%). TLC: Rf=0.50 (dichloromethane/methanol 10:1).