Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C1C=CC=CN=1)[CH:19]=[O:20]>C1COCC1.C(OCC)C.C1COCC1>[C:1]1([C:7]2[O:11][C:10]([CH:19]=[O:20])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnco2)cc1
Reactant: CN(C=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ncc(-c2ccccc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
According to reference (Synthesis 1984, 1048–1050), to a solution of 5-phenyloxazole (1.5 g, 10.3 mmol) in THF:diethyl ether (2:1, 50 mL) at −78° C. is added n-butyl lithium (7.1 mL of 1.6 M solution in hexanes, 11.4 mmol). The reaction is stirred at −78° C. for 30 minutes after which time a solution of N-methyl-2-pyridyl formamide (1.85 mL, 15.5 mmol) in THF (20 mL) is added. The reaction mixture is stirred at −78° C. for 30 min and then at 25° C. for 14 hours. It is quenched by addition of water and extracted with ethyl acetate. The combined organic layers are washed with 10% HCl, saturated sodium bicarbonate and brine before being dried over sodium sulfate and concentrated. The resulting oil is purified by column chromatography (5% ethyl acetate in hexanes) to afford 246 ng of 5-phenyl-1,3-oxazole-2-carbaldehyde.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2.[OH2:36]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][C:30](=[O:36])[NH:31]2
Reactant: O
Reactant: c1cc(-c2nccs2)c2cc[nH]c2c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2nccs2)N1
Reaction time: 1.5 h

Procedure:
Pyridinium tribromide (90% (Aldrich), 1.9 g, 5.34 mmol) was added portion-wise over 10 minutes to a suspension of 4-thiazol-2-yl-1H-indole (360 mg, 1.78 mmol) in 2-methyl-2-propanol (15 mL), ethanol (9 mL) and acetic acid (5 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (18 mL), water (1 mL) and zinc dust (1.5 g, 23.14 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was removed by filtration and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (50 mL) overnight. The solid which formed was filtered, washed with water to remove the zinc and pyridine salts and dried under high vacuum to give 4-thiazol-2-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:21]([O:25][N:26]1N=NC2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C1COCC1>[CH3:21][O:25][N:26]([CH3:27])[C:15]([C:10]1[C:11]([CH3:14])=[N:12][S:13][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nsc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1c(C)nsc1NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-3-methylisothiazole-4-carboxylic acid (2.10 g, 8.13 mmol) in THF (45 mL) at 0° C. were added HATU (3.70 g, 9.76 mmol) and Hunig's base (3.15 g, 24.4 mmol). After a period of 5 min, N,O-dimethylhydroxylamine hydrochloride (1.03 g, 10.6 mmol) was added to the previous mixture. After a period of 1.5 h at rt, the resulting mixture was evaporated under reduced pressure and purified by flash chromatography (EtOAc/hexane 1:9 to 10:0) to give tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylisothiazol-5-ylcarbamate as an oil (1.60 g). LRMS (M+H)+: 302 m/z.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:20].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:20])=[CH:19][CH:18]=1)=[O:8]
Reactant: [OH-]
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1cccc(C)c1NC(=O)c1ccc(C(N)=O)cc1
Yield: 43 %

Procedure:
Ten grams of 4-cyano-N-(2,6-dimethylphenyl)benzamide and 3 grams of finely powdered potassium hydroxide were slurried in t-butanol and heated at reflux for 50 minutes. The homogeneous mixture was poured into a saturated sodium chloride solution and extracted in chloroform. Material which was insoluable in both the organic and water phases were recovered by filtration, crystallized from methanol, and provided the title compound in 43% yield, m.p. 246°-248° C.
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]([O:15]C)=[C:10]([CH2:12][CH2:13]O)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:2][CH2:13][CH2:12][C:10]1[CH:11]=[C:6]([Cl:5])[C:7]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]=1[OH:15]
Reactant: BrB(Br)Br
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(N2CCCCC2)c(Cl)cc1CCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 ml of boron tribromide are added dropwise over a period of approximately 5 minutes to a solution, cooled to 0°, of 2.70 g (10 mmole) of 2-[5-chloro-2-methoxy-4-(piperidin-1-yl)-phenyl]-ethanol in 70 ml of absolute methylene chloride. The reaction mixture is then stirred for a further 5 hours at room temperature, poured onto ice and the resulting suspension is adjusted to pH 6-7 with solid sodium carbonate and extracted with methylene chloride. The organic extracts are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Recrystallisation from petroleum ether yields 1-bromo-2-[5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenyl]-ethane, melting point 115°-116°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].C1(Br)CCCC1.C1(O)C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)c(OC3CCCC3)c2)c1
Agent: BrC1CCCC1
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Yield: 53.9 %

Procedure:
2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) was dissolved in DMF (40 ml) and treated with Cs2CO3 (730 mg, 2.24 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnight at RT some of the phenol remained (SiO2 :t.l.c, CH2Cl2). Cs2CO3 (870 mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added. After stirring at RT for 3 h the phenol had been consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (50 ml), filtered, and concentrated in vacuo to give a yellow solid which was recrystallised from dichloromethane/hexane to afford the title compound (378 mg) as yellow needles. δH (CDCl3 ; 80 mHz) 1.5-2.1 (8H, br m, (CH2)4), 3.87 (3H, s, OMe), 4.84 (1H, br m, OCHCH2), 6.91 (1H, d, J 9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArH meta to OMe), 7.54 (1H, d, J 7.5 Hz, ArH meta to NO2), 7.80 (1H, ca. dt, J ca 7.5, 1.5 Hz, ArH para to NO2), 8.09 (1H, ca. dt, J ca.8, 1.5 Hz, ArH para to aryl), 8.33 (1H, ca. t, J ca 2 Hz, ArH ortho to NO2 and aryl); m/z 313 (M+, 7%), 246 (17), 245 (M+ -cyclopentyl, 100), 230 (41), 202 (8), and 139 (9).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:26])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:24][C:22]([F:23])([F:25])[O:21][C:17]1[CH:16]=[C:15]([NH:14][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:26])[CH:20]=[CH:19][CH:18]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.52 g, 22.6 mmol) in CH2Cl2 (50 mL) was added TFA (8.65 mL, 113 mmol) and solution was stirred at RT for 12 h. The crude reaction mixture was concentrated under vacuum, Et2O was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC/MS): 275.2 [M+H]+, 273.3 [M−H]−; tR (HPLC conditions a) 2.47 min.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:10]O>[B-](F)(F)(F)F.[Ag+]>[CH3:10][O:7][C:6](=[O:8])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:9]
Reactant: CO
Reactant: CC(=O)NC(C)C(=O)O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COC(=O)C(C)NC(C)=O
Reaction time: 0.33 h

Procedure:
In a glove box, ((tert-Bu)2P(CH2)2P(Me)(tert-Bu))2Rh2Cl2 (4.1 mg, 0.005 mmol) was dissolved in 2 mL MeOH, followed by addition of AgBF4 (1.9 mg, 0.10 mmol, 2 equiv.). The solution turned from pale yellow to yellow with gray precipitates. After being stirred for 20 minutes the solution was filtered into a high-pressure tube containing a stir bar and one of the enamides (1 mmol, 100 equiv.). Another 3 to 5 mL MeOH was added and the solution generally turned lighter upon the addition of the enamide substrate. The vessel was then put under H2 of 30 to 40 Psig and stirred at room temperature. After the reaction was finished, the vessel was then take out of the glove box, and an aliquot of the reaction solution was taken from the vessel and analyzed directly or after work up to determine enantiomeric excess of the reaction product. Reaction of enamide (a) to form 2-acetylamino-propionic acid and reaction of enamide (b) to form 2-acetylamino-propionic acid methyl ester, yielded greater than 99% enantiomeric excess in both instances. Reaction of enamide (c) to form 2-acetylamino-3-phenyl-propionic acid and reaction of enamide (d) to form 2-acetylamino-3-phenyl-propionic acid methyl ester, yielded greater than 98% and 95% enantiomeric excess, respectively.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8](OC)=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[C:4]([CH2:2][C:1]#[N:3])(=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: N#CCC(=O)c1ccccc1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of acetonitrile (76 g) in DMSO (100 mL) was added methyl p-anisate (100 g) and the mixture was stirred with heating at 60° C. for one hour. The reaction mixture was allowed to cool, and cold water (500 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give benzoylacetonitrile (60 g) as colorless crystals. A solution of 2-chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and benzoylacetonitrile (1.8 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.63 g) as colorless crystals.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(c1csc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 71 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-phenylthiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (74.9 mg, 0.126 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 40.4 mg (71%) of the desired product as a white solid. LC-MS: RT=4.45 min, [M+H]+=381.0.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:24][C:25](O)=[O:26])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2].[C:28](N1C=CN=C1)([N:30]1C=CN=[CH:31]1)=O.CNC>O1CCCC1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:24][C:25]([N:30]([CH3:31])[CH3:28])=[O:26])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCn1c2ccc(F)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: CNC
Solvent: C1CCOC1
Product: CCn1c2ccc(F)cc2c2c(CC(=O)N(C)C)nn(-c3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
A suspension of 1 g (2.73 mmol) of 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 0.7 g (4.3 mmol) of 1,1′-carbonylbis-1H-imidazole in 200 ml of tetrahydrofuran is stirred for 3 h at 50° C. The reaction mixture is cooled to 25° C., an excess of liquefied dimethylamine is added and the reaction mixture is stirred for 12 h at room temperature. It is concentrated under reduced pressure, 100 ml of dichloromethane and 100 ml of water are added and the organic phase is separated, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The resulting oil crystallizes from ether. After filtering and recrystallizing from ethyl acetate, 0.75 g (1.9 mmol) of white crystals is isolated.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:9])(=O)[CH3:7].[CH3:10][CH:11]([CH2:14]CC#N)[C:12]#[N:13].C([O-])([O-])=[O:19].[Na+].[Na+]>O>[CH3:10][CH:11]1[CH2:14][CH2:7][C:6](=[O:9])[NH:13][C:12]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)O
Reactant: CC(C#N)CCC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1CCC(=O)NC1=O
Temperature: 130 °C
Yield: 67 %

Procedure:
A solution of H2SO4 (80 ml), acetic acid (500 ml) and 2-methylpentanedinitrile (128.0 g, 1184 mmol) was stirred at room temperature. An aqueous solution of acetic acid (100 ml in 32 ml water) was then added dropwise. Upon completion of the addition, the reaction was heated to 130° C. for 1 hour. The reaction was then allowed to cool to room temperature and filtered to remove solids, which were washed with acetic acid (100 ml). The filtrate was then concentrated until a residue resulted. This residue was poured into water (0.75 l), and adjusted to pH 5 with Na2CO3. The resulting solid was collected by filtration and washed with cold water to give the title compound (101 g, 67%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@H:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].[Li+].[CH3:30][CH:31]([N-]C(C)C)[CH3:32].ICC=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[CH:11]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:13][C@@H:14]([CH2:32][CH:31]=[CH2:30])[C:15]1=[O:16])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Agent: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (200 mg, 0.5 mmol, 1.0 equiv) in THF (2.0 mL) was added LDA (2.0 M in THF, 0.3 mL, 0.6 mmol, 1.2 equiv) at −78° C. and the resulting solution was stirred at −78° C. for 10 minutes. To the solution was then added 3-iodo-propene (250 mg, 1.5 mmol, 3.0 equiv) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched by addition of water. The mixture was extracted with EtOAc. The organic layer was washed with sat. NaHCO3 aq. solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, Heptane/DCM (contained 3% EtOAc) to give 60 mg of less polar diastereomer and 100 mg of more polar diastereomer. MS: 442 [M+H+].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([F:18])[F:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:12]([O:14][C:15](=[O:20])[C:16]([F:18])([F:17])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:13]
Reactant: Ic1ccc2ncccc2c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
To a suspension of 6-iodo-quinoline (1.0 g, 4 mmol) and Cu(0) (559 mg, 8.8 mmol) in dry DMSO was added bromodifluoro-acetic acid ethyl ester (893 mg, 4.4 mmol). The reaction mixture was stirred under N2 at 55° C. for 15 h. The mixture was poured in a solution of K2CO3 and extracted with EtOAc. The organic layer was collected and dried over MgSO4. The crude was purified by silica gel column to give the title compound as a red oil (310 mg, 30%). 1H-NMR (400 MHz, CDCl3) δ ppm 1.33 (t, 3H), 4.334 (q, 2H), 7.52 (m, 1H), 7.93 (m, 1H), 8.15 (s, 1H), 8.20-8.23 (m, 2H), 9.03 (s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19]C)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:2][NH2:3])=[O:19])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN

Procedure:
0.4 g of hydrazine hydrate is added to a solution of 1.3 g of methyl 3-(tert-butoxycarbonylamino)thiophene-2-carboxylate in 10 ml of ethanol and the mixture is heated to reflux for 5 hours. After the volatile fractions had been removed under reduced pressure at 40° C., the remaining oil was purified by column chromatography (silica gel, eluent: methylene chloride:methanol=95:5).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-:7][Cr](Cl)(=O)=O.[CH3:12][C:13]1([CH3:35])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)(O)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][CH2:14]1>C(Cl)Cl>[CH3:12][C:13]1([CH3:35])[CH2:14][C:15](=[O:7])[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:17]1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC1(C)CC=C(c2ccccc2)C1(O)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)CC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Yield: 16.8 %

Procedure:
To a suspension of PCC (4 g) and 10 g of 4 Å molecular seives in 100 mL of CH2Cl2 was added a solution of the product of Step 5 (1.2 g) in 10 mL CH2Cl2. The reaction mixture was stirred for 12 hand then diluted with 200 mL of 1:1 hexanes/EtOAc, and filtered through a pad of silica gel. The filtrate was concentrated and the residue was purified by chromatography eluting with 3:2 hexanes/EtOAc to give 200 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[CH3:11]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: CI
Reactant: Cc1cc(O)nc(C)c1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(Br)c(C)n1

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol (7 g), methyl iodide (21.6 mL) and silver carbonate (19.1 g) was stirred in a chloroform solvent (140 mL) at room temperature for 36 hours. The reaction mixture was subjected to silica gel pad and eluted with a mixed solvent of (ethyl acetate:n-heptane=2:8). The resulting solution was concentrated under reduced pressure to give the title compound (6.98 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[C:5]2[N:14]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][C:4]=2[CH:3]=1.[CH3:37][N:38](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH3:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:14]2[C:5]3[C:6]([C:8]4[CH:13]=[N:12][CH:11]=[CH:10][N:9]=4)=[N:7][C:2]([C:37]#[N:38])=[CH:3][C:4]=3[N:16]=[C:15]2[N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32]1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cnccn4)c32)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cnccn4)c32)CC1
Temperature: 140 °C

Procedure:
To a sealable tube were added 6-chloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine (250 mg, 0.497 mmol) and Zn(CN)2 (46 mg, 0.397 mmol). DMF (4 mL) was added, and the mixture was purged with nitrogen for 5 minutes. Pd(dppf)Cl2 dichloromethane complex (20.2 mg, 0.024 mmol) was added, and the mixture was degassed with nitrogen again for 5 minutes. The tube was sealed and heated to 140° C. for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column using 30-45% ethyl acetate/petroleum ether as eluent to afford 3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calc'd. for C29H31N7O [M+H]+ 494. found 494.