Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:28])([F:27])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.FC(F)(F)C1C=C(C(F)(F)F)C=CC=1N>O1CCOCC1>[F:5][C:6]([F:27])([F:28])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=1[NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:1]=[O:2])[CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Agent: Nc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C=Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a 1,4-dioxane solution (20 ml) of 0.57 g of phosgene dimmer was added a 1,4-dioxane solution (5 ml) of 2.0 g of N-(2,4-bistrifluoromethylphenyl) 3-aminobenzamide (produced by using 2,4-bistrifluoromethylaniline as a starting material according to the process described in Example 1-2), and the resultant mixture was stirred at 60° C. for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 10 ml of 1,4-dioxane. Then, the solvent was again distilled off under reduced pressure. The product was washed with n-hexane and filtered off to obtain 1.54 g (yield 72%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][C:17]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 3-(benzyloxy)-4-methylbenzoic acid (2.80 g) in THF (10 mL) was added dropwise a 1.0 M solution of borane-THF complex in THF (23 mL) at room temperature over 30 min, and the mixture was stirred for 2 hr. Methanol (20 mL) was added dropwise to the reaction mixture over 20 min, and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.60 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2].[H-].[Na+].C(O)(=O)[CH2:35][C:36](CC(O)=O)([C:38](O)=O)[OH:37]>C(O)(C)C>[C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:37][CH:36]([CH3:38])[CH3:35])[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2]
Reactant: CS(=O)c1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 5 ml of isopropanol was suspended 100 mg of 1-(2-cyano-benzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7(2)), 26.3 mg of sodium hydride was added to the mixture and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were successively added an aqueous citric acid solution and an aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 68 mg of the title compound as powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C1CCN2C(=NCCC2)CC1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 7 h

Procedure:
To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrous acetonitrile (50 mL) at ~0° C. under argon was added DBU (9.90 mL, 66.2 mmol). After the solution had cooled to ~0° C., 3-chloro-3-methyl-1-butyne (7.10 g, 69.2 mmol) was added followed by copper(II) acetylacetonate (87.4 mg, 033 mmol). After stirring at ~0° C. for 7 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (70 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (9.56 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](CC)[C:5]=1[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2].[OH-].[K+].Cl>C(O)C.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: CCc1c(C(=O)[O-])ccc([N+](=O)[O-])c1OC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
To a solution of 4-nitro-3-isopropoxy-ethylbenzoate (11.85 g, 0.047 mol) in ethanol (200 mL) was added a solution of potassium hydroxide (2.6 g, 0.047 mol) in water (5 mL). The reaction mixture was heated to reflux for 2 hours. The ethanol volume was reduced to 100 mL and the mixture then poured into 1 N HCl (100 mL). The crystals that precipitated, were filtered off and dried in a vacuum oven to yield 9.35 g (88%) of 4-nitro-3-isopropoxybenzoic acid. MS ES− 225, ES+ 223.
Reaction SMILES: FC1C=CC(C[P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=CC=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]Br)=[CH:18][CH:17]=1.COP(OC)OC>>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:18][CH:17]=1
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Clc1ccc(CBr)c2ccccc12
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccc(Cl)c2ccccc12)OC

Procedure:
Following the procedure of Compound 11, 4-chloro-1-bromomethylnaphthalene is reacted with trimethylphosphite.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[S:46][C:42]=2[C:41]([N:48]([CH2:50][CH2:51][O:52][CH3:53])[CH3:49])=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH:47][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:46][C:42]=2[C:41]([N:48]([CH2:50][CH2:51][O:52][CH3:53])[CH3:49])=[CH:40][CH:39]=1
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(C)c3)sc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.[NH2:43][CH2:44][C:45]1[C:55]2[CH2:54][CH2:53][N:52]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:50][C:49]=2[CH:48]=[CH:47][C:46]=1[Cl:63]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:59]([O:58][C:56]([N:52]1[CH2:53][CH2:54][C:55]2[C:45]([CH2:44][NH:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[C:46]([Cl:63])[CH:47]=[CH:48][C:49]=2[CH2:50][CH2:51]1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CN)c2CC1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CNc3ccccn3)c2CC1
Temperature: 95 °C
Reaction time: 20 h
Yield: 203.5 %

Procedure:
Add tris(dibenzylideneacetone)dipalladium(0) (52 mg, 0.06 mmol), DPPP (47 mg, 0.11 mmol), sodium tert-butoxide (26 mg, 0.27 mmol) and 2-bromopyridine (23 μl, 0.23 mmol) to a solution of 6-aminomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60 mg, 0.19 mmol) in anhydrous toluene (3 mL). Degas the slurry under house vacuum, then flush with nitrogen. Stir the mixture at 95° C. for 20 h. Cool the mixture to room temperature, dilute with diethyl ether (20 mL) and filter through Celite®. Concentrate the filtrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylaminomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg). Continue processing with the crude mixture. MS (ES+) m/z: 388.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[C:10][Si](C)(C)C)=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=[C:5]([CH3:19])[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:19])=[N:6][C:7]=1[C:15]([F:18])([F:16])[F:17])#[CH:10]
Reactant: COc1nc(C)nc(C(F)(F)F)c1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(OC)nc(C)nc1C(F)(F)F
Yield: 49.3 %

Procedure:
5-Iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (5.0 g) was dissolved in DMF (50 ml) and N,N-diisopropylethylamine (6.5 g), copper(I) iodide (0.3 g), dichlorobis(triphenylphosphine)palladium(II) (1.12 g) and trimethylsilylacetylene (15.4 g) was added at room temperature with stirring. The mixture was heated (50° C.) in nitrogen atmosphere for 7 hr and cool to room tempeature. The reaction mixture was added methyl tert-butyl ether (MTBE) (200 ml). The insoluble matter was removed by filtration through Celite and the filtrate was washed with water and brine, respectively. The MTBE solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.3 g) as pale yellow oil. This crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.2 g) was dissolved in THF (100 ml) and tetrabutylammonium fluoride (1M THF solution, 18 ml) was added under ice cooling with stirring. After stirring 30 min at this temperature, the reaction mixture was added water in one portion under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give 5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) as colorless crystalline solid, mp 77° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:20])([F:19])[C:14]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccoc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (20 g) was added to a solution of n-butyllithium (2.5M in hexanes, 60 ml) in diethyl ether (200 ml) at -70° C. After 30 minutes, ethyl trifluoroacetate (28.6 g) was added slowly. After a further 1 hour the mixture was allowed to warm to room temperature and was then left to stir overnight. 1M Hydrochloric acid (100 ml) was added and the mixture stirred for 5 minutes. The organic layer was separated, washed, dried and evaporated. The residue was distilled to give the title compound. B.p. 118° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:45]([O:47][CH3:48])=[O:46].O>C1COCC1>[CH3:48][O:47][C:45](=[O:46])[N:7]([CH2:6][C:5]1[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=1)[CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
A mixture of {5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl }-cyclopentylmethyl-ethyl-amine (0.25 g, 0.47 mmol) and potassium carbonate (0.19 g, 1.4 mmol) in THF (10 mL) was stirred for 20 min at RT. Thereafter, methyl chloroformate (0.55 mL, 0.7 mmol) was added and stirring was continued overnight. To this mixture was added water (100 mL) and the product was extracted with ethyl acetate (×30 mL). Theorganic extracts were combined and concentrated and the residue was purified by column chromatography over 230-400 mesh silica gel. Elution with 20% ethyl acetate in hexanes gave the pure product as a colorless, gummy mass (yield: 55%).
Reaction SMILES: C([O:8][C:9]([C@H:11]([CH3:38])[CH2:12][C@H:13]([NH:27][C:28]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[N:31]1)=[O:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@@H:13]([NH:27][C:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[N:31]2)=[O:29])[CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH3:38])=[CH:16][CH:17]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)O

Procedure:
Next, to a solution of 1H-pyrazole-3-carboxylic acid (20.5 mg, 0.183 mmol) in DMF (1 mL) is added diisopropylethylamine (0.032 mL, 0.183 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid. Next, a solution of 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.117 mmol) in EtOAc (10 mL) is hydrogenated over 10% Pd/C (40 mg) at 1 atm for 5 hours. The catalyst is filtered through Celite and the filtrate evaporated under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid. HPLC Retention time 0.96 minutes (condition A); MS 422.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07Hz, 3H), 1.78 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.86 (m, 1H), 2.98 (m, 1H), 4.14 (m, 1H), 6.84 (d, J=2.65Hz, 1H), 7.28 (d, J=8.34Hz, 2H), 7.33 (t, 1H), 7.43 (t, 2H), 7.56 (d, J=8.34Hz, 2H), 7.63 (d, J=7.07Hz, 2H), 8.29 (d, J=2.78Hz, 1H), 8.58 (d, J=9.09Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[H-].[Na+].[I-].[K+].Cl[CH2:12][C:13]([O-:15])=[O:14].[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:1]([CH2:4][CH2:5][O:6][CH2:12][C:13]([OH:15])=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: O=C([O-])CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCOCC(=O)O
Yield: 54.7 %

Procedure:
A solution of 50.0 g of 2-azidoethanol (574 mmol) in 100 mL of dry THF was added dropwise to a stirred (mechanical stirrer) suspension of 25.3 g of NaH (632 mmol), in 250 mL of dry THF over a period of 1 hour. The reaction mixture was charged with 18.5 g of tetrabutylammonium bromide (57.4 mmol) and 9.52 g of potassium iodide (57.4 mmol) in one portion. Finally, a solid addition funnel was used to add 73.6 g of sodium chloroacetate (632 mmol) to the reaction mixture. The resulting suspension was heated at reflux temperature for 20 hrs. The reaction mixture was quenched with 200 mL of water (added dropwise with cooling), and the THF was removed in vacuo. The resulting basic solution was washed with dichloromethane (8×200 mL). The aqueous extract was acidified to pH=1 (concentrated HCl), saturated with solid NaCl, and extracted with 6×350 mL of dichloromethane. The combined dichloromethane extracts were dried overnight over Na2SO4, solvent removed in vacuo to give 45.6 g of III as a yellow oil (55%). The product was used in the next coupling experiment after spectral characterization. Carbonyldiimidazole (9.83 g, 60.6 mmol) and (2-azidoethoxy)acetic acid (II) (8.00 g, 55.1 mmol) in 100 mL of dry dichloromethane were stirred at room temperature for 1 hour. A solution of 8.7 g of 2,2-dimethyl-1,3-dioxane-4,6-dione (60.6 mmol, Meldrum's acid) and 4.4 g of dry pyridine (55.1 mmol) in 30 mL of dry dichloromethane were added to the reaction mixture, and stirred for 16 hrs at room temperature. The reaction mixture was washed with aqueous 2 N HCl solution (2×60 mL), water (2×40 ml), and brine (40 mL), dried (MgSO4), and the solvent removed under reduced pressure to give 15 g of the desired product (IV) (100%). TLC showed small amounts of Meldrum's acid in the crude product. The crude product was used in the next experiment without any further purification.
Reaction SMILES: C[Mg]I.[CH2:4]([N:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]([NH:20][S:21]([CH2:24][C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:22])([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)=[CH:9][C:8]([CH:29]=[O:30])=[N:7]1)[CH3:5].[CH2:31]1COCC1>CCOCC>[CH2:4]([N:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]([NH:20][S:21]([CH2:24][C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:22])([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)=[CH:9][C:8]([CH:29]([OH:30])[CH3:31])=[N:7]1)[CH3:5]
Reactant: CCn1nc(C=O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Mg]I
Solvent: CCOCC
Product: CCn1nc(C(C)O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of MeMgI (1.47 mmol) in Et2O (3.0 M, 0.49 mL) was added dropwise over 2 min to a stirred mixture of the aldehyde from Step 1 and THF (10 mL) at 0° C. under N2. The reaction mixture was stirred for 15 min and then quenched by the addition of NH4Cl solution (15 mL). The organics were extracted into EtOAc (40 mL), concentrated under reduced pressure, and purified by column chromatography on silica, eluting with 80% EtOAc/iso-hexane to yield the alcohol (121 mg, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.60-7.45 (3H, m), 7.35 (1H, d, J=7.6 Hz), 6.23 (1H, s), 5.08 (1H, s), 4.98 (1H, q, J=6.5 Hz), 4.15-4.07 (2H, m), 3.53-3.42 (2H, m), 1.82 (6H, s), 1.57 (3H, d, J=6.5 Hz), 1.39 (3H, t, J=7.2 Hz). MS (ES+) C18H24F3N3O3S requires: 419, found: 420 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])[CH3:35]>>[C:34]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:39][CH:38]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccc(C(C)=O)cc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 51 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 4-acetylphenyl boronic acid. The title compound (83 mg) was obtained as a pale green solid, (yield=51%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])[CH:3]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][N:5]=1)=[NH:10]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccccc1CNC(=N)Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1CNC(=N)Nc1cc(-c2ccccc2)ccn1
Temperature: 110 °C
Yield: 35 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.150 g (0.447 mmol) N-(4-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.081 g (0.651 mmol) phenylboric acid, 0.142 g (1.343 mmol) sodium carbonate, and 0.036 g (0.031 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 17.5 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 52 mg pure N-(2-methoxybenzyl)-N′-(4-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12]C)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:14][CH3:15])[CH:3]=1.N>Br>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:14][CH3:15])[CH:3]=1
Reactant: CCc1cc(Cl)c2cccc(OC)c2n1
Agent: Br
Agent: N
Product: CCc1cc(Cl)c2cccc(O)c2n1
Yield: 83.5 %

Procedure:
A solution of 4-chloro-2-ethyl-8-methoxyquinoline (4.0 g) in 48% hydrobromic acid (80 ml) was refluxed for 2 days. The mixture was adjusted to pH 12 with 28% ammonia solution. The precipitate was collected by vacuum filtration, and was washed with water and hexane to give 4-chloro-2-ethyl-8-hydroxyquinoline (3.13 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[C:19]3=[O:31])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl>CCOC(C)=O.C(O)(C)C>[NH2:23][C@H:20]1[CH2:21][CH2:22][N:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=3)[CH2:13][CH2:14]2)[C:19]1=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of (S)-tert-butyl 1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (4 g, 8.6 mmol) in EtOAc (20 mL) was added HCl in isopropanol (5-6 M, 16 mL) and the reaction was stirred overnight at ambient temperature. The reaction was concentrated under vacuum and the material dissolved in water (about 20 mL). The aqueous layer was basified to about pH 12 using NaOH (1 N) and the aqueous layer extracted with DCM (150 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (3.1 g, 100%).