Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:35]=[C:34]([CH2:36]OCOC)[C:33]([B:41]4[O:45]C(C)(C)C(C)(C)[O:42]4)=[C:32]([F:50])[CH:31]=3)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([NH:22][CH3:23])=[O:21])[C:9]=3[CH:24]=2)[CH2:4][CH2:3]1>C1COCC1.CO.C(Cl)Cl>[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:31]=[C:32]([F:50])[C:33]4[B:41]([OH:42])[O:45][CH2:36][C:34]=4[CH:35]=3)[S:26]([CH3:29])(=[O:27])=[O:28])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([NH:22][CH3:23])=[O:21])[C:9]=3[CH:24]=2)[CH2:4][CH2:3]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(B4OC(C)(C)C(C)(C)O4)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c4c(c3)COB4O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 7 %

Procedure:
Aqueous hydrochloric acid (4 mL, 1 N) was added to a solution of 5-cyclopropyl-6-(N-(3-fluoro-5-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (306 mg) in THF (4.0 mL) and MeOH (0.8 mL). The mixture was heated to 70° C. under N2 overnight. The mixture was cooled to room temperature and the organic solvent was removed under reduced pressure. The crude was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. MeOH (6 mL) was then added to the crude and stirred for 15 min. A white solid was formed which was filtered to give 170 mg crude product (90% purity). 50 mg crude product was purified by silica gel chromatography (0-100% EtOAc in DCM, then 0-10% MeOH in DCM) to give 5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (17 mg, 6.24% yield). Another 120 mg crude product was washed with MeOH and dried to give 5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (106 mg, 36.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50 (br. s., 1H), 0.81 (br. s., 2H), 0.97 (br. s., 1H), 2.06 (br. s., 1H), 2.84 (d, J=4.3 Hz, 3H), 3.48 (s, 3H), 4.95 (s, 2H), 7.02 (d, J=9.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.41 (t, J=8.8 Hz, 2H), 7.97 (dd, J=8.5, 5.6 Hz, 2H), 8.04 (s, 1H), 8.49 (d, J=4.5 Hz, 1H), 9.28 (s, 1H). LCMS (m/z, ES+)=553 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCc1ccccc1OC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
The 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.27 mmol) was dissolved in DMA (5.0 mL). 2-Trifluoromethoxybenzyl amine (153 mg, 0.80 mmol) was added followed by diisopropylethylamine (0. 14 mL, 0.80 mmol). The reaction was heated to 100° C. and stirred for 18 h, then cooled to 25° C. The volatiles were removed in vacuo and the crude product was purified by flash column chromatography (SiO2, 15-50% EtOAc-hexanes) to afford 4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyridin-4-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (91 mg, 64%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C:9]1([CH2:13][CH2:14][CH3:15])[CH2:12][O:11][CH2:10]1.C(N(CC)CC)C.O>ClCCl>[CH:8]([C:9]1([CH2:13][CH2:14][CH3:15])[CH2:12][O:11][CH2:10]1)=[O:7]
Reactant: CCCC1(CO)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1(C=O)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
A solution on dimethyl sulphoxide (12 ml) in dry dichloromethane (4.0 ml.) was added to a solution of oxalyl chloride (7.4 ml) in dichloromethane (25 ml) stirred at -70° under nitrogen. After the addition was complete the resulting mixture was stirred for a further 5 minutes at -70° before a solution of 3-hydroxymethyl-3-n-propyloxetane (10.0 g) in dichloromethane (25 ml) was added, dropwise, over 10 minutes. The resulting mixture was allowed to stir for a further 30 minutes when neat triethylamine (54 ml) was added over approximately 30 minutes. The reaction mixture was allowed to warm to room temperature over 3 hours when it was poured into water. The organic phase was separated and the aqueous layer further extracted with fresh dichloromethane. The combined organic extracts were washed with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The resulting organic phase was dried over anhydrous magnesium sulphate and evaporated in vacuo to give 3-formyl-3-n-propyloxetane (10.5 g) as a yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH3:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:9](=[O:10])[CH2:8][CH2:7][C:6](=[O:5])[CH3:12])=[CH:17][CH:16]=1
Reactant: Clc1ccccc1
Reactant: CC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCC(=O)c1ccc(Cl)cc1
Reaction time: 0.54 h
Yield: 13.6 %

Procedure:
To a well stirred suspension of anhydrous aluminium chloride (29.66 g, 0.223 mol) in 154.7 ml of chlorobenzene was added 4-oxopentanoylchloride (25.0 g, 0.187 mol) drop-wise, over a period of 30-35 minutes at room temperature (25-30° C.). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10 ml) the precipitated solid was filtered and filtrate was concentrated in a rotary evaporation to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2×100 ml), brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform-hexane (90:10) as eluent to give 5.3 g (13.60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[F:30][C:31]([F:44])([F:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[CH2:17]([S:16][C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[N:12]=[CH:13][C:14]=1[C:20]([N:40]1[CH2:41][CH2:42][CH:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([F:30])([F:43])[F:44])[CH2:39]1)=[O:22])[CH2:18][CH3:19]
Reactant: FC(F)(F)c1ccccc1C1CCNC1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7) was dissolved in DCM (3 mL). 1 drop of DMF and oxalyl chloride to (71 μL, 0.83 mmol) was added. The mixture was stirred at ambient temperature for 2 h and then volatiles were removed by evaporation under reduced pressure. The residue was dissolved in DCM (5 mL) and added to a solution of 3-[2-(trifluoromethyl)phenyl]pyrrolidine HCl (105 mg, 0.42 mmol) and DIPEA (217 μL, 1.25 mmol) in DCM (5 mL). Water (10 mL) was added and the mixture stirred vigorously and passed through a phase separating column. The filtrate was purified by chromatography on silica gel, eluting with 0-20% EtOAc/DCM to give the title compound as a clear colourless oil (177 mg, 81%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Na].[CH3:8][C:9]1([CH3:18])[O:13][C:12]([CH3:17])([C:14]([O-:16])=O)[CH2:11][O:10]1.[Na+].[C:20]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30])#[N:21].C([O-])(O)=O.[Na+]>O1CCCC1.C(N(CC)CC)C.CC(N(C)C)=O.C(OCC)(=O)C.CCCCCCC>[C:20]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:14]([C:12]2([CH3:17])[CH2:11][O:10][C:9]([CH3:8])([CH3:18])[O:13]2)=[O:16])=[CH:24][C:23]=1[C:29]([F:30])([F:31])[F:32])#[N:21]
Reactant: CC1(C)OCC(C)(C(=O)[O-])O1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCCCCCC
Product: CC1(C)OCC(C)(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)O1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
In a 50 ml 3-necked flask, equipped with a magnetic stirrer, under nitrogen at −20° C., 0.3 ml of oxalyl chloride in 1 ml of tetrahydrofuran was added slowly to 0.364 g of the sodium salt of the Example 5 (compound (8), R═Na) in a mixture of 0.5 ml of triethyl amine in 5 ml of dimethylacetamide. The resulting mixture was stirred for 30 minutes at −10° C. Then, a solution of 0.372 g of 4-cyano-3-trifluoromethylaniline in 2 ml of dimethylacetamide was added dropwise and slowly. The conversion was followed by TLC analysis (eluens: ethyl acetate/heptane=2/3). After ˜1 hour at room temperature, the reaction mixture was poured into 200 ml of saturated aqueous NaHCO3 solution, and was subsequently extracted with 2×30 ml of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried (Na2SO4) and concentrated at reduced pressure to give a dark-brown oil, which was purified by column chromatography (Merck 60 SiO2, eluens ethyl acetate/heptane=2/3). Isolated yield: 0.336 g light brown clear oil (51%). 1H-NMR confirmed the structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I-:16].O>C(#N)C.[Ag+].FC(F)(F)C([O-])=O>[I:16][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:3][C:2]=1[F:1]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reactant: [I-]
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In 300 ml of acetonitrile was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.[C:33]([C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([C:35]1[S:39][C:38]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=2)=[CH:37][CH:36]=1)#[N:34]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccc(C#N)s4)c3C2=O)c(OC)c1
Temperature: 160 °C

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (114 mg, 0.245 mmol), 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol), tris(dibenzylideneacetone)di-palladium(0) (13.47 mg, 0.015 mmol), and 2-(dicyclohexylphosphino)biphenyl (5.16 mg, 0.015 mmol) in dioxane (2 mL) and DMF (0.5 mL) was heated to 160° C. under microwave irradiation for 45 min. UPLC showed 50% conversion. The reaction mixture was subsequently heated at 160° C. under microwave irradiation for 45 min. Additional 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol) was added and the reaction mixture was heated at 160° C. under microwave irradiation for 60 min. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40-80% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C27H28FN5O4S, 538. found, 538.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])(=O)C.[In+3:13].C([O-])(=O)C.C([O-])(=O)C>C1(C)C(C)=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[In+3:13].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[In+3:13]
Reactant: Oc1ccccc1O
Agent: CC(=O)[O-]
Agent: [In+3]
Solvent: Cc1ccccc1C
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (3.30 g, 30 mmol) and xylene (90 ml) was dehydrated by distilling 10 mL of the solution. Thereafter, 5.84 g (20 mmol) of indium acetate was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 132° C. or higher, distilled until the amount of the solution became half. After the distillation, volatile components of the residual mixed solution were vaporized under reduced pressure by a rotary evaporator. The residual solid content was further heated to 100° C. under vacuum using a vacuum dryer so that the remaining volatile components were completely removed. The solid content (catechol-indium complex) was green in color. The yield amount was 5.54 g (20 mmol), and the yield percentage was 100%. 6.93 g of catechol-indium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34]O)[O:31][C:30]4=[O:36])=[CH:25][C:24]=3[F:37])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:50]=[N+:51]=[N-:52].[Na+]>ClCCl.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][N:50]=[N+:51]=[N-:52])[O:31][C:30]4=[O:36])=[CH:25][C:24]=3[F:37])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCN(C4CCN(C(=O)OCc5ccccc5)CC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
To a solution of 3.67 g 4-{4-[2-fluoro-4{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-piperazin-1-yl}-piperidin-1-carboxylic acid benzyl ester (7.16 mmol) and 1.99 ml of triethylamine (14.3 mmol) in 50 ml dichloromethane was added at 0° C. 0.66 ml of methansulfonyl chloride (8.59 mmol). The reaction was stirred at room temperature and monitored by TLC. The reaction was diluted with water and washed with water and brine. The org. layer was dried over Mg sulfate, filtered and evaporated. The oily residue was dissolved in 15 ml DMF. 100 mg of tetrabutyl ammonium iodide and 0.930 g sodium azide (14.32 mmol) were added and the mixture stirred under nitrogen at 80° C. The reaction was monitored by TLC. The DMF was evaporated, the residue dissolved in ethyl acetate and washed with water and brine. The org. layer was dried over Mg sulfate, filtered and evaporated. The residue was crystallized from an ethyl acetate/ether mixture.
Reaction SMILES: Br[C:2]1[Te:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Te:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc[te]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc[te]2)c(F)c1F

Procedure:
A mixture of 10.0 g (38.7 mmol) of 2-bromotellurophene, 8.0 g (39.6 mmol) of 4-ethoxy-2,3-difluorophenylboronic acid, 3.5 g (3.0 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 100 ml of 2 N sodium carbonate soln. in 200 ml of toluene/ethanol (1:1) is heated under reflux for 1.5 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)tellurophene is obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1)([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:30])=[CH:23][CH:24]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 3 (70 mg, 287 μmol) and 4-formyl-benzoic acid mono tert-butyl ester (150 mg, 727 μmol) in MeOH (3 ml) was stirred at 45° C. for overnight to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Crystallization from EtOAc/hexanes afforded a white solid as desired product (116 mg, 93% yield). MS +m/z: 434 (M+H)+
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[CH3:17])=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[CH3:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C#N)cc2C)cc1
Agent: BrB(Br)Br
Product: Cc1cc(C#N)ccc1-c1ccc(O)cc1
Yield: 98 %

Procedure:
The product from Example 165A and 1.0M BBr3 were processed as described in Example 164B to provide the title compound (98% yield). 1HNMR (300 MHz, CDCl3) δ2.42 (s, 3H), 5.2 (s, 1H), 6.70-7.54 (m, 7H); MS (DCI) m/z 210 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH2:9]([O:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH3:10].[Na]>C(OCC)C>[C:14]([C:13](=[C:4]([OH:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:12]([O:11][CH2:9][CH3:10])=[O:16])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: CCC(CC)C(=O)Cl
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)C(C#N)=C(O)C(CC)CC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 74 g (0.55 mol) of 2-ethylbutyryl chloride were added dropwise to a suspension of 150 g (1.1 mol) of sodium cyanoacetate ethyl ester in diethyl ether. The reaction mixture was stirred at 25° C. for 16 h and then hydrolyzed, and the organic phase was separated off. The aqueous phase was washed with ether and then acidified to pH 3. The enol released in this manner was extracted, washed and dried. Customary purification gave 81 g (70% of theory) of the title compound as a viscous colorless liquid (b.p. 78 to 81° C./1.2 mbar).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[C:13]1(=O)[CH2:18]CC[CH2:15][CH2:14]1>>[NH2:10][C:8]1[C:7]2[N:6]([C:13]([CH3:18])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: O=C1CCCCC1
Product: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 5,6-diamino-nicotinic acid methyl ester (1 eq., 5.1 g) in cyclohexanone (50 ml) bromobutanone (1.2 equiv., 3.9 ml) was added over 10 min. The mixture was heated to 100° C. (inner temperature) and stirred 2.5 h at this temperature. The mixture was cooled to room temperature and the pale solid was filtered off and was washed with TBME (3×10 ml). Drying under reduced pressure at 45° C. Yield: 6.53 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:18][C:19]1[CH:20]=[C:21]([NH2:33])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)COc1ccc(-c2cccs2)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3cccs3)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from 2-chloro-4-thiophen-2-yl-phenoxy)-acetic acid (131b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).