Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:14]N(C=O)C>>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:14])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Sodium hydride 4.59 g (7.64 g as 60% mineral oil dispersion) was suspended in DMF (64 ml) under a nitrogen atmosphere. To this was added 4-fluoro-2-nitrophenol in 64 ml DMF over 30 minutes at room temperature. Stirring continued for 15 minutes. Methyl iode was then added over 15 minutes. The mixture was further stirred for 3 hours. The precipitates which formed were filtered off and the filtrate was evaporated to dryness. The residue was dissolved in benzene and the filtrate washed with water, aqueous sodium hydroxide and with brine. This solution was dried over sodium sulfate and evaporated to give 21.1 g of the title compound: m.p. 60° C.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:12][CH:11]=1>C1COCC1>[N:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:12][CH:11]=1)=[C:2]=[O:3]
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C=Nc1ccc(N2CCCCC2=O)cc1

Procedure:
1.2 0.032 ml of trichloromethyl chloroformate is added under a nitrogen atmosphere to a solution of 50 mg of 1-(4-aminophenyl)piperidin-2-one (prepared from 1-(4-nitrophenyl)piperidin-2-one by hydrogenation using Raney nickel as catalyst) in 5 ml of THF, and the mixture is subsequently refluxed for 1.5 hours, giving 1-(4-isocyanatophenyl)piperidin-2-one (“AB”).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[S:5][CH2:4]1.[Br:15]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:15][CH2:2][CH:3]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[S:5][CH2:4]1
Reactant: COc1ccc2c(c1)CC(CO)CS2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COc1ccc2c(c1)CC(CBr)CS2

Procedure:
The alcohol (3.43 g, 16.31 mmol) is dissolved in 150 ml of acetonitrile and treated with dibromotriphenylphosphorane (6.88 g, 16.31 mmol). The solvent is removed in vacuo, and the residue is triturated with ether. The solid is removed by filtration and washed with ether. The ether solution is concentrated and the residue is chromatographed (silica gel, 20% EtOAc/hexane) to give 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-benzothiopyran as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 307.7 %

Procedure:
3-Methylpyrazole-1-carboxylic acid tert-butyl ester (6.0 g, 33 mmol), N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) were dissolved in 20 mL of carbon tetrachloride. The reaction was heated at reflux for 16 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) gave a light yellow oil (4.5 g, 53%): 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=2.6 Hz, 1H), 6.47 (d, J=2.6 Hz, 1H), 4.48 (s, 2H), 1.64 (s, 9H).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CC([Cl:28])=O)C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[Cl:28][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cncc(-c2ccccc2)c1Cl
Yield: 90 %

Procedure:
A mixture of ethyl 1,4-dihydro-4-oxo-3-phenyl-5-pyridinecarboxylate (prepared from phenylacetyl chloride according to the procedures described in J. Org. Chem. 1978, 43, 2087-2088 and J. Heterocyclic Chem. 1980, 17, 359-368) (3.82 g, 15.7 mmol) and phosphorus oxychloride (50 ml) was heated at reflux overnight. The excess solvent was removed in vacuo. The residue was partitioned between ice-cold aqueous Na2CO3 and ethyl acetate, and the organic layer was evaporated in vacuo to afford 3.72 g (90%) of the title compound as a brown solid; 1H NMR (250 MHz, CDCl3) δ1.44 (3H, t, J 7.2 Hz), 4.47 (2H, q, J 7.2 Hz), 7.40-7.54 (5H, m), 8.62 (1H, s), 8.91 (1H, s); MS (ES+) m/z 262/264 [MH]30 .
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:9]2[CH:15]=[CH:16][C:6]([C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:7][CH:8]=2)[CH2:19][CH2:18]1
Reactant: c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: NC1CC1
Product: OC(CNC1CC1)COc1ccc(-c2ncc[nH]2)cc1

Procedure:
A mixture of 3-[p-(2-imidazolyl)phenoxy]-1,2-epoxypropane (4.95 g, 0.023 m) in cyclopropylamine (50 ml) is refluxed at 60° for 30 hours. The mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with 5-10% MeOH--CHCl3 saturated with NH3. The free base (IV) (1.21 g, 19%) is crystallized as the dihydrochloride salt from EtOH--MeOH--ether (m.p. 214°-5°).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([OH:44])(=[O:43])[CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]([NH:27][CH2:28][C@@H:29]2[NH:40][C:39]3[C:37](=[O:38])[NH:36][C:34]([NH2:35])=[N:33][C:32]=3[NH:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22])[C:17]([OH:19])=[O:18].C(O)=O>CN(C)C=O>[CH:1]([N:40]1[C@@H:29]([CH2:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])[NH:20][C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][C:13]([OH:44])=[O:43])=[CH:42][CH:41]=2)[CH2:30][NH:31][C:32]2[N:33]=[C:34]([NH2:35])[NH:36][C:37](=[O:38])[C:39]1=2)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Solvent: CN(C)C=O
Solvent: O=CO
Product: Nc1nc2c(c(=O)[nH]1)N(C=O)[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
The method of claim 1 wherein said treating comprises adding 1,1'-carbonyl-diimidazole to a solution of (6S)-tetrahydrofolic acid and formic acid in substantially dry N,N-dimethyl-formamide, whereby N5-Formyl-(6S)-tetrahydrofolic acid is produced.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cccc3[nH]ccc23)c(F)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a mixture of 4-bromoindole (6.2 g, 31.7 mmol), and 2,4-difluorophenylboronic acid (5 g, 31.7 mmol) in THF (108 mL) were added Palladium catalyst Pd(PPh3)4 (0.67 g, 0.95 mmol) and the freshly prepared sodium hydroxide solution (3.8 g, 95 mmol in 45 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 80° C. oil bath for over the weekend. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 6.55 g (90%) of 4-(2,4-difluoro-phenyl)-1H-indole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH2:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of the product of Step B (1.06 g; 4.15 mmol) in anhydrous THF (20 ml) was added drop wise to a suspension of LiAlH4 (0.52 g; 13.7 mmol) in anhydrous THF (10 ml) over a period of 1 h at room temperature with vigorous stirring. After additional stirring for 2 h, the reaction mixture was quenched with H2O (1 ml), followed by 10% NaOH (2 ml) and H2O (1 ml). This was stirred for additional 30 min and precipitate formed was filtered off, washed with CH2Cl2 (3×20 ml) and combined filtrates were evaporated to dryness to give the crude title compound (0.71 g; 75%), as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 1.5 (broad s, 2H+H2O); 2.71 (tr, 2H, J=6.8 Hz); 2.94 (tr, 2H, J=6.8 Hz); 5.04 (s, 2H); 6.17-6.84 (m, 3H); 7.17-7.43 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:5]=2[S:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].P(Cl)(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=O>>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:5]2[S:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([N:1]=[C:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:15]
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1C
Reactant: CN1CCCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1sc2c(c1N=C1CCCN1C)c1ccccc1c(=O)n2-c1ccccc1C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-amino-4,5-dihydro-4-(2-methylphenyl)-5-oxo-thieno[2,3-c]isoquinoline-2-carboxylate [M.P. 236°-237° C.), 510 mg] in 5 ml of N-methyl-2-pyrrolidone, which was prepared by a similar manner to that described in Example 2, was added 1.57 ml of phosphorus oxychloride at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 50 ml of water, and neutralized with a saturated sodium bicarbonate aqueous solution. Precipitates were collected by a filtration, washed with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain 583 mg of the desired product as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)nc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-aminopyridine (3.0 g, 17.3 mmol) in THF (44 mL) cooled to 0° C. was added pyridine (1.8 mL, 21.7 mmol) followed by phenylchloroformate (2.3 mL, 18.2 mmol). A precipitate formed and the reaction was stirred at 0° C. for 1 h. The reaction was stirred at RT overnight and quenched with 1N HCl. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give the title compound as a biege solid (4.81 g, 94% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([Br:11])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH3:17][N:18](C)C=O>>[Br:11][C:5]1[C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2]([C:17]#[N:18])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: CCCc1cc(Br)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1cc(C#N)ncc1Br
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of 2,5-dibromo-4-propylpyridine (100 mg, 0.444 mmol) in N,N-dimethylformamide (0.9 mL), dinitrile zinc (57 mg, 0.449 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.0222 mmol) were added at room temperature, and the mixture was stirred under microwave irradiation at 100° C. for 20 minutes. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane/ethyl acetate (4/1). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (60 mg (yield 60%)) was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(NC3C=C(C(F)(F)F)C=CC=3F)=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:29]#[N:30].O.NN>C(O)CC>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:29]#[N:30])=[C:2]([Cl:1])[N:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)nc1Cl
Agent: NN
Solvent: CCCO
Solvent: O
Product: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Temperature: 80 °C
Yield: 132.5 %

Procedure:
0.46 mmol (200 mg) of 1-[4-(6-chloro-5-cyanopyridin-2-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea is suspended in 3.2 ml of 1-propanol. 0.13 ml (0.14 g, 2.76 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated at 80° C. for 10 h. The mixture is filtered and the solid is dried so as to obtain 140 mg of the expected product.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:31])([CH3:30])[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29].[H-].[Na+].Cl>C1COCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([O:20][CH2:19][C:17]2[CH:16]=[CH:15][C:14]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=3[F:29])=[C:13]([CH2:12][C:11]([CH3:31])([CH3:30])[CH3:10])[N:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3C)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 4,6-dichloro-5-methylpyrimidine (160 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (300 mg) in THF (8.0 mL) was added 60% sodium hydride (60 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (340 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C(N(CC)CC)C.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: OCc1cccc(O)c1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Oc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
3-Hydroxybenzylalcohol (5 g, 40 mmol) and triethylamine (5.2 ml, 60 mmol) were dissolved in benzene (250 ml), and thionylchloride (5.2 ml) dissolved in benzene (50 ml) was added thereto at 0° C. The brownish reacting solution was stirred at room temperature for 6 hours. When the reaction was completed, the solution was washed with brine, and the water layer was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to obtain the title compound (5.7 g, 99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.N.[H][H]>CO.[Ni]>[NH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:3]1([CH2:2][OH:1])[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1
Reactant: N#CCCNC1(CO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNC1(CO)CCN(Cc2ccccc2)CC1
Yield: 86.2 %

Procedure:
A mixture of intermediate (14) (0.0159 mol) in methanol saturated with NH3 (150 ml) was hydrogenated at 14° C. with Raney nickel (½ spoon) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 3.8 g of 4-[(3-aminopropyl)amino]-1-(phenylmethyl)-4-piperidinemethanol (intermediate 15).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1>C(#N)C>[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:31][CH2:32][N:33]([CH2:14][CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH2:34][CH2:35]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1
Reactant: COc1cc(N)c(Cl)cc1-c1nn(C2CCNCC2)c(=O)o1
Reactant: BrCC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1-c1nn(C2CCN(CC3CCCCC3)CC2)c(=O)o1
Temperature: 70 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
2.01 ml (13.92 mmol) of triethylamine and then 0.92 g (5.2 mmol) of cyclohexylmethyl bromide in 5 ml of acetonitrile are successively added at room temperature, under an argon atmosphere and with magnetic stirring, to a solution of 1.13 g (3.48 mmol) of 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 40 ml of acetonitrile and the mixture is stirred at 70° C. for 2 days. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried, the solvent is evaporated under reduced pressure and the residue is crystallized from acetone. 0.7 g of white solid is obtained. Melting point: 186.5-186.7° C.
Reaction SMILES: [C:1]1([NH:7][CH:8]2[C@:17]3([OH:18])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[OH:18][C@:17]12[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[N:11]([C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH2:10][CH2:9][CH:8]2[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CC(=O)Cl
Reactant: O[C@]12CCCC[C@@H]1NCCC2Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(Nc2ccccc2)[C@@]2(O)CCCC[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (4aR,8aS)-4-(phenylamino)octahydroquinolin-4a(2H)-ol (20 mg, 0.081 mmol) in 1:1 CH2Cl2:sat'd. aq. NaHCO3 (3 mL) was added 3-methylbutanoyl chloride (0.049 g, 0.406 mmol). The mixture was stirred at rt for 1 hr. The mixture was diluted with sat'd. aq. NaHCO3 and CH2Cl2 and extracted 3× with CH2Cl2. The combined organics were dried (anted. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22-7.40 (m, 5H), 4.38 (d, 1H, J=10.4 Hz), 3.96 (d, 1H, J=10.2 Hz), 3.35 (t, 1H, J=9.4 Hz), 2.62-2.85 (m, 2H), 1.15-2.40 (m, 12H), 0.81-0.99 (m, 6H). HRMS (ES) m/z M+H calc'd:331.2380. found: 331.2379.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=1>[Ni].CO.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 82.4 %

Procedure:
A suspension of (5-bromo-2-nitro-phenyl)-tert-butyl-amine (Step 24.3) (6 g, 21.97 mmol) and Raney nickel (2 g) in MeOH/THF (1:1 v/v, 600 mL) is stirred for 9 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 97:3→3:1) to afford 4.4 g of the title compound as a black oil: ESI-MS: 243.0/245.0 [M+H]+; tR=2.75 min (System 1); TLC: Rf=0.89 (Hex/EtOAc, 1:1).
Reaction SMILES: [C:1]([NH:4][C:5](=[N:8][N+:9]([O-:11])=[O:10])SC)(=[O:3])[CH3:2].[NH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1>C(#N)C>[C:1]([NH:4][C:5]([NH:12][CH2:13][C:14]1[CH:19]=[N:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[N:8][N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: NCc1ccc(Cl)nc1
Reactant: CSC(=N[N+](=O)[O-])NC(C)=O
Solvent: CC#N
Product: CC(=O)NC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of 0.5g of N-acetyl-S-methyl-N'-nitroisothiourea and 5ml of acetonitrile was dropwise added a solution of 0.44g of 5-(aminomethyl)-2-chloropyridine in 3ml of acetonitrile under ice-cooling, followed by stirring for 30 minutes under ice-cooling. The reaction mixture was concentrated and the residue was recrystallized from ethanol to afford 0.59g of N-acetyl-N'-(6-chloro-3-pyridylmethyl)-N"-nitroguanidine (Compound No. 42) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:4][C:3]1=[O:13]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Solvent: CN(C)C=O
Product: CCCCOc1cc(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10.0 g. of 1-methyl-4-hydroxyquinolin-2(1H)-one in 150 ml. of dimethylformamide is added 2.4 g. of pentane washed with sodium hydride and the resulting mixture stirred for 2 hours at room temperature. There is then added 10.6 g. of n-butyl iodide and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture is then poured onto 1.3 liters of cold water, extracted with ethyl acetate, washed 3 times with water, dried, charcoaled, filtered and evaporated in vacuo. The resulting oil is dissolved in 120 ml. of ether and cooled in an acetone/dry ice bath to crystallize solids which are filtered off and washed with cold ether to obtain 1-methyl-4-butoxyquinolin-2(1H)-one, m.p. 77°-80° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Na].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc2ccccc2n1
Agent: [Na]
Solvent: CN(C)C=O
Product: c1ccc2nc(-n3cncn3)ccc2c1

Procedure:
1.64 g of 2-chloro-quinoline and 1.1 g of the sodium salt of 1H-1,2,4-triazole are reacted in 10 ml of dimethyl formamide for 20 hours at 100° C. and worked up as in Example 1 to give 1.43 g of 2-(1H-1,2,4-triazole-1-yl)-quinoline /yield 53%/
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][C:16]4[O:17][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:19][N:20]=4)=[CH:6][CH:7]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.