Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27].[CH:42]([CH:44]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:41][C:39]1[CH:38]=[C:4]([CH:3]=[C:2]([F:1])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:42][CH:44]2[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:45]2)=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: Nc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-amino-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide (240 mg, 0.42 mmol) in dichloromethane (20 mL) were added tert-butyl 3-formylazetidine-1-carboxylate (116 mg, 0.63 mmol), trifluoroacetic acid (0.32 mL) and tetramethylammonium triacetoxyborohydride (165 mg g, 0.63 mmol). The mixture was stirred at room temperature overnight, then diluted with dichloromethane, washed with NaHCO3 sat.sol. and brine, dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: C(O[K])(C)(C)C.[N:7]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:11]=[CH:10][N:9]=[CH:8]1.N1C=CNC1=S.F[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.[Na]>CS(C)=O.O>[N:7]1([N:12]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: FC(F)(F)c1ccc(Nn2ccnc2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)O[K]
Agent: S=c1[nH]cc[nH]1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N(c2ccc(C(F)(F)F)cc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a cold solution (10-15° C.) of tBuOK (1.06 g, 0.00895 mol) in DMSO (18 ml) was added portionwise N-(1H-imidazol-1-yl)-4-trifluoromethylaniline (1.85 g, 0.00814 mol) (prepared by desulfurization from the corresponding 2,3-dihydro-1H-imidazol-2-thione, J. G. Schantl, Heterocycles, 37(3), 1873, 1994). The reaction mixture was stirred at room temperature for 1 h, then 4-fluorobenzonitrile (0.936 g, 0.00773 mol) in DMSO (18 ml) was added, the reaction mixture was stirred for 2 h and pourred into water and concentrated sodium hydroxyde solution. The precipitate was collected and dried under vacuum. Flash chromatography on silica gel (toluene/dioxane: 7/3) and crystallization from diisopropyl ether yielded a solid (1.6 g, 60%), mp 104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])(=[O:19])=[O:18]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of o-anisidine with 2-methyl-benzenesulfonyl chloride
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][Br:18])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 54 g of 2-phenyl-6-methyl-quinoline, 68 g of N-bromosuccinimide and 1.5 g of dibenzoyl peroxide in 700 ml of carbon tetrachloride is kept for 18 hours under reflux. Thereafter the reaction mixture is cooled to room temperature and the precipitate is filtered off. The filter residue is rinsed with carbon tetrachloride. The filtrate is evaporated and the residue is dissolved in ethyl acetate. This solution is washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. The residue is taken up in 1.8 litres of ether and the insoluble constituents are filtered off. Concentration of the solution yields 2-phenyl-6-bromomethyl-quinoline of melting point 126°-127°C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N+:22]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][OH:25])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: OCCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(N3CCN(CCO)CC3)n1-2

Procedure:
In the manner given in Example 1, 1-bromo-8-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-nitro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=3)=[CH:20][N:19]=[C:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[OH-:36].[K+].[C:38](#[N:40])[CH3:39]>O>[NH2:8][C:3]1[S:4][CH:39]=[C:38]([C:9](=[O:10])[C:2]([NH:1][C@@H:2]2[C:9](=[O:10])[N:8]3[C@@H:3]2[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]2[C:21]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=4)=[CH:20][N:19]=[C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:17]=2)=[C:7]3[C:11]([OH:13])=[O:12])=[O:36])[N:40]=1
Reactant: [OH-]
Reactant: CC#N
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(-c4ccccc4)ncc3-c3ccc(O)c(O)c3)CS[C@H]12
Agent: [K+]
Solvent: O
Product: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1

Procedure:
(6R,7R)-7-Amino-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.02 g) (2 mmol) are suspended in 25 ml of water and 25 ml of acetonitrile. While stirring there are added dropwise thereto at 0° C. 27 ml of 0.1N aqueous potassium hydroxide and the solution is treated portionwise with 1.0 g (3 mmol) of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl) ester. The mixture is stirred at 0° C. for 1 hour and at 15°-20° C. for 2 hours. The suspension is now filtered and filter material is washed with water. The mother liquor and wash solution are combined, washed with ethyl acetate and finally acidified (pH~4) with dilute, aqueous hydrochloric acid. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. After drying in a high vacuum at room temperature there is obtained 0.5 g of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxy-phenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][C:13]([CH3:15])=O.N1CCCC1.Cl>C1(C)C=CC=CC=1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:13]([CH3:15])([CH3:12])[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)=O
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone 10.0 g (46.5 milli mole), acetone (17 ml) and pyrrolidine (3.9 ml) in toluene (100 ml) was refluxed for 4 hours. To the mixture was added acetone (17 ml), and the mixture was refluxed for 15 hours. To the mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brined, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:7) to give yellow oil of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-1-benzopyran-4-one (7.57 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20]>C(O)CCCCCCCCC.C[O-].[Ti+4].C[O-].C[O-].C[O-]>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:9][CH2:10][CH2:11][CH3:12])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Agent: [Ti+4]
Agent: C[O-]
Solvent: CCCCCCCCCCO
Product: CCCCCCCCCCOC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Yield: 173.4 %

Procedure:
Methyl 4-amino-3-chloro-5-fluoro-6-(4-chlorophenyl)pyridine-2-carboxylate (0.545 g, 1.73 mmol) was suspended in decanol (20 mL) and titanium methoxide (0.029 g, 1.73 mmol) was added and the mixture heated under reflux for five hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic phase was dried (MgSO4) and concentrated to give decyl 4-amino-3-chloro-5-fluoro-6-(4-chlorophenyl)pyridine-2-carboxylate (0.67 g, 1.5 mmol), mp 62-63° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCCCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
6.3 G. of 4-chloro-5-cyano-2-(4-n-heptyloxyphenyl)-pyrimidine are reacted in 275 ml. of 50% dioxane with 23.9 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-heptyloxyphenyl)-pyrimidine as colorless crystals having a melting point of 102.4° C. (smectic); nematic at 126.9° C; clearing point at 129.5° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N#N>ClCCl>[CH2:17]([O:24][N:25]=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCCC=O
Reactant: NOCc1ccccc1
Agent: N#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCC=NOCc1ccccc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Octanal (385 mg, 469 μL, 3.0 mmol) was weighed into a 10 mL round bottom flask previously flushed with N2 and containing a stifling bar. To the flask was anhydrous Na2SO4 (4.26 g, 30 mmol), 6 mL of dry dichloromethane and finally, O-benzylhydroxylamine (369 mg, 349 μL, 3 mmol) over 2 min while maintaining positive N2 pressure. The reaction mixture was stirred overnight. The salt was filtered off and rinsed with dichloromethane. The combined filtrates and rinsings were concentrated. The crude material was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (95:5) to give 328 mg (47%) of a clear oil: Rf=0.45 and 0.51 (two isomers) (hexanes/ethyl acetate, 95:5, v/v); 1H NMR (CDCl3) δ 7.43 (t, 3J=6.3 Hz, 0.5H), 7.36-7.25 (m, 5H), 6.66 (t, 3J=5.5 Hz, 0.5H), 5.08 (s, 1H), 5.03 (s, 1H), 2.37-2.32 (m, 1H), 2.18-2.14 (m, 1H), 1.49-1.41 (m, 2H), 1.33-1.18 (m, 8H), and 0.86 (t, 3J=7 Hz, 3H). Exact mass (FAB+) calculated for C15H24NO [M+H] 234.1852. Found 234.1856.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:5]=1[C:6]([C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[O:7].C(O)(=O)C.O>O1CCCC1>[F:3][C:4]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:5]=1[CH:6]([C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[OH:7]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
Sodium borohydride (1.49 g) was added portionwise to a stirred mixture of 2'-(2,4-difluorobenzoyl)-4'-nitromethanesulfonanilide (5.6 g) in tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 4 hours, treated with acetic acid (5 ml) and water (20 ml), had concentrated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried and evaporated to give a powder of 2'-(2,4-difluoro-α-hydroxybenzyl)-4'-nitromethanesulfonanilide (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1Br)[CH3:5].[CH3:27][N:28](C)C=O>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:27]#[N:28])[CH3:5]
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 5 h

Procedure:
A 10 g of methyl-α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy)phenoxy]propionate produced in Example 1 was dissolved in 15 ml of dimethyl formamide, and 2.4 g of cuprous cyanide was added to the solution and the reaction was conducted under reflux condition with stirring the mixture for 5 hours.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=2)=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=1[Cl:8].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1.CCOC(C)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:1][C:2]3[C:3]([N:19]=2)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=3[Cl:8])[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)cc(Cl)c3[nH]2)on1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (36.2 mg, 0.0825 mmol, prepared as described in STEP B above) in 1,4-dioxane (10 mL) was treated with (+)-10-camphorsulfonic acid (38.3 mg, 0.165 mmol), and the mixture was heated to 100° C. for 5 h. The cooled mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified on an 8-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-7-chloro-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.8 Hz, 1H), 7.58-7.64 (m, 1H), 7.50-7.58 (m, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 1.88 (br. s., 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C20H16N4OClF3: 421.1 (M+H); Measured: 421.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:19][CH:18]=1)#[N:27]
Reactant: N#Cc1ccccc1-c1ccc(N)cc1
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(Nc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
1.4 g (7.7 mmol) of the chloride from Example 1, Step B and 1.5 g (7.7 mmol) 4-Amino-2'-cyanobiphenyl were heated in 30 ml dry ethanol for 5 h. After removal of the solvent in vacuo the nitrile was obtained in colorless crystals from ethanol, m.p. 247°-248° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with (bromomethyl)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 26% yield: mp 162-164° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 10H), 6.01 (br s, 1H), 4.57 (d, J=5.3 Hz, 2H), 4.32-4.18 (m, 1H), 4.02-3.88 (m, 1H), 3.47-3.38 (m, 1H), 2.87-2.69 (m, 2H), 2.64 (s, 3H), 2.07-1.45 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.2, 162.7, 157.0, 152.2, 138.9, 137.9, 129.2, 128.8, 128.6, 127.9, 127.7, 126.5, 119.4, 48.1, 44.1, 44.0, 37.6, 24.8, 21.2, 17.4; MS (ES+) m/z 420.5 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].O1CCC[CH2:19]1.[Li+].CCC[CH2-].IC>CCCCCC.O>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[CH3:19])=[O:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a chilled (28° C.) solution of 4.91 g of 2,2-dimethyl-N-(4-trifluoromethylphenyl)propanamide and 80 ml tetrahydrofuran, was added over two mins, 18.5 ml of a 2.5M solution of N-butyllithium in hexane, with stirring. The reaction mixture was stirred for two hours at 0° C. and added, dropwise over eight minutes, to a solution of 3.19 g of iodomethane and 7 ml of hexane, keeping the temperature between -2° C.+1° C. The solution was stirred for 45 mins (internal temperature reached 18° C.). Water (20 ml) was added and the mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated by preparative HPLC (Waters Associates Prep LC/System 500, silica gel, sample applied in and eluted with methylenechloride, 200 ml/min flow rate). The appropriate fractions were combined, concentrated, and the residue was recrystallized from toluene to give 2.23 g of product, mp 111°-114° C.
Reaction SMILES: [CH2:1]([P:17]([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:20]O>O>[CH2:1]([P:17](=[O:20])([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OO
Reactant: CCCCCCCCCCCCCCCCP(O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCP(=O)(O)O
Reaction time: 6 h
Yield: 97 %

Procedure:
29.0 g (0.1 mol) of hexadecylphosphonous acid (produced as in example 7) are suspended in 150 ml of water and at about 30° C. 30% strength hydrogen peroxide solution is passed through the suspension at a flow rate of 1 mol equivalent per hour. After the reaction has ended after 6 hours, the reaction solution is filtered and the residue is dried under reduced pressure to obtain 29.7 g (97% of theory) of hexadecylphosphonic acid as a colorless solid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([CH2:12][NH2:13])[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22](Cl)=[O:23])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:20]([O:21][C:22](=[O:23])[NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: NCC1CCc2ccccc2CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCc2ccccc2CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (100 mg, 0.472 mmol) in tetrahydrofuran (5 ml) was added benzyl chloridocarbonate (0.074 ml, 0.520 mmol) and diisopropylethylamine (0.181 ml, 1.039 mmol). The mixture was stirred overnight at 25° C., and then concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% EtOAc in hexanes over 10 column volumes to provide the title compound (133 mg, 0.430 mmol, 91% yield). Mass spectrum (ESI) 310.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(OO)(=[O:11])C.Cl>CC(O)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: Cc1ccnc(Cl)c1
Reactant: CC(=O)OO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(Cl)c1
Temperature: 70 °C
Yield: 101.6 %

Procedure:
A mixture of 2-chloro-4-methylpyridine (10.0 g, 78.3 mmole) and 34% peracetic acid (76.05 g, 91.0 mmole) in glacial AcOH (10 mL) was heated at 70° C. for 3 hr. The reaction mixture was cooled, conc. HCl (35 mL) was added, and the mixture was concentrated on the rotavap. Recrystallization from n-butanol followed by trituration with ether gave the title compound (7.16 g, 51%) as a white solid: MS (ES) m/e 143.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH:6]=1.[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:15]([O:18][CH2:19][CH2:20][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:5]2[CH:6]=[C:2]([Br:1])[CH:3]=[N:4]2)[CH:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCBr
Reactant: Oc1cccc(Cn2cc(Br)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(Cn2cc(Br)cn2)c1
Temperature: 200 °C
Yield: 33.6 %

Procedure:
A mixture of 3-((4-bromo-1H-pyrazol-1-yl)methyl)phenol (0.6 g, 2.37 mmol), 2-bromoethyl acetate (0.792 g, 4.74 mmol) and potassium carbonate (0.655 g, 4.74 mmol) in DMF (5 mL) was heated at 200° C. in a microwave reactor for 1 h. After this time, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.27 g, 34% yield) as a colorless oil. LCMS, [M+H]+=339.0. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.34 (s, 1H), 7.24 (dd, J=8.3, 7.6 Hz, 2H), 6.83 (dd, J=8.3, 2.4 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.20 (s, 2H), 4.41-4.32 (m, 2H), 4.14-4.08 (m, 2H), 2.06 (s, 3H).