Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:38]=[CH:37][C:21]([C:22]([CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])=[O:23])=[CH:20][CH:19]=1)[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].FC(F)(F)C(O)=O.[OH-].[K+]>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23])=[CH:37][CH:38]=1)[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: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CC(=O)OCC)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of t-butyl ethyl p-(hexadecylamino)benzoylmalonate in 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is washed with water and dried. Recrystallization from chloroform gives the desired product.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>O>[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=[S:10])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=S)cc1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-disulfide) (640 mg, 1.58 mmol) was added to a solution of N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}methanesulfonamide (4) (1008 mg, 2.63 mmol) in abs. toluene (30 mL). The reaction mixture was heated to the boil over a period of 5 h. The reaction mixture was then stirred overnight. Water (40 mL) was added and the mixture was extracted with chloroform (3×30 mL). The combined organic phases were washed with H2O (2×20 mL), dried over Na2SO4, and the solvent was removed in vacuo. Following purification of the residue by means of column chromatography (SiO2 (150 g); 1000 mL cyclohexane/EtOAc 4:1), the desired product N-{4-[3-(4-tert-butylbenzyl)-2-thioxoimidazolidinylmethyl]phenyl}methanesulfonamide (1) (545 mg, 52% of theory) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]2[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]2[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#CC2CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C#CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of methyl 2-chloro-4-(2-cyclopropylethynyl)benzoate (310 mg, 0.0013 mol), 2N aq. NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) was stirred at rt for 5 h. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HCl to pH 2-3, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the product (270 mg, 93%) as a yellow solid. LC-MS: 3.18 min, 218.9 & 220.9 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[C@H:29]([CH2:30][CH:31]=[CH2:32])[CH2:28][CH2:27][C:26](=[O:33])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](O)[CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CCCCC.CCOCC.C1C=CC=CC=1>[CH2:35]1[O:36][C:26]2([CH2:27][CH2:28][C@@H:29]([CH2:30][CH:31]=[CH2:32])[C@H:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:33][CH2:34]1
Reactant: OCCO
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: O
Product: C=CC[C@@H]1CCC2(C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1)OCCO2

Procedure:
A mixture of 17.0 g. (38.1 mmoles) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanone, 47.2 g. (0.762 mole) ethylene glycol and 250 mg. of p-toluenesulfonic acid monohydrate in 200 ml. of benzene was heated at reflux for 3 hours with a Dean-Stark trap. The reaction was cooled and added to 200 ml. 1N sodium hydroxide, 100 ml. ether and 100 ml. pentane. The organic extract was washed twice with 200 ml. portions of water, twice with 200 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) giving a quantitative yield of the title compound.
Reaction SMILES: NC1N=N[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:6](N)[N:7]=1.ClC1C(Cl)=CC=CC=1C(Cl)=[O:21]>C(#N)C>[Cl:15][C:11]1[C:10]([Cl:16])=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:5]([C:6]#[N:7])=[O:21]
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: CC#N
Product: N#CC(=O)c1cccc(Cl)c1Cl

Procedure:
There is disclosed an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which process comprises the step of reacting 2,3-dichlorobenzoylchloride with cuprous cyanide in presence of acetonitrile and a cosolvent to produce dichlorobenzoyl cyanide, said dichlorobenzoyl cyanide is reacted with aminoguanidine bicarbonate to produce an intermediate product, which is cyclized in presence of aqueous potassium hydroxide to produce 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5]([C:13](=[O:15])[CH3:14])[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.C([OH:18])C>N1C=CC=CC=1>[CH2:9]1[C:10]2[C:6](=[C:5]([C:13](=[O+:15][O-:18])[CH3:14])[C:4]3[CH2:3][CH2:2][CH2:1][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCO
Reactant: CC(=O)c1c2c(cc3c1CCC3)CCC2
Solvent: c1ccncc1
Product: CC(=[O+][O-])c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-ethanone (33 grams), ethanol (250 mL) hydroxylamine hydrochloride (58.5 grams) and pyridine (80 mL) was heated to reflux for a period of 12 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was then treated with 500 mL of water and extracted with chloroform-methanol. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 32 grams of the title compound as a mixture of E and Z isomers, 178.6-182.3° C.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[OH:16].Cl.[CH3:32]O>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[O:16][CH3:32]
Reactant: N=C(N)NCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Reactant: CO
Agent: Cl
Product: COC(NC(=O)C=CCCCCNC(=N)N)C(=O)NCCCCNCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 50.3 mg (0.10 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2-(7-guanidino-2-heptenamido)-2-hydroxyethanamide trihydrochloride in 1 ml of anhydrous methanol was added 0.1 ml of 2N hydrogen chloride-methanol. The mixture was stirred overnight at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was purified in a manner similar to that in Example 7 using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 37.2 mg (72.4% yield) of N-[4-(3-aminopropyl)aminobutyl]-2-(7-guanidino-2-heptenamido)-2-methoxyethanamide trihydrochloride.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:20]([CH:28]=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:32][CH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1>>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:20]([CH2:28][N:40]3[CH2:41][CH2:42][C:37]4([O:36][CH2:35][CH2:34][CH:33]4[OH:32])[CH2:38][CH2:39]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:30])([F:31])[F:1])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1CCOC12CCNCC2
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)OCCC3O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This product was prepared according to the procedure described in Example 2 using (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (WO 0056727) and 4-hydroxy-1-oxa-8-azaspiro[4.5]decane (Description 20).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[C:18]([NH:27][CH2:28][C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][CH:22]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5]1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:23]([C:20]1[N:19]=[C:18]([NH:27][CH2:28][C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[C:17]([C:15]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C@H:8]2[CH2:9][C@@H:4]([C:2]#[N:1])[CH2:5][N:6]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7]2)=[O:16])=[CH:22][N:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 88.6 %

Procedure:
tert-Butyl (3R*,5S*)-3-(aminocarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1-carboxylate (469 mg) was dissolved in pyridine (5 ml), trifluoroacetic anhydride (0.25 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 11 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The solution was washed successively with 1 M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object compound (402 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:14][CH2:12][CH3:13])=[S:10])[CH:7]=1
Reactant: CCN
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: CCNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (18.3 g; 0.1 mol) was added dropwise to aqueous ethylamine (200 mL of 70% solution). The mixture was stirred for 18 hour at ambient temperature. Excess ethylamine was removed under a stream of nitrogen. The residue was diluted with water. The solids were collected by filtration, washed with water and dried to give N-(5-chloro-2-methylphenyl)-N ′-ethylthiourea (18.9 g). A sample crystallized from ethyl acetate afforded a solid, m.p. 120–122° C. Mass spectrum;; FAB (M+H)+ m/z 228. 1H-NMR (DMSO-d6; 300 MHz): δ 9.01 (br s, 1H), 7.67 (br s, 1H), 7.35 (br s, 1H), 7.25–7.16 (m, 2H), 3.44 (m, 2H), 2.13 (s, 3H), and 1.08 ppm (t, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[C:15]1([CH3:25])[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(=O)C(C)C.C(Cl)Cl>[CH:16](=[N:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14])[CH:15]([CH3:25])[CH3:20]
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(C)c1nnc(SC)n(N=CC(C)C)c1=O

Procedure:
42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one were dissolved in 60 ml of isobutyraldehyde. 0.2 g of p-toluenesulfonic acid was added, the mixture was stirred until the slightly exothermic reaction had subsided and was diluted with 200 ml of methylene chloride, and the whole was stirred with 100 ml of water, containing 0.5 g of sodium carbonate. The organic phase was separated off, washed with water and concentrated on a rotary evaporator. The residue which remained consisted of 52.0 g (97.5%) of 4-isobutylideneamino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one, melting point 16° C (from pentane); nD 20 1.5493.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:3]1[C:4](=[O:17])[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:8][C:6]=2[N:7]=[C:2]1[CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1sc2nc(C)[nH]c(=O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc2nc(C)n(Cc3ccccc3)c(=O)c2c1C
Yield: 45 %

Procedure:
A mixture of 252 mg of ethyl 2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 138 mg of potassium carbonate, 15 mL of acetonitrile and 1 mL of benzyl chloride was heated under reflux overnight. After condensing the reaction mixture under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=100:1) to provide 153 mg (45%) of the title compound.
Reaction SMILES: [C:1](=[S:7])([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:8]([CH:10](Cl)[C:11](OCC)=O)=[O:9].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:9][CH2:8][C:10]1[S:7][C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])=[N:6][CH:11]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CC(C)CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ncc(CO)s1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Isovalerothioamide (6.0 g, 51 mmol) and ethyl formylchloroacetate (Heterocycles 32 (4), 693-701, (1991), 5.0 g, 33 mmol) are dissolved in dry DMF (20 mL), and heated to 95 degrees C. for 4 hours. The reaction is subsequently cooled to 0 degrees C., and cold water (50 mL) is added. The mixture is basified to pH=8 with solid sodium bicarbonate, then extracted with ether (3×35 mL). The combined organic extracts are washed with water, then saline and dried over magnesium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (ethyl acetate/hexanes 4-10% elution) to give the desired product. NMR (CDCl3, 300 MHz) δ 8.27, 4.45-4.30, 3.70-3.50, 3.00-2.80, 2.30-2.10, 1.40-1.20, and 1.10-0.90.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)=[N:4][C:3]=1[C:20]#[N:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)=[N:4][C:3]([C:20]#[N:21])=[C:2]2[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(Cl)c2c1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(-c3cccnc3)c2c1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
4-chloro-6-methoxy-1-(4-methyl-1H-imidazol-1-yl)isoquinoline-3-carbonitrile (0.055 g, 0.184 mmol), 3-pyridylboronic acid (0.034 g, 0.276 mmol), Pd2(dba)3 (0.017 g, 0.018 mmol), tricyclohexylphosphene (0.015 g, 0.055 mmol) and K3PO4 (0.117 g, 0.552 mmol) were taken in 7 mL dry dioxane and heated at 100° C. under argon atmosphere for 22 h. The reaction mixture was filtered through celite and concentrated. To the resulting residue all of the above reagents and 6 mL dioxane were added and then the mixture was heated at 100° C. for 22 h. The reaction was cooled to rt, filtered through celite (washing with CH2Cl2) and the filtrate was concentrated, then purified by flash chromatography: 3% to 6% MeOH—NH4OH (90:10, v/v) in EtOAc. Irnpure fractions from the flash chromatography were combined and purified by reverse phase HPLC to give a white solid (0.025 g, 40%).
Reaction SMILES: [F:1][C:2]1[C:38]([CH3:39])=[CH:37][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[C:8]([N:10]2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[CH:4][C:3]=1[CH3:40].[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[F:1][C:2]1[C:38]([CH3:39])=[CH:37][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[C:8]([NH:10][OH:48])=[O:9])=[CH:4][C:3]=1[CH3:40]
Reactant: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of (R)-3-((S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one (0.040 g, 0.0728 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), KCN (0.001 g, 0.015 mmol) was added. After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The filtrate was purified by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 23% yield). LC-MS: tR=9.6 min, m/z 406 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.28-1.51 (m, 4H), 1.52-1.70 (m, 2H), 2.18 (s, 6H), 2.25 (s, 3H), 2.26-2.33 (m, 1H), 2.52-2.63 (m, 1H), 2.68-2.79 (m, 1H), 3.44 (t, J=6.30 Hz, 2H), 4.40 (s, 2H), 6.81 (d, J=7.03 Hz, 2H), 6.97 (t, J=9.08 Hz, 1H), 7.09-7.15 (m, 1H), 7.18 (d, J=7.32 Hz, 1H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[C:12](Br)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)=[O:2]
Reactant: O=CNCCc1ccccc1
Reactant: CC(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CCNC=O)cc1

Procedure:
This was prepared in an identical manner to the compound described in Description 10 using N-formyl-2-phenylethanamine (95 g), acetylbromide (128 ml), aluminium chloride (288 g) in 1,2-dichloroethane (900 ml). 25 g of the crude produce was chromatographed on Kieselgel 60 (1 Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18 g). τ(CDCl3) 7.42 (3H, s), 7.1 (2H, t, J=7 Hz), 6.5 (2H, m), 3.45 (1H, broad), 2.7 (2H, d, J=8 Hz) 2.1 (2H, d, J=8 Hz), 1.9 (1H, s).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[C@H:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[CH2:7]1.C(N(CC)CC)C.[CH3:44][S:45]([Cl:48])(=[O:47])=[O:46]>ClCCl>[ClH:48].[F:22][C:19]([F:21])([F:20])[C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([C:23]([F:24])([F:26])[F:25])[CH:16]=1)[C:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][NH:3][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:7][C@H:8]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C[C@@H]2CN(CCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCNS(C)(=O)=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-piperazine dihydrochloride (110 mg), triethylamine (0.2 ml) in dichloromethane (10 ml) was added methanesulfonyl chloride (0.1 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with aqueous saturated sodium bicarbonate solution and brine, and dried. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (40:1) and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(mesylamino)ethyl]piperazine hydrochloride (50 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: COc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Furaldehyde (5 mmol, 437 μL) and (4-methoxyphenyl)methanamine in MeOH (20 mL) was stirred at ambient temperature overnight then sodium borohydride (300 mg, 7.89 mmol) was slowly added. The resulting mixture was stirred at room temperature for 15 minutes and quenched with NaOH (1 N, aq). Methanol was removed in vacuo and the resulting slurry was redissolved in ethyl acetate then, washed with water, brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (Ethyl acetate:Hexanes 7:3) gave 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine as an oil. MS (M+H, 218.10); 1H NMR (400 MHz, CDCl3): δ, ppm: 3.64 (s, 2H), 3.74 (s, 2H), 3.80 (s, 3H), 6.39 (m, 1H), 6.86 (m, 1H), 6.88 (m, 1H), 7.23 (m, 1H), 7.25 (m, 1H), 7.35 (m, 1), 7.38 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>>[CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: Cc1ncc([N+](=O)[O-])[nH]1

Procedure:
A method for the safe nitration of 2-methylimidazole with high output comprising nitrating the 2-methylimidazole with nitric acid and sulfuric acid as nitrating agents to produce 2-methyl-5-nitroimidazole, and controlling the reaction by adding as an inhibitor the reaction product itself or an excess of the concentrated nitric acid. The reaction can be carried out in stages with a reduced temperature in the first stage and an increased temperature in a subsequent stage.