Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.Cl.[C:6]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])[CH2:7][CH2:8][CH3:9]>O1CCOCC1.[Rh]>[CH:17]1([C:11]2([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Agent: [Rh]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
In a Parr bomb under a hydrogen pressure of 6 bar, 100 mg of rhodium on alumina and 0.2 ml of acetic acid are added to a solution of 100 mg (0.5 mmol) of 4-butyryl-4-phenylpiperidine hydrochloride in 10 ml of dioxane. The reaction medium is heated at 80° C. for 12 hours. The reaction is stopped and then filtered through Celite and washed with dichloromethane. The solvents are evaporated off and the residue is taken up in water, basified with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phases are dried over sodium sulfate. The solvents are evaporated off and the residue is chromatographed on silica gel (eluent: 9/1 dichloromethane/methanol). 51.2 mg of 1-(4-cyclohexylpiperidin-4-yl)-butan-1-one in the form of a white powder are obtained in a yield of 61%.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH2:29][C:28]#[CH:27])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (160 mg, 0.451 mmol) in DMF (2 mL) was added propargyl bromide (80 mg, 0.672 mmol) and powdered cesium carbonate (219 mg, 0.672 mmol). The mixture was stirred under nitrogen at ambient temperature for 18 h. The reaction was diluted with water and extracted twice with ethyl acetate. The residue obtained from the combined organic extracts was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (143 mg, 80%) as a white solid. TLC Rf=0.19 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 2.30 (m, 1H), 4.69 (m, 2H), 4.96 (m, 2H), 5.66 (m, 1H), 7.28 (m, 3H), 7.39 (s, 5H), 7.48 (m, 1H). MS APCI, m/z=293 (M+1). LC/MS: 2.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:27]2[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(N3CCC(O)CC3)ccc21
Yield: 48.1 %

Procedure:
12-Chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (100 mg, 0.3 mmol), 4-hydroxy piperidine (121 mg, 1.2 mmol) and NMP (2 ml) were heated in microwave at 180° C. for 4 h. After cooling, the mixture was poured into ice cold water and the resulting precipitate was collected by filtration and dried. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (60 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]([C:10]1[S:11][C:12]([S:39][CH3:40])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]#[N:38])=[O:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1SC(SC)=C(S(C2C=C(C3C(C)=CC=CC=3N)C=CC=2)(=O)=O)C=1)=N)(C)(C)C.NCCC#N.[N:81]([Si](C)(C)C)=[N+:82]=[N-:83].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:39][CH3:40])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]3[N:81]=[N:82][NH:83][N:38]=3)=[O:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCC#N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Agent: N#CCCN
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of [(4-{2′-[3-(2-cyano-ethyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (31 mg, 51 μmol), as prepared from {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester and 3-aminopropionitrile according to the procedure of step e of Example 179, azidotrimethylsilane (40 μL, 0.30 mmol), dibutyltin oxide (3.5 mg, 10 μmol), and toluene (1.5 mL) was heated at 70° C. for 16 h and 80° C. for 4 h. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with EtOAc/DCM (50, 100%) followed by MeOH/DCM (5, 10%) to give the title compound (14 mg, 42% yield) as a colorless oil.
Reaction SMILES: Cl.[C:2]1(=[C:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)C.CO.[C].[Pd]>[CH:2]1([CH:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=C3CCCCC3)C(C)(C)O4)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C3CCCCC3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 1-(3-cyclohexylidene-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine hydrochloride obtained in Example 45 (390 mg, 0.79 mmol), 10% palladium-carbon (300 mg) in ethanol (10 ml) and methanol (10 ml) was stirred at room temperature under hydrogen pressure of 4–5 atmospheres for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with 10% aqueous potassium carbonate, and the aqueous layer was made alkaline and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 95 mg (yield 26%) of the title compound via recrystallization (ethanol). mp. 119–121° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[OH:1][C:2]1[C:3]([C:12]([NH:20][C:19]2[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Yield: 46.9 %

Procedure:
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[CH:12]=2)[N:7]=1)([CH3:5])[CH3:4].C(C1C(C)=C([O:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH:3]([C:6]1[C:15]([CH3:16])=[C:14]([O:17][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:33])[C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[CH:12]=2)[N:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C(C)C)nc2cc(F)c(F)cc2c1O
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(C)C)nc2cc(F)c(F)cc2c1OC(=O)C1CC1
Reaction time: 1 h

Procedure:
3,4-Difluoroaniline (4.5 g) and 6 g of ethyl-2-methyl isovalerylacetate were refluxed in toluene (50 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction mixture was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 246 mg of a mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 10 ml of dimethyl formamide was suspended 20 mg of 60% sodium hydride. Separately, 100 mg of the mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) was suspended in 20 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 100 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 44.1 mg of 2-isopropyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (compound 34). 1H-NMR data are shown in Table 3.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:5]([O:7]C)=O.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25].C(N(CCCC)CCCC)CCC>CO>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:4]1[C:3]([OH:17])=[N:18][C:19]2[N:23]([N:22]=[CH:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[C:5]=1[OH:7]
Reactant: COC(=O)c1cn[nH]c1N
Reactant: COC(=O)C(C(=O)OC)c1c(F)cccc1Cl
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1cnn2c(O)c(-c3c(F)cccc3Cl)c(O)nc12
Yield: 139.1 %

Procedure:
At room temperature, 15 g (57.5 mmol) of dimethyl(2-chloro-6-fluorophenyl)malonate were mixed with 9.4 g (57.5 mmol) of methyl 5-amino-1H-pyrazole-4-carboxylate and 15 ml (63.3 mmol) of tri-n-butylamine. The mixture was then stirred at 185° C. for 8 hours, during which time methanol was distilled off. After cooling, excess tri-n-butylamine was carefully decanted off. Concentration under reduced pressure gave 27 g of methyl 6-(2-chloro-6-fluorophenyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (logPs=0.55; content according to HPLC: 83%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[N:4]=1.[CH3:30][NH:31][CH3:32]>C(O)C>[CH3:30][N:31]([CH3:32])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[CH:9]=2)[N:4]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2-Dimethylpropyl 4-{4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}-1-piperazinecarboxylate (133 mg) obtained in Example 32 was dissolved in ethanol (4 mL), and aqueous 50% dimethylamine solution (1 mL) was added thereto, and stirred at room temperature for 3 hours. Then, the solvent was evaporated away and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 49.1 mg of the entitled compound as a colorless oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[N:35]=1)([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O>[CH:30]([O:33][C:34]1[N:35]=[C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[N:14][N:15]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:21])=[O:22])[CH:3]=2)[CH:37]=[CH:38][CH:39]=1)([CH3:32])[CH3:31]
Reactant: CC(C)Oc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
A yellow suspension of 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (300 mg, 0.536 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CombiPhos Catalysts, Inc., Princeton, N.J.; 198 mg, 0.751 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (Aldrich; 18.99 mg, 0.027 mmol), and potassium phosphate (341 mg, 1.609 mmol) in a mixture of IPA (3.5 mL) and H2O (1.50 mL) was stirred at 100° C. for 10 min. The mixture was partitioned between EtOAc (80 mL) and H2O (50 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-60% EtOAc/Hex) furnished 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (89.3 mg, 0.157 mmol, 29%) as a colorless oil. MS (ESI, pos. ion) m/z: 569.1 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].Cl[C:22]1C=CC(C(O)=O)=C(OCC(F)(F)F)N=1.FC(F)(F)COC1N=C(OCC(F)(F)F)C=CC=1C(O)=O>CO>[Cl:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:22])=[O:9]
Reactant: O=C(O)c1ccc(Cl)nc1OCC(F)(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1Cl
Agent: O=C(O)c1ccc(OCC(F)(F)F)nc1OCC(F)(F)F
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OCC(F)(F)F)nc1Cl
Reaction time: 3 h
Yield: 67 %

Procedure:
Thionyl chloride (4.7 mL, 63.9 mmol) is added dropwise a solution of 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid including 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinic acid and 2,6-bis(2,2,2-trifluoroethoxy)nicotinic acid (4.08 g, Step-1) in methanol (50 mL) and refluxed with stirring for 3 hours. After removal of solvent, the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (20:1) to give 2.90 g (67% yield) of the title compound including methyl 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinate as a white solid. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:34])[CH3:33]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CS(C)=O.O>[CH2:17]([O:24][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 1.80 g, 45 mmol) was added to a solution of 4-fluoro-3-trifluoromethyl benzoic acid (4.162 g, 20 mmol) and benzyl alcohol (3.25 g, 30 mmol) in DMSO (50 mL). The mixture was stirred overnight at room temperature, poured into water (50 mL) and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, dissolved in ethyl acetate (ca 50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane. Yield: 4.252 g (72%). 1H-NMR (400 MHz, CDCl3) δ=5.37 (s, 2H), 7.32-7.48 (m, 6H), 8.12 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.6, 2.0 Hz, 1H), 13.16 (br s, 1H, —COOH). LRMS (FAB+): 91.1 (100), 297.1 (18, [M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18]C(=O)C3C=CC=C(C#N)C=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:32]([OH:35])(=O)[CH3:33].O.[PH2]([O-])=O.[Na+]>N1C=CC=CC=1.[Ni]>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]([C:32](=[O:35])[C:33]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]#[N:11])[CH:29]=2)[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)N(C(=O)c2cccc(C#N)c2)c2ccccc2N)cc1
Temperature: 45 °C
Yield: 6 %

Procedure:
To a mixture of N2-(4-tert-butylbenzoyl)-N1-(3-cyanobenzoyl)-1,2-benzenediamine (1.0 g, 2.5 mmol), water (25 mL), and acetic acid (25 mL) in pyridine (50 mL) was added sodium hypophosphite monohydrate (270 mg, 5.0 mmol) and Raney nickel (400 mg). The reaction mixture was heated at 45° C. for 3 h, cooled to room temperature, and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% ethyl acetate/95% methylene chloride) to give 56 mg (6%) of the title compound as a white amorphous solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>N1CCCCC1.C(Cl)(Cl)Cl>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:16][C:17]2[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(=O)C1=C(O)C(C(=O)C=Cc2ccc(C)cc2)C(=O)OC1=O

Procedure:
Following the procedure of Example 1, a mixture of 8.48 g. (0.04 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 4.8 g. (0.04 m.) of p-methylbenzaldehyde in 100 ml. of chloroform and 20 drops of piperidine is refluxed for 10 hours, concentrated and filtered to yield 5-acetyl-4-hydroxy-3-(p-methylcinnamoyl)-2H-pyran-2,6(3H)-dione, m.p. 188°-190° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH2:11][Br:20])[C:5]=2[S:4][CH:3]=1
Reactant: Cc1cnc(Cl)c2c(Br)csc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)c2scc(Br)c12
Temperature: 25 °C

Procedure:
A solution of Example 277C (1 g, 3.81 mmol) in CCl4 (30 mL) was treated with NBS (0.755 g, 4.24 mmol) and benzoyl peroxide (0.093 g, 0.38 mmol), heated to reflux for 24 hours, cooled to room temperature, and filtered. The filtrate was concentrated to provide 3-bromo-7-(bromomethyl)-4-chlorothieno[3,2-c]pyridine, which was used directly. MS (ESI(+)) m/e 339.5, 341.6, 343.4 (M+H)+. The crude product was dissolved in DMF (7.5 mL), treated with sodium acetate (1.6 g, 19.5 mmol), heated to 100° C. overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (NaSO4), filtered, and concentrated. The residue was purified by silica gel chromatography with 10% ethyl acetate/hexanes to provide 0.65 g (53% yield) of the desired product. MS (ESI(+)) m/e 319.7, 321.7, 323.7 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].CC(=O)CC>C(OCC)C>[Cl:20][CH2:19][CH2:18][O:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9]
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate (60 g, 0.43 mol), 1-bromo-2-chloroethane (32.5 g, 0.23 mol) and 2-butanone (500 mL) was heated to reflux for 2 hours and allowed to cool to ambient temperature. The solids were filtered and the solvent was removed under vacuum to afford an oil. The oil was dissolved in diethyl ether (300 mL) and washed with water, dried over anhydrous magnesium sulfate, charcoalized, and filtered through Solka floc to afford 65.9 g (97.2%) of an oil; MS EI m/e 330/332/334/336 (M+ ; 1H NMR (CDCl3) δ 3.89 (2H, t, J=6.1 Hz), 4.23 (2H, t, J=6.1 Hz), 7.28 (2H, d, J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:32])[CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:32])[CH2:18][CH:19]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC(C1CCCCC1)C1CCCCC1
Yield: 99 %

Procedure:
A solution of (2S,3S)-2-t-butoxycarbonylamino-1-cyclohexyl-5,5-diphenyl-3-hydroxypentane (0.74 g) in acetic acid (50 ml) was hydrogenated over platinum oxide (0.2 g) at 3 atmospheric pressure of hydrogen gas for 2 hours at 37° C. The solution was filtered and concentrated in vacuo to give (2S,3S)-2-t-butoxycarbonylamino-3-hydroxy-1,5,5-tricyclohexylpentane (753 mg) as an oil. Rf: 0.72 (n-hexane:ethyl acetate, 2:1, V/V)