Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:39])[N:9]([CH3:38])[CH:10]([CH3:37])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:16]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:15]=1)=[O:12])([CH3:6])([CH3:5])[CH3:4].[CH3:40]OS(OC)(=O)=O>C1COCC1>[C:3]([O:7][C:8](=[O:39])[N:9]([CH3:38])[CH:10]([CH3:37])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:40])[C:21]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:16]([C:29]#[C:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:15]=1)=[O:12])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
At RT NaH (60% dispersion in mineral oil, 2.3 mg, 0.0.06 mmol) is added to tert-butyl-N-methyl-N-[1-[[5-(oxane-4-carbonylamino)-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate E5b (35 mg, 0.04 mmol) in THF (1 ml). After stirring for 10 minutes dimethylsulfate (4 μl, 0.06 mmol) is added to the mixture and stirring continued for 20 minutes. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 5 mg (23%). HPLC-MS: M+H=521; tR=2.06 min (*Method—2).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=O)[C:5]([CH3:10])([CH3:9])[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:9][C:5]1([CH3:10])[CH2:6][NH:7][C@@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: CC1(C)C[C@H](CO)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CN[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
Prepared according to US patent: 20070032433A1. To a solution of (R)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.30 mmol) in THF (50.8 mL) cooled to 0° C., lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added. The mixture was stirred at room temperature overnight (16 h). Additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the solution was refluxed for 6 h. The reaction mixture was cooled and additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0° C. in an ice bath prior to addition of water (3.67 mL) followed by 15% aqueous NaOH (3.67 mL) and water (10.9 mL). It was then stir vigorously at room temperature for 1 h and filtered on a medium porosity sintered glass frit with cotton and celite washing with EtOAc. The solution was then concentrated affording crude (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.73 mmol, 87% yield) as yellow viscous oil. MS (ESI) 130.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15](O)=[O:16])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:39][C:40]1[S:41][S:42][C:43](=[S:45])[N:44]=1>O1CCCC1.O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]([NH:39][C:40]2[S:41][S:42][C:43](=[S:45])[N:44]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1OCc1ccc(F)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1OCc1ccc(F)cc1)Nc1nc(=S)ss1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
2-{2-[(4-Fluorobenzyl)oxy]phenyl}acetic acid (1.04 g, 3.99 mmol) was dissolved in tetrahydrofuran (13 ml), and 1,1′-carbonyidiimidazole (0.777 g, 4.79 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.160 g, 3.99 mmol) was suspended in tetrahydrofuran (13 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.601 g, 3.99 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 16 hours at room temperature. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel chromatography (chloroform), to give 2-{2-[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 7) (0.523 g, 33%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:19]([CH:33]=1)[CH2:20][N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH2:32])=O)=[CH:26][N:25]=1)[CH2:22][CH3:23]>N1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:19]([CH:33]=1)[CH2:20][N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:32])=[CH:26][N:25]=1)[CH2:22][CH3:23]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)cn1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Trifluoroacetic anhydride (0.51 ml) was added dropwise to a mixture of 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]pyridine-5-carboxamide (1.05 g) in pyridine (0.58 ml) and THF (20 ml) at 20° C. The mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate, washed with water, saturated aqueous NaHCO3 and brine, and dried (MgSO4). The solvent was evaporated and the residue purified by MPLC, eluting with dichloromethane/methanol mixtures (100:0 to 95:5) to give 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]-5-cyanopyridine (0.81 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3ccc(F)cc3)nccc12
Reactant: O=C1CCC(=O)N1Cl
Product: Fc1ccc(-c2nccc3c(CCl)cccc23)cc1

Procedure:
1-(4-Fluorophenyl)-5-methylisoquinoline was reacted with N-chlorosuccinimide in the same way as in step (a) of Example 2 to afford 1-(4-flurophenyl)-5-chloromethylisoquinoline as colorless needles having a melting point of 109.5° to 111.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(F)cc1C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-N-methoxy-N-methylpropanamide (example 141, step 3) to give the title compound as a light yellow oil, MS (ESI+): m/z=430.06 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.CS(C)=[O:26]>OO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH2:11])=[O:26])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OCCc2ccc(Cl)cc2Cl)c1
Reactant: CS(C)=O
Agent: OO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(N)=O)c(OCCc2ccc(Cl)cc2Cl)c1

Procedure:
To a solution of 100 mg 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester in 2 ml DMSO 93 mg K2CO3 and 68 μl H2O2 (35%) were added at RT. After stirring the reaction over night the mixture was taken up in 5 ml ethyl acetate and 3 ml water and filtered through a chem elut® cartridge by elution with ethyl acetate. After removal of the solvent the crude product was subjected to the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([Br:25])=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:26][C:13]([F:12])([F:27])[C:14]1[C:15]([Br:25])=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Br
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Br)c1cc(Cl)ccc1O
Yield: 14.5 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)-2-bromoaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)CCC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 67.7 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and n-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.9 g of p-cyanobenzamide (yield 68%).
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:41][CH2:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: COc1ccc(CCN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(CCNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 47 %

Procedure:
Prepared analogously to Example 8a) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-methoxybenzenethanamine and TBTU in a yield of 47% of theory.
Reaction SMILES: CS(OCC1C(C2C=CC(Cl)=CC=2)=CSC=1C(F)(F)F)(=O)=O.CC1C(C)=C(O)C=CC=1CCC(OCC)=O.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH2:55][O:56][C:57]3[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([O:67]CC)=[O:66])=[C:59]([CH3:70])[C:58]=3[CH3:71])=[C:48]([C:51]([F:54])([F:53])[F:52])[S:49][CH:50]=2)=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH2:55][O:56][C:57]3[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[C:59]([CH3:70])[C:58]=3[CH3:71])=[C:48]([C:51]([F:54])([F:52])[F:53])[S:49][CH:50]=2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.38 (m, 4H), 6.97 (d, J=6.5 Hz, 1H), 6.63 (d, J=6.5 Hz, 1H), 4.90 (s, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.24 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a cooled solution of 12.1 (1.01 g, 3.38 mmol) in dry THF (10.0 mL) at 0° C., was added LAH (1.0 M solution in THF (6.7 mL, 6.7 mmol)). Upon complete addition, the reaction was allowed to warm to room temperature and monitored by TLC and LCMS. Upon completion, 1N NaOH (5 mL) was carefully added to quench the reaction. The resulting solution was extracted with EtOAc (3×10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-40% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 12.2 as a colorless oil (0.82, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 7.56 (1H, s), 7.29 (1H, t, J=3.8 Hz), 7.24 (1H, m), 7.07 (1H, d, J=7.6 Hz), 6.93 (2H, m), 6.86 (1H, d, J=1.5 Hz), 4.77 (2H, s), 3.85 (3H, s), 1.72 (1H, s), 1.26 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][NH2:12]>[Cu].Cl>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CN
Reactant: CC(=O)c1ccccc1Cl
Agent: [Cu]
Agent: Cl
Product: CNc1ccccc1C(C)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2'-chloroacetophenone (309 g), industrial methylated spirit (252 ml), methylamine (33% w/w solution in industrial methylated spirit, 1085 ml) and copper lining powder (2.7 g) was stirred in a sealed pressure vessel for 3 hours at 80° C. The reaction vessel was allowed to cool to 40° and the mixture was washed out of the vessel with industrial methylated spirit (60 ml). The combined reaction mixture and washing were stirred at 50 to 55°, a solution of sodium sulphide trihydrate (6.6 g) in water (45 ml) was added dropwise and the stirring and heating were continued for 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name HYFLO SUPERCEL) and the filter bed washed with industrial methylated spirit (300 ml). The combined filtrate and washing were evaporated under reduced pressure to give an oil which was added to hydrochloric acid (5M, 900 ml) and then stirred and heated under reflux for 2 hours. The mixture was cooled to 30°, washed with hexane (2×990 ml) and then adjusted to pH 2 to 3 by addition of aqueous sodium hydroxide (5M, 750 ml) whilst maintaining the temperature at 30 to 35°. The mixture was then extracted with dichloromethane (990 ml) and the extract evaporated under reduced pressure to give the novel compound 2'-(methylamino)acetophenone, m.p. 34°-35°.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:53][C:54]([NH2:58])([CH3:57])[CH2:55][NH2:56]>CN(C=O)C>[NH2:58][C:54]([CH3:57])([CH3:53])[CH2:55][NH:56][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:18]
Reactant: CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.31 mmol), 151 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.47 mmol) and 127 mg of 4-methylmorpholine (1.26 mmol) were initially charged in 2 ml of DMF. 55 mg of 2-methylpropane-1,2-diamine (0.63 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The crude product was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate. The mixture was then filtered and the filtrate was concentrated and lyophilized. This gave 80 mg of the title compound (66% of theory).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: Cc1ccccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: Cc1ccccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Yield: 28 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 55, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide (36 mg, 28%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.55 (d, 2H), 7.26-7.08 (m, 6H), 7.05-6.91 (m, 4H), 5.24 (q, 2H), 4.56-4.49 (m, 1H), 3.88-3.80 (m, 1H), 2.82-2.64 (m, 3H), 2.30 (s, 3H), 2.28-1.89 (m, 2H). MS (EI) for C29H28FN5O3. found 514.0 (MH+).
Reaction SMILES: C([N:8]([CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17])[CH2:9][CH:10]([F:12])[F:11])C1C=CC=CC=1.Cl>O1CCOCC1.C(O)C.[OH-].[Pd+2].[OH-]>[F:11][CH:10]([F:12])[CH2:9][NH:8][CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17]
Reactant: CC1CC1CN(Cc1ccccc1)CC(F)F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CC1CC1CNCC(F)F
Reaction time: 1 h

Procedure:
A solution of N-benzyl-2,2-difluoro-N-[(2-methylcyclopropyl)methyl]ethanamine (1.25 g, 5.2 mmol) and hydrochloric acid (5.7 mmol, 1.44 mL of a 4M solution in dioxane) in ethanol (50 mL) was degassed with nitrogen and treated with palladium hydroxide (125 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 1 hour. The reaction was filtered through celite, washed with methanol and concentrated in vacuo to give (2,2-difluoroethyl)[(2-methylcyclopropyl)methyl]amine as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 6.35 (tt, 48, 3 Hz, 1H), 3.56 (td, J=15.6, 3.1 Hz, 2H), 3.03 (m, 2H), 1.11 (d, J=5.9 Hz, 3H), 0.83 (m, 2H), 0.60 (m, 1H), 0.50 (m, 1H).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(=O)(O)(O)O.COC1C=CC(O)=CC=1>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH2:8]([N:20]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: COc1ccc(O)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A glass flask having an inner volume of 3 liters was fitted with a theremometer, a stirrer and a water separater. This reactor was charged with 240 g of a xylene solution containing 120 g of maleic anhydride. Then, a solution of 220 g of dodecylamine in 1880 g of xylene was added thereto gradually and piecemeal at 40° C. over a period of 120 minutes. After the addition was completed, the resultant mixture and 65.4 g of ortho-phosphoric acid (purity 89% by weight), 0.672 g of p-methoxyphenol, and 0.05 g of zinc acetate added thereto were heated at 150° C. for four hours to effect reaction. Thereafter, the resultant reaction mixture was cooled to 30° C., washed with 400 ml of water, and separated into a water layer and a xylene layer. The xylene layer was filtered to effect removal of insolubles. The xylene layer now free from insolubles was distilled to expel xylene. Consequently there was obtained 260 g of slightly impure N-dodecyl maleimide. It was found to have purity of 91.2% by weight, indicating the yield thereof to be 75.3 mol % based on dodecylamine.
Reaction SMILES: [Sn].[SnH](CCC(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(CCC(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)CCC(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.[C:66]12(Br)[CH2:75][CH:70]3[CH2:71][CH:72]([CH2:74][CH:68]([CH2:69]3)[CH2:67]1)[CH2:73]2>>[CH:66]12[CH2:75][CH:70]3[CH2:71][CH:72]([CH2:74][CH:68]([CH2:69]3)[CH2:67]1)[CH2:73]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[SnH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Sn]
Product: C1C2CC3CC1CC(C2)C3

Procedure:
Illustrative examples of the uses of one of these fluorous tin reagents, (C6F13CH2CH2)3SnH, are shown in FIG. 2. Reduction of adamantyl bromide with 1 equiv of (C6F13CH2CH2)3SnH followed by fluorous-organic liquid-liquid extraction provides the organic product adamantane on evaporation of the organic liquid phase and the fluorous product (C6F13CH2CH2)3SnBr on evaporation of the fluorous phase. A similar reduction can be conducted in a more economical way by using a catalytic amount of the fluorous tin hydride along with an inexpensive inorganic reductant like sodium cyanoborohydride. A three-phase liquid extraction then provides the respective products: inorganic salts (from the aqueous phase), adamantane (from the organic phase), and the tin hydride catalyst (from the fluorous phase).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.Cl.C([O:40][C:41](=[O:44])[CH2:42][NH2:43])C>>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:43][CH2:42][C:41]([OH:40])=[O:44])=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)CN
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCNCC(=O)O
Yield: 41 %

Procedure:
The title compound (59 mg) is prepared as a pale yellow solid in analogy to the procedures given in Example 1 starting from 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (150 mg, 0.291 mmol) and glycine ethyl ester hydrochloride (203 mg, 1.46 mmol); LC-MS: tR=0.96 min, [M+H]+=495.25; 1H NMR (CD3OD): δ 7.88 (s, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 3.98-4.03 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.38-3.44 (m, 2H), 3.24-3.31 (m, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.41 (s, 3H), 2.23-2.32 (m, 2H), 2.06-2.17 (m, 2H), 1.85-1.97 (m, 4H), 1.72-1.82 (m, 2H), 1.32 (t, J=7.5 Hz, 3H).