Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1.[F:25][C:26]([F:55])([F:54])[C:27]1[C:31](B(O)O)=[CH:30][N:29]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[O:11]=[C:8]1[NH:7][C:6]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]2[CH:3]=[C:2]([C:31]3[C:27]([C:26]([F:54])([F:55])[F:25])=[N:28][N:29]([C:35]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:30]=3)[S:10][C:9]1=2
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)sc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
tert-butyl(25)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (1.41 g) produced in Example 83, step B, [3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]boronic acid (1.72 g), sodium carbonate (902 mg), ethanol (15 mL) and water (3 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (197 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80° C. for 15 hr. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give tert-butyl(2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate as a colorless oil. To a solution of tert-butyl(2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate produced above in methanol (4 mL) was added 4M hydrochloric acid/ethyl acetate solution (1 mL), and the mixture was stirred at 60° C. for 15 hr. The precipitated solid was collected by filtration to give the title compound (530 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:45])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH:27]([CH2:32][C:33]([O:35]C)=O)[C:28]([O:30][CH3:31])=[O:29])([N+:24]([O-])=O)[CH2:20][C@@H:19]2[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[CH3:44])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Ni]>[F:46][C:2]([F:47])([F:1])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:45])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]3([NH:24][C:33](=[O:35])[CH2:32][CH:27]3[C:28]([O:30][CH3:31])=[O:29])[CH2:20][C@@H:19]2[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[CH3:44])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)CC(C(=O)OC)[C@@]1([N+](=O)[O-])CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1CC(=O)N[C@@]12CCN(C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H](c1ccc(F)cc1C)C2
Reaction time: 3 h
Yield: 30.7 %

Procedure:
Dimethyl 2-[(2R,4R)-1-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-nitro-4-piperidinyl]butanedioate (Intermediate 39, 250 mg, 0.368 mmol) was dissolved in Methanol (6 ml) and to this solution was added Raney®-Nickel. The reaction mixture was left stirring under H2 at 1 atm for 3 hrs. The solid was filtered out and the solution was refluxed for 2 hrs. The solvent was removed in vacuo and the crude purified by Flash Chromatography (SP4, 25M cartridge, eluent from 90%:10% to 70%:30% Cy:EtOAc). The solvent was removed in vacuo obtaining the title compound (70 mg, 0.113 mmol, 30.8% yield) as a mixture of diastereoisomers. UPLC: Rt=0.83 mins, nm/z=618 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:13](I)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:16]([C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]([CH3:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:17]
Reactant: COC(=O)c1cc(I)c(C2CC2)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C2CC2)cc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 142.2, 2.00 g, 6.01 mmol, 1.00 equiv, 95%) in DMF (16 mL) was added Zn(CN)2 (890 mg, 7.58 mmol, 1.27 equiv) and Pd(PPh3)4 (731 mg, 0.630 mmol, 0.11 equiv). The resulting solution was stirred at 100° C. under nitrogen overnight. After cooling to ambient temperature, the reaction was then quenched by the addition of 100 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as eluent to yield 1.10 g (81%) of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH:2]1([NH:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Nc1ccccc1
Reactant: C1=CCCC=C1
Solvent: C1CCOC1
Product: C1=CC(Nc2ccccc2)CCC1
Reaction time: 0.02 h
Yield: 86.8 %

Procedure:
Twelve enantioselective Examples are shown in Table 5 below (entries 1-12). A typical procedure is as follows: [Pd(π-allyl)Cl]2 (2.3 mg, 0.0063 mmol) and the (R,R)-Naphthyl-Trost ligand (10.9 mg, 0.0138 mmol) were dissolved in 0.1 mL of dry THF in a screw-capped vial. After stirring for one min, aniline (11.4 μL, 0.125 mmol) was added, and the color of the solution turned bright yellow. After addition of cyclohexadiene (47.6 μL, 0.500 mmol), the vial was sealed with a cap that contained a PTFE septum, and the reaction mixture was stirred at room temperature for 120 h. After removal of all volatile compounds using a rotary evaporator, the residue was purified by chromatography on silica gel (Hexanes : EtOAc=200:1) to give 18.8 mg (87%) of N-cyclohex-2-en-1-ylaniline as a colorless oil with 89% ee and the [α]D24° C. value of −84.5 (c 1.0222, CH2Cl2)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@H:27]([S:38][CH3:39])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].C1C=C(Cl)C=C(C(OO)=[O:50])C=1.C1CCCCC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C@@H:27]([S@@:38]([CH3:39])=[O:50])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1[S@@](C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.) in CH2Cl2 (0.10 M) in a 0° C. bath was added mCPBA (1.2 equiv.). The capped solution was left stirring at rt for 1 hr. cyclohexene (10.0 equiv.) was added to quench any remaining mCBPA and after stirring for 5 minutes the solution was directly loaded onto ISCO SiO2 column and purified to yield tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-((R)-methylsulfinyl)cyclohexylcarbamate in 31% yield, LC/MS=603.2 (MH+), Rt=0.66 min; and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexylcarbamate in 37% yield. LC/MS (m/z)=619.2 (MH+), Rt=0.88 min.
Reaction SMILES: [CH3:1][B:2](OC(C)C)[O:3][CH:4]([CH3:6])[CH3:5].[C:11]1([C:17]#[C:18][Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:1][B:2]([C:18]#[C:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][CH:4]([CH3:6])[CH3:5]
Reactant: CB(OC(C)C)OC(C)C
Reactant: [Li]C#Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CB(C#Cc1ccccc1)OC(C)C
Yield: 817.2 %

Procedure:
The reaction was run following the method of Example 14 using methyldiisopropoxyborane (6.34 g, 44 mmol) in ethyl ether (44 mL) and phenylethynyllithium (4.9 mmol) in ethyl ether (50 mL), then quenched with hydrogen chloride (14.33 mL, 49 mmol). Volatiles were removed under reduced pressure at ambient temperature to yield 7.45 g (91%) of the title product; n20D 1.5290; proton NMR (CDCl3) δ7.23 (m, 5H), 4.73 (septet, J=18 Hz, 1H), 1.23 (d, J=18 Hz, 6H), 0.53 (bs, 3); boron NMR (EE) δ+40.2 ppm(s). Mass spectrum (chemical ionization, isobutene) m/e 187 (M+H, 6%); IR (thin film) 2178, 1326 cm-1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C[N:12]1[CH2:17][CH2:16][C:15]2([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:13]1>C(Cl)Cl>[O:4]([C:2]([N:12]1[CH2:13][CH2:14][C:15]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17]1)=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Oc1ccccc12
Reaction time: 8 h

Procedure:
A solution of phenyl chloroformate (8 ml.) in methylene chloride (75 ml.) is added dropwise with stirring to a solution of 1'-methylxanthene-9-spiro-4'-piperidine (17.0 g.) in methylene chloride (200 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed successively with 3 N sodium hydroxide solution, 3 N hydrochloric acid and water, dried (MgSO4) and the methylene chloride evaporated to dryness. The gummy residue is crystallised from methanol to give 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine, m.p. 105°-107° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:17]([CH3:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c23)CC1
Yield: 36 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 36% yield; NMR Spectrum: 1.96 (s, 3H), 2.19 (s, 3H), 2.44 (s, 3H), 2.46 (t, 2H), 2.50 (hidden by DSMO, 2H), 2.86 (t, 2H), 3.36-3.42 (m, 4H), 4.46 (t, 2H), 6.95 (d, 1H), 7.17-7.25 (m, 2H), 7.60 (d, 1H), 7.65 (s, 1H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:24]([C:5]1[C:6]2[N:7]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:25][CH3:26])(=[O:30])[CH3:29]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a stirred solution of 1-[10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]propan-1-ol (200 mg, 0.470 mmol) in pyridine (1.0 mL) was added acetic anhydride (133 μL, 1.41 mmol) at room temperature. After 18 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water, hydrochloric acid (1 M) and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (207 mg, 0.443 mmol, 94%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: II
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of iodine (46.0 g, 0.180 mol) and silver sulfate (56.3 g, 0.180 mol) in anhydrous ethanol (500 mL) was added 4-nitroaniline (25.0 g, 0.180 mol) and the reaction mixture was stirred for 5 h at rt. The resulting yellow solution was filtered and concentrated in vacuo. The resulting residue was dissolved into 400 mL ethyl acetate, washed with 1N sodium hydroxide solution (2×250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to yield 45.5 (95%) of compound 489A, as a yellow solid. HPLC: 98% at 2.837 min (retention time) (Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.1% trifluoracetic acid, 4 mL/in, monitoring at 220 nm). MS (ES): m/z 265.08 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:21])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:14]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
To a solution of 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (300 mg) in THF (20 mL) were added a solution of ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (283 mg) in THF (5.0 mL), 1,1′-(azodicarbonyl)dipiperidine (523 mg) and tri-n-butylphosphine (420 mg) at 0° C., and the mixture was stirred at 0° C. for 5 min. The mixture was further stirred at room temperature for 16 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (384 mg) as a colorless oil.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2cccc(C)c2)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)c1
Reaction time: 24 h
Yield: 62 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (31 mg, 0.074 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a colourless oil (18 mg, 62%).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([C:39]1([C:47](Cl)=[O:48])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:39]1([C:47](=[O:48])[NH:2][OH:3])[CH2:45][CH:44]2[CH2:40][CH:41]([CH2:42][CH2:43]2)[O:46]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C2)O1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: N#Cc1cnc(Br)s1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)c(Cl)c1Cl

Procedure:
To a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 0.330 g, 1.058 mmol) in NMP (2 ml) was added TEA (0.150 ml, 1.058 mmol) followed by the addition of 2-bromo-1,3-thiazole-5-carbonitrile (prepared according to F. Campagna et al. Tet. Lett, 1977, 21, 1815-1816) (0.200 g, 1.058 mmol) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes. The crude mixture was diluted with EtOAc and washed with water several times. The extracts were combined dried over magnesium sulfate and concentrated to give the desired product. (0.450 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a suspension of 4-bromophenol (2.00 g, 11.56 mmol) and potassium carbonate (4.79 g, 34.68 mmol) in DMF (12 mL) was added 1,3-dibromopropane (7.00 g, 37.3 mmol). The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-5% ethyl acetate/petroleum ether to afford the title compound (2.35 g, 69%) as a colorless oil. 1H NMR (400 MHz, CDCl3) ppm 7.39 (d, 2H), 6.80 (d, 2H), 4.16-4.01 (m, 2H), 3.55-3.53 (m, 2H), 2.41-2.26 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.