Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+:8]=[N-:9])=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>CCO>[NH2:12][C:11]1[N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[N:8]=[N:9][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC#N
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccc(C)cc2)c1N
Yield: 73.5 %

Procedure:
Reaction of p-tolyl azide (9.38 g; 0.0705 mole) with ethyl cyanoacetate (7.96 g: 0.0705 mole) as described in example 1a gave 12.76 g (74%) of the triazole of mp (EtOH) 152-153° C. (lit mp 147.5° C., B. R. Brown, D. L. Hammick and S. G. Heritage J. Chem. Soc. 3870 [1953]). (Found; C, 58.38; H 5.90; N, 22.89; C12H14N4O2 requires; C, 58.52; H, 5.73; N, 22.75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[Cl:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 82.3 %

Procedure:
Following general procedure F, tert-butyl 2-{4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (74 mg, 0.140 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.210 mmol) to afford the crude product (68 mg) as a yellow solid: ESI MS m/z 590 [C33H33ClFN3O4+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1ccc(-c2cc3ccccc3[nH]2)cc1
Product: CN1CCN(CCCOc2ccc(-c3cc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (2-(4-(3-chloropropoxy)phenyl)indole (1 mmol, 285 mg) and 4-methylpiperazine (2 mL) was heated at 80° C. for 5 h. After concentration, the residue was purified by column chromatography (MeOH/CH2Cl2) afforded the title compound (285 mg): 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.53 (m, 3H), 7.32 (bd, 1H, J=8.1 Hz), 7.1 (td, 1H, J=1.1, 7.0 Hz), 7.05 (td, 1H, J=1.1, 7.0 Hz), 6.90 (m, 2H), 6.64 (m, 1H), 3.99 (t, 2H, J=6.3 Hz), 2.48 (m, 10H, J=6.4 Hz), 2.25 (s, 3H), 1.93 (quintet, 2H, J=6.3 Hz); EIMS m/z 350 (M+H+).
Reaction SMILES: [Fe:1](Cl)Cl.[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].C(O)C.O>CCCCCC>[Fe:1].[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cl[Fe]Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: [Fe]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
As the first exemplary example for demonstrating the method of synthesizing monodisperse nanoparticles according to the present invention, 10.8 g of iron chloride [FeCl3.6H2O, 40 mmol] and 36.5 g of sodium oleate (120 mmol) were dissolved in a mixture of solvents containing 80 mL of ethanol, 60 mL of distilled water, and 140 mL of hexane, and thereafter the resulting mixture was heated to 70° C. and kept at the same temperature for 4 hours to obtain an iron-oleate complex. During this process, the initial scarlet color in aqueous phase became clear, and the initial transparent organic phase turned to scarlet, indicating that iron-oleate complex was successfully synthesized. When the reaction was completed, the upper organic layer containing the metal-oleate complex was separated and thereafter the hexane was evaporated off, resulting in a waxy solid form. In FIG. 1, the FT-IR spectrum of the resulting iron-oleate complex shows a C═O stretching peak at 1700 cm−1, which is a unique characteristics for a metal-oleate complex.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:27](Br)[CH:28]=[C:29]([CH3:31])[CH3:30]>C(O)(C)C>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:12][CH2:13]2)=[O:7])=[CH:25][CH:26]=1)[CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: CC(C)=CCBr
Reactant: O=C(c1ccc(O)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CC(C)O
Product: CC(C)=CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1

Procedure:
1-[1-(4-Hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg), prenyl bromide (0.5 ml) and 1,8-diazabicyclo[5.4.0]-undecene-7 (0.65 ml) are dissolved in isopropanol (10 ml) and the mixture is refluxed with heating for 4 hours. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=2:1) to give 1-{1-[4-(2-isopentenyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.159 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[C:11]([C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)O)cc1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To 5-tert-butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 1.75 mmol) in a 40 mL scintillation vial was added 2 mL THF and 2 mL 1N LiOH. The reaction was heated at 50° C. for 1 hr after which the reaction mixture was concentrated under vacuum and the crude residue was diluted with 5 mL 1N HCl. The reaction slurry was then extracted with DCM (3×25 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO4. The resulting solution was concentrated under vacuum to yield the desired product (0.432 g, 96%) in >95% purity. The isolated material was used without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][N:12]1[C:16]([NH2:17])=[C:15]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]2=[N:13]1>O>[CH3:11][N:12]1[C:16]([NH:17][CH:1]=[O:3])=[C:15]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]2=[N:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc2c(oc3ccccc32)c1N
Solvent: O=CO
Solvent: O
Product: Cn1nc2c(oc3ccccc32)c1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (200 mL) and 98% formic acid (10 mL) was heated at 50°-60° C. for 15 minutes. After cooling, 2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (5.0 g, 27 mmol, described in Example 6) was added. After stirring overnight at room temperature, the mixture was poured on a mixture of ice and water and extracted with methylene chloride. The organic extract was dried and evaporated. The residue was chromatographed through silica gel using 5% EtOH--CH2Cl2 (v/v) and the eluates were evaporated. Trituration of the resulting residue with diethyl ether gave 3.0 g of N-(2-methyl-2H-benzofuro[3,2-c]pyrazol-3-yl)formamide: mp 184°-187° C.; IR (mineral oil) 3190 and 1670 cm-1 ; UV max (MeOH) 269 nm (ε=21100), 222 (19500) and shoulder at 291 and 215; NMR (DMSO-d6) δ3.85 (3H, s), 7.5 (4H, m), 8.4 (1H, s) and 10.4 (1H, br); and Anal. Calcd for C11H9N3O2 : C, 61.39% H, 4.21% N, 19.53% and Found: C, 61.17% H, 4.27% N, 19.37%.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CC(C)=O>[Br-:1].[CH2:2]([N+:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:17][C:26](=[O:28])[CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCC[N+](C)(C)CCO
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCC[N+](C)(C)CCOC(C)=O
Temperature: 60 °C

Procedure:
In a reaction vessel was placed 13.14 grams of dodecyl dimethyl 2-hydroxyethyl ammonium bromide, 21.22 grams of acetone solvent and 4.72 grams of sodium carbonate. While stirring under nitrogen, 3.27 grams of acetyl chloride was added dropwise. Gas evolution occurred. The mixture was then refluxed (approx. 60° C.) for 6 hours. The solvent was removed under vacuum. The residue was extracted with isopropanol to dissolve the quat and the solution was filtered hot to remove sodium chloride and sodium carbonate. The filtrate was evaporated under vacuum leaving as the product dodecyl dimethyl acetyloxyethyl ammonium bromide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][C:10]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1ncccc1-c1cc[nH]c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1-c1ccn(CCCCCl)c(=O)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of 4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (199 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.38 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (160 μl, 1.38 mmol) was added and the mixture was stirred at room temperature for 1 hour and heated at 70° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 161 mg of the title compound that was used in the next step without further purification (54% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9][CH:8]=1.[CH3:18][C:19]1([CH3:36])[CH2:28][C:27](=O)[C:26]2[C:21](=[CH:22][C:23]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:24][CH:25]=2)[O:20]1>O1CCCC1.CCOCC>[CH3:18][C:19]1([CH3:36])[CH:28]=[C:27]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][CH:8]=2)[C:26]2[C:21](=[CH:22][C:23]([O:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[CH:24][CH:25]=2)[O:20]1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: Cc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3cc(OCCN(C)C)ccc32)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of butyl lithium (12.5 ml, 0.03 mole, 2.4M solution in hexane) was added dropwise over 20 minutes a solution of 1-bromo-4-methylnaphthalene (6.63 g, 0.03 mole) in dry tetrahydrofuran (10 ml), the reaction mixture being cooled throughout by a water bath. After being stirred at ambient temperature for 15 minutes the resulting suspension was treated with a solution of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4-chromanone (4.0 g, ~0.015 mole) in dry tetrahydrofuran (15 ml), the precipitate almost immediately dissolving to give a golden yellow solution. The resulting solution was stirred under reflux for 5 hours, then left overnight at ambient temperature, stirred under reflux for a further 7 hours and again left overnight at ambient temperature. After work up with acid, by an analogous process to that described in Example 1 and chromatography on alumina in 8% ether - 92% petroleum ether (b.p. 60°-80°) the title compound was obtained as a colourless oil (0.65 g, 11%). Its hydrochloride salt was m.p. 215°-216.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[CH2:5][CH2:4]1.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[O:7]=[C:6]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:3][CH2:4][CH:5]1[C:15]([O:16][CH3:17])=[O:18]
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2ccccc2C1=O
Temperature: 85 °C

Procedure:
A solution of dimethyl carbonate (20 mL) was treated with NaH (3 g, 60% dispersed in oil, 75 mmol) and heated to 85° C. To the mixture was dropwise added a solution of bezosuberone (3 g, 18.75 mmol) in dimethyl carbonate (10 mL). The resulting mixture was refluxed for 3 hours, cooled to 0° C., quenched with HCl (1N) (100 mL) and extracted with ether. The organic layer was washed with NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound as a brownish oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cc3ccccc3o2)c2cccc(C(F)(F)F)c2n1
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A solution of 4-bromo-2,8-bis(trifluoromethyl)quinoline (500 mg, 1.45 mmol) in dry dimethoxyethane (10 mL) was treated with tetrakis(triphenylphosphine)palladium (2.3 mg, 10 mol %), stirred for 10 min, treated with benzofuran-2-boronic acid (235 mg, 1.45 mmol) and 2-M Na2CO3 solution (1.45 mL, 2.9 mmol) then refluxed for 2 h. The mixture was cooled, treated with water (10 mL), extracted with EtOAc (3×20 mL), the organic phase was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the resulting yellow solid recrystallised from heptane to give the title compound (351 mg, 64%) as an off-white crystalline solid: mp 129-130° C.; IR νmax (Nujol)/cm−1 2924, 1592, 1463, 1314, 1145, 1116, 1010, 749 and 691; NMR δH (400 MHz, CDCl3) 7.35 (1H, t, J 7.1 Hz), 7.42-7.47 (2H, m), 7.65 (1H, d, J 7.5 Hz), 7.73 (1H, d, J 8.0 Hz), 7.80 (1H, t, J 7.9 Hz), 8.19-8.23 (2H, m) and 8.86 (1H, d, J 9.0 Hz).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][S:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:23])=[O:22])[CH2:9]1)[CH3:4]
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
8.1 A suspension of 540 mg ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride (example 1.2) in 5 ml THF was treated with 1.2 ml TEA and 530 mg 5-chlorothiophene-2-sulfonylchloride. The reaction mixture was stirred over night at r.t., then taken up in EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 690 mg [(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester. Oil. 353.1 ([M+H]+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CCc1nccn1-c1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 4′-fluoro-3′-nitroacetophenone 2.04 g, ethyl 3-(1H-imidazol-2-yl)propanoate 1.87 g, potassium carbonate 3.07 g and N,N-dimethylacetamide 28 mL was heated at 100° C. for 16.5 hours. The reaction liquid was allowed to cool off and to which 60 mL of diethyl ether was added, followed by filtration. Adding 100 mL of water to the filtrate, the organic layer was separated. The aqueous layer was extracted with 100 mL of diethyl ether. The extract was combined with the organic layer, washed twice with 20 mL of water and once with 10 mL of saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, 2.54 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccncc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccncc3)c2c1
Yield: 20 %

Procedure:
This compound was prepared from 6b using 4-pyridinylboronic acid according to method P. Yellow powder; Yield: 20%; mp>350° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.02 (d, J=2.6 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.34 (dd, J=9.0, 2.6 Hz, 1H), 7.64 (d, J=5.9 Hz, 2H), 7.93 (s, 1H), 7.95-8.00 (m, 2H), 8.08 (dd, J=13.0, 2.1 Hz, 1H), 8.79 (d, J=3.9, 2H), 10.02 (s, 1H), 10.22 (s, 1H); MS (ESI) m/z 331 ([M−H]−), 333 ([M+H]+); Anal. Calcd for C20H13FN2O2: C, 72.28; H, 3.94; N, 8.43. Found: C, 70.79; H, 4.08; N, 7.87.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH:8]=[O:9])[CH2:5][CH:4]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)C1CC(CO)CC1CC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CC(C=O)CC1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.84 g, 24.2 mmol) in DCM (100 mL) was added pyridinium chlorochromate (10.42 g, 48.3 mmol). The reaction mixture was stirred at about 25° C. for about 3 h. Silica gel (1 g) was added. The mixture was stirred at about 25° C. for about 30 min. The solid was removed by vacuum filtration, while rinsing with DCM (100 mL). The filtrate was concd under reduced pressure. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-40% EtOAc/Heptane to give ethyl 2-ethyl-4-formylcyclopentanecarboxylate (3.03 g, 63%) as a clear oil: 1H NMR (DMSO-d6) δ 9.66-9.47 (m, 1H), 4.12-3.94 (m, 2H), 2.94-2.73 (m, 2H), 2.19-1.90 (m, 4H), 1.55-1.65 (m, 1H), 1.37-1.23 (m, 1H), 1.23-1.06 (m, 4H), 0.96-0.82 (m, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.ClCCl.[NH2:13][C:14]1[C:19]([OH:20])=[C:18]([F:21])[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]=1[C:29]#[N:30].CC([O:34][C:35]1[C:40]([C:41](Cl)=O)=[CH:39][CH:38]=[CH:37][CH:36]=1)=O>O>[F:21][C:18]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]([C:29]#[N:30])=[C:14]2[C:19]=1[O:20][C:41]([C:40]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:34])=[N:13]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3O)nc2c1C#N
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Diisopropylethylamine (435 μl, 2.5 mmol) was added to a dichloromethane (10 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methyl-biphenyl-3-carbonitrile (I-41) (353 mg, 1.46 mmol), then after cooling with ice, O-acetylsalicyloyl chloride (318 mg, 1.6 mmol) was added, followed by stirring at the same temperature for 30 minutes. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. In xylene (30 ml) and in the presence of a catalytic amount of p-tosylic acid, the resulting residue was heated under reflux for 2 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, and the resulting residue was dissolved in chloroform, washed with saturated sodium bicarbonate water, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by nitration to obtain the entitled compound (320 mg, 64%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][C:17]([CH2:19][C:20](OC)=[O:21])=[CH:18][C:11]=3[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[OH:14][C@@H:13]1[C:12]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][OH:21])=[CH:18][C:11]=2[O:10][CH2:9][C@H:8]1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCC(=Cc1ccccc1)C2=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)OC[C@@H](Cc1ccccc1)[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred solution of 3-phenylmethylene-7-methoxycarbonylmethyl-2H-1-benzopyran-4-one (4.2 g, 14.3 mmole) in THF (70 ml) at 0° C. was added lithium aluminum hydride (2.16 g, 57.1 mmole) portionwise over 10 minutes. The mixture was slowly warmed to room temperature then heated at reflux for 5 hours. The mixture was cooled to 0° C. and 200 ml of saturated sodium-potassium tartrate solution was carefully added over 10 minutes. The mixture was stirred at room temperature overnight, the clear organic phase separated and the clear aqueous layer extracted with 2×100 ml of ether. The combined organic layers were washed with water and brine then dried over MgSO4. Filtration followed by evaporation in vacuo and chromatography (silica gel 2:1→1:5 hexane:ether) gave 2.61 of the title compound (64% yield).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16](O)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16]([Cl:27])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
A 50 mL round bottom flask was charged with 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid (116 mg, 0.36 mmol) suspended in DCM and cooled in an ice bath for 20 minutes. Thionyl chloride (2 mL) was added to the suspension, which became a solution in about 10 minutes. The ice bath was removed and the reaction mixture was concentrated under reduced pressure to give 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinoyl chloride which was used without purification for the next reaction.