Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH2:12]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([F:32])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1)(=[O:16])=[O:15])[CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([F:32])=[C:19]([C:2]2[CH:3]=[C:4]([O:10][CH3:11])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:18]=1)(=[O:15])=[O:16])[CH3:13]
Reactant: CCS(=O)(=O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1cc(Br)cn(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(F)c(-c2cc(OC)c(=O)n(C)c2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of 5-bromo-3-methoxy-1-methylpyridin-2-one (694 mg, 3.18 mmol), 2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 3.18 mmol), Pd(dppf)Cl2 (233 mg, 318.00 umol) in dioxane (26 mL) and H2O (2.6 mL) was added K3PO4 (2.02 g, 9.54 mmol, 3.00 Eq). The reaction was stirred at 70° C. under N2 for 6 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE/EA=3/1 to 1/2) to afford the title compound (0.9 g, 87%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 7.93 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 7.88-7.84 (m, 1H), 7.35 (dd, J1=10.0 Hz, J2=8.8 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 6.83 (s, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.16 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). LCMS: 325.9 (M+H)+
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH3:21])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C[O:26]C(C)=N1.Cl>C(O)(=O)C>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:26])=[C:10]([CH3:21])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=1
Reactant: CC1=NC(C)CO1
Reactant: Cc1cc(C2(O)CCCCC2)ccc1C1=NC(C)(C)CO1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C2=CCCCC2)ccc1C(=O)O
Yield: 80.8 %

Procedure:
To a solution of 2-[4-(1-hydroxy-1-cyclohexyl)-2-methylphenyl]-4,4-dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% hydrochloric acid (20 ml), and the mixture is refluxed for two days. The precipitated crystals are collected by filtration, washed with water, and dried to give 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) as white powder.
Reaction SMILES: C(OC([N:11]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:26]=1)[CH2:12][CH3:13])=O)C1C=CC=CC=1>[Pd].CO>[CH2:12]([NH:11][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:26]=1)[CH3:13]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)O)c1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)O)c1

Procedure:
A solution of {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-5-fluoro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.025 g, 0.05 mmol) and 10% palladium on carbon (catalytic) in MeOH was hydrogenated under a balloon of H2 at room temperature for 2 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the title compound. M+H is 382.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2L of toluene and 1.8L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][N:29]4C(OC(C)(C)C)=O)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:41])[N:7]([CH3:42])[C:6]1=[O:43])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:26][CH:27]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:41])[N:7]([CH3:42])[C:6]1=[O:43])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4C(=O)OC(C)(C)C)cc3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4)cc3)nc21
Temperature: 25 °C
Yield: 50.8 %

Procedure:
tert-butyl 2-(4-((7-isobutyl-5-methyl-4,6-dioxo-3-(phenylamino)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)piperidine-1-carboxylate (76 mg) is dissolved in 2 mL of dichloromethane, and then TFA (2 mL) is added. The mixture is stirred at room temperature for an hour. After evaporation, the residue is purified by a semi-preparative HPLC to give 32 mg of pure product as white solids. MS (ESI) m/z 487.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol in methylene chloride (1 mL) was added methanesulfonyl chloride (2.7 μL, 0.034 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired compound as TFA salt (1.9 mg, 16%) as TFA salt. LCMS calculated for C18H25N4O3S2 (M+H)+: m/z=409.1. Found: 409.1.
Reaction SMILES: CO.C[O-].[Na+].[CH3:6][C:7]1[C:8]([C:31]([O:33]CC)=O)=[C:9]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:38]=1[CH2:39]Br>C(#N)C.O>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:38]=1[CH2:39][N:21]1[C:9]2[S:10][C:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[C:7]([CH3:6])[C:8]=2[C:31](=[O:33])[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]1=[O:23]
Reactant: CCOC(=O)c1c(NC(=O)Nc2ccccc2)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Reactant: Fc1cccc(F)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccc([N+](=O)[O-])cc2)sc2c1c(=O)n(-c1ccccc1)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Acetonitrile (240 ml), methanol (150 ml) and 28% sodium methoxide (15.24 g, 78.97 mmol) were added to ethyl 4-methyl-5-(4-nitrophenyl)-2-(3-phenylureido)thiophene-3-carboxylate (30.00 g, 70.51 mmol), and the mixture was stirred for 1 hour while refluxing under heating. 2,6-difluorobenzyl bromide (17.52 g, 84.61 mmol) was dissolved in acetonitrile (60 ml), and the solution was added to the previous reaction mixture under refluxing. After refluxing under heating for 5 hours, 28% sodium methoxide (1.36 g, 7.05 mmol) was added thereto under reflux, and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature, water (150 ml) was added dropwise, which was stirred at room temperature for 1 hour. The crystals were filtered and washed with water (240 ml) and diisopropyl ether/ethanol=9/1 (240 ml). The resulting crystals were suspended in ethyl acetate (600 ml), and the suspension was stirred for 1 hour under reflux. The mixture was cooled to room temperature and, after stirred for 1 hour, the crystals were filtered, washed with ethyl acetate (60 ml) and dried under vacuum at 60° C. to give 1-(2,6-difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (31.4 g, 62.12 mmol, 88.1%).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=2)[CH2:11]1)[CH3:5]>O1CCCC1.O>[CH2:4]([O:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=2)[CH2:11]1)[CH3:5]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)OC)cc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cc2F)C1
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
Lithium hydroxide hydrate (62 mg, 2.6 mmol) was added to a solution of methyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.65 g, 1.7 mmol) in tetrahydrofuran (8 mL) and water (8 mL), and the resulting solution was stirred at 20-25° C. for 18 h. The mixture was then diluted with water (20 mL) and was washed with ethyl acetate (2×30 mL). The aqueous layer was acidified with citric acid solution (pH-2) and was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to afford (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid as a white solid (0.50 g). 1H NMR (400 MHz, DMSO-d6) δ 12.85 (br s, 1H), 8.46 (s, 1H), 7.68 (dd, 1H), 7.00 (dd, 1H), 6.87 (m, 3H), 4.39 (m, 1H), 4.02 (dd, 1H), 3.89 (m, 2H), 3.68 (m, 3H), 1.97 (m, 2H), 1.79 (m, 1H), 1.55 (m, 1H), 1.22 (t, 3H). MS (ES+) 361.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>C(Cl)Cl.S(=O)(=O)(O)O.CN(C1C=CC=CN=1)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH:4][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: CN(C)c1ccccn1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Yield: 88.4 %

Procedure:
A mixture of 6.0 g (0.034 mole) of 2,5-difluoro-4-nitroaniline, 6.5 g (0.064 mole) of acetic anhydride, and approximately 0.1 g (0.0008 mole) of dimethylaminopyridine in 300 ml of methylene chloride was stirred and heated at reflux for two hours. The reaction mixture was allowed to cool and stir at room temperature for approximately 18 hours. The solvent was removed from the mixture by distillation under reduced pressure, leaving a residue. To this residue was added 32.5 g (0.318 mole) of acetic anhydride and several drops of concentrated sulfuric acid. This mixture was stirred at room temperature for approximately 18 hours. Approximately 300 ml of water was added to the mixture causing a vigorous exotherm and a solid to form. This solid was collected by filtration. The filter cake was washed with water and was dried under reduced pressure to yield 6.5 g of N-(2,5-difluoro-4-nitrophenyl)acetamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@@H:14]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Reactant: Clc1ccc(Br)c(Cl)c1
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(Cl)c1

Procedure:
Using 2,4-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 75 as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.70-1.90 (br s, 1H), 1.90-2.20 (m, 2H), 2.70-2.80 (m, 4H), 2.91 (t, 1H, J=9.3 Hz), 3.30-3.60 (m, 5H), 3.54 (m, 1H), 5.78 (br s, 1H), 6.51 (s, 1H), 6.68 (s, 1H), 6.79 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.25 (s, 1H). LRMS (ES)+: 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.CO[CH:26](OC)[N:27](C)C.C([O-])(=O)C.[K+].Cl.NO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:23][N:27]=[CH:26][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:21])[CH3:22])=[N:18][N:19]=2)[N:16]=1
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: COC(OC)N(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: CC(C)c1nnc2ccc(-c3cnoc3-c3ccc(F)cc3F)nn12
Temperature: 95 °C
Yield: 58.4 %

Procedure:
A solution of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.10 g, 0.316 mmol; Preparation #K.1), N,N-dimethylformamide dimethyl acetal (0.070 g, 0.57 mmol) and toluene (2 mL) was heated at about 110° C. in an oil bath for about 30 min. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was dissolved in EtOH (2.0 mL) and then potassium acetate (0.12 g, 1.26 mmol) and hydroxylamine hydrochloride (0.090 g, 1.26 mmol) were added. The mixture was heated at about 95° C. in an oil bath for about 30 min. The mixture was concentrated under reduced pressure and then acetic acid was added and the material was purified by RP-HPLC (Table 1, Method d). The appropriate fractions were lyophilized to give the title compound (0.063 g, 58%): LC/MS (Table 1, Method a) Rt=2.11 min; MS m/z: 342.2 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:40][C@:41]2(C)[CH2:43][O:42]2)(=O)=O)C=CC=1)([O-])=O.CN(C=O)C>O>[C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:40][C@@H:41]2[CH2:43][O:42]2)[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1OC[C@@H]1CO1)c1ccccc1
Yield: 98.6 %

Procedure:
To a stirred solution of 4-(benzoylamino)-2-chloro-5-hydroxyphenyl benzoate (103 mg, 0.28 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (73 mg, 0.28 mmol) in DMF (3 mL) cesium carbonate (98 mg, 0.3 mmol) was added. The stirring was continued at ambient temperature over night. The mixture was poured into water and partitioned between water and ethylacetate. The organic phase was washed with water, dried and concentrated in vacuo to give a white solid (117 mg, 98%). The solid was used without further purification.
Reaction SMILES: C1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=O)[CH:9]=CC=2OC(F)(F)F)CC1.[Cl:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.CC1(C)COCN1>>[Cl:20][C:21]1[N:26]=[C:25]([C:27]([N:11]2[C:10]([CH3:12])([CH3:9])[CH2:4][O:5][CH2:6]2)=[O:29])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)n1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1
Agent: CC1(C)COCN1
Product: CC1(C)COCN1C(=O)c1ccc(OCC2CC2)c(Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using the mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (13 mg, 23%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 311.1158 [MH+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH2:18]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(-c2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
33.8 g (0.1 mol) of methyl 4′-iodobiphenyl-4-carboxylate are introduced together with 29.3 g (0.125 mol) of glycol ester of 4-n-pentoxyphenylboronic acid, 70 mg of bis(triphenylphosphine)palladium dichloride and 15.9 g (0.15 mol) of sodium carbonate into 300 ml of DMF and stirred at 80° C. for 12 hours. After filtration and washing with water, the dried residue is recrystallized from DMF. This affords 20.5 g (45%) of methyl 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylate of melting point 248° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O.N1C=CC=CC=1.S(Cl)([Cl:20])=O.Cl>C1C=CC=CC=1.O>[CH2:10]([Cl:20])[CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCOCCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COCCOCCOCCCl

Procedure:
19.02 g (0.116 mol) of triethylene glycol monomethyl ether and 21 ml (20.54 g=0.26 mol) of pyridine in 110 ml of benzene are heated to reflux, and 19 ml (31 g=0.26 mol) of thionyl chloride are added dropwise thereto. The mixture is boiled under reflux for a further 20 hours. When the reaction solution has cooled, a mixture consisting of 5 ml of concentrated hydrochloric acid and 20 ml of water is added thereto, with stirring. The organic phase is separated off and washed repeatedly with water and brine. The solvent is extensively distilled off using a Vigreux column and the residue is purified on silica gel in hexane/ethyl acetate (4:1). The product-containing fractions are concentrated and the residue is distilled, yielding 3,6,9-trioxadecyl chloride (J. Am. Chem. Soc. 89, 7017 (1967)); b.p. 76° C./2 mbar, NMR (CDCl3): 3.8-3.5 (m,12H); 3.37 (s,3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:21]([O:25][C:26](=[O:38])[NH:27][C:28]1([C:36]#[CH:37])[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[C:21]([O:25][C:26](=[O:38])[NH:27][C:28]1([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(CCCOc2ccc(Br)cc2C#N)c1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(CCCOc2ccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C#N)c1

Procedure:
Compound 208-1 (1.04 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.885 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.093 g), bis(acetonitrile)palladium(II) dichloride (0.017 g), cesium carbonate (2.67 g) were stirred in acetonitrile (30 ml) at 90° C. for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give [5-(2-{3-cyano-4-[3-(3-methylphenyl)propoxy]phenyl}ethynyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester as a pale-brown solid. The solid was dissolved in ethyl acetate (10 ml), 10% palladium carbon (containing about 50% water, 0.140 g) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The solution was filtered, and the filtrate was concentrated to give the object product (0.360 g) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(I)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
A 500 ml round-bottomed flask is charged with 66 g of 2-bromo-1-(4-iodophenyl)ethanone in 140 ml of DMF and 38 g of potassium phthalimide. The mixture is stirred at RT for 4 h and the precipitate formed is filtered off on a glass frit and washed with 3 times 50 ml of isopropyl ether. Drying under RP gives 80 g of 2-[2-(4-iodophenyl)-2-oxoethyl]isoindole-1,3-dione in the form of a white solid, which is used as it is in the following step. MS (E/I): m/z=391 (M+); 1H NMR: 5.21 (s, 2H); 7.84 (d, J=8.5 Hz, 2H); from 7.88 to 7.98 (m, 4H); 8.00 (d, J=8.5 Hz, 2H). m.p. (Kofler): 230° C.