Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCCS
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCSC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
542 mg (1.89 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone, 212 mg (2.36 mmole) of butyl mercaptan, 381 mg (3.77 mmole) of triethylamine and 1.04 g (3.78 mmole) of diphenylphosphoryl azide were dissolved in 10 ml of N,N-dimethylformamide and the solution was allowed to stand overnight at room temperature. After dilution with ethyl acetate, the mixture was washed with water several times and then dried. The solvent was distilled off and the residue (1.25 g) was purified by column chromatography through 23 g of silical gel, eluted with mixtures of hexane and ethyl acetate in volume ratios ranging from 4:1 to 2:1, to give 649 mg (yield 96%) of the title product. Recrystallization from hexane gave colourless needles, melting at 56.5°-57° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Reaction time: 1 h

Procedure:
The 2-butyl-1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline from the previous step and tetrabutylammonium fluoride (142 mL of a 1 M solution in tetrahydrofuran) were dissolved in tetrahydrofuran (THF) (400 mL) and stirred for 1 hour, then concentrated under reduced pressure to provide 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g) as a light brown solid after chromatography on silica gel (elution with 10% methanol in dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17](N(OC)C)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17]([C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: Cc1cscn1
Reactant: CON(C)C(=O)Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1csc(C(=O)Cc2ccc3c(c2)OCO3)n1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A 2.6M solution of n-butylithium in hexane (34 ml) was dropped into a solution of 4-methylthiazole (8.0 g) of tetrahydrofuran (150 ml) at −70° C. and the mixture was stirred for 30 minutes. Further, a solution of 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetamide (20.0 g) in tetrahydrofuran (20 ml) was dropped therein and the mixture was stirred for 1 hour. This solution, to which a saturated aqueous solution of ammonium chloride was added, was extracted with ethyl acetate, and after the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated. The resultant residue was purified by silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane to yield 2-benzo(1,3)dioxol-5-yl-1-(4-methylthiazol-2-yl)ethanone (19.3 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:30][CH:31]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[N:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: Brc1ccc(OC2CCCC2)nc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC3CCCC3)nc2)cc1

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 5-bromo-2-cyclopentoxypyridine (see Example 36(b)), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:41])=[O:40])[CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (0.0075 g, 0.061 mmol), benzenesulfonyl chloride (0.108 g, 0.610 mmol), and Hünig's base (0.159 mL, 0.915 mmol). The resulting mixture was stirred at room temperature. After 2 h, the mixture was concentrated and the crude product was purified by column chromatography (40 g of silica, 10 to 40% acetone in hexanes) to give N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)benzenesulfonamide (0.176 g) as a mixture of two isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[H][H]>CO.[Pd]>[F:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1

Procedure:
3.88 g of 4-(2,6-difluoro-4-nitro-phenyl)-morpholine are dissolved in 50 mL methanol and combined with Pd/C. The mixture is hydrogenated for 18 h at 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)=[O:31])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of rac-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (1.08 g, 2.28 mmol) in CH2Cl2 (25 ml) was added TFA (5 ml) at RT. Stirring was continued one hour. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.72 g (85%) of the title compound as light yellow foam. ES-MS m/e: 374.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1([C@H:26]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:31][C@H:28]2[CH2:29][CH2:30][C@H:26]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[CH2:27]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CC[C@H](n2cccn2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](n4cccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 10.5 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (702 mg, 2.53 mmol), trans-3-(1H-pyrazol-1-yl)cyclopentylamine (460 mg, 3.04 mmol) and di-isopropylethylamine (0.970 mL, 5.57 mmol) in anhydrous DMSO (14 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/10→EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[trans-3-(1H-pyrazol-1-yl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (108 mg, 10%) as a yellow powder.
Reaction SMILES: N[C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:17]>>[Cl:17][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCc1ncccc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NCCCCc1ncccc1Cl

Procedure:
a. Reaction of 3-amino-2-(4-aminobutyl)pyridine with sodium nitrite/hydrochloric acid and treatment of the resultant diazonium salt with cuprous chloride yields 3-chloro-2-(4-aminobutyl)pyridine. By a similar procedure employing cuprous bromide and hydrobromic acid 3-bromo-2-(4-aminobutyl)-pyridine may be produced and when the diazonium salt is treated with sulphuric acid the product is 3-hydroxy-2-(4-aminobutyl) pyridine.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:8]([O:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:11]=2[Cl:10])=[CH:7][CH:6]=[N:5]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1nccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1nccc1OC(=O)c1ccc(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
In 30 ml of an aqueous solution containing 4.0 g (0.1 mol) of sodium hydroxide was dissolved 9.8 g (0.1 mol) of 1-methyl-5-hydroxypyrazole at room temperature. To the resulting aqueous solution maintained at 10° C. was added dropwise a solution prepared from 23.0 g (0.11 mol) of 2,4-dichlorobenzoyl chloride and 100 ml of chloroform with stirring over 1 hour, followed by additional stirring for 2 hours at a temperature below about 20° C. Then the chloroform layer was separated and washed successively with water, 5% aqueous sodium bicarbonate and saturated brine and, after drying, solvent was distilled off under reduced pressure to give 23.5 g of 1-methyl-5-(2,4-dichlorobenzoyloxy)-pyrazole (yield: 86%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1coc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-fluoro-1-benzofuran-3-yl)acetate (1.11 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4; filtered and concentrated. The product, 2-(5-fluoro-1-benzofuran-3-yl)ethanol obtained as white oil and was pure enough to be taken to the next step without purification. Yield: 820 mg (91%); 181 (M+H).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.C>CS(O)(=O)=O.C(O)CC>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A solution of 10.3 gm. of N-isopropyl-(3,4-methylenedioxyphenyl)urea, 7.1 ml. of benzaldehyde, and 3 drops of methanesulphonic acid in 250 ml. of toluene is refluxed under a water separator for 21 hours. The cooled solution is then washed with 200 ml. of water, dried and evaporated to yield a powder. This product is decolorized in hot propanol with a small amount of activated charcoal and recrystallized from propanol to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 169°-172°C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:16])[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1>ClC1C=CC=CC=1>[F:5][CH:6]([F:16])[C:7]1[C:11]([C:12]([Cl:3])=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1
Reactant: Cn1cc(C(=O)O)c(C(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: Cn1cc(C(=O)Cl)c(C(F)F)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 195.3 %

Procedure:
69.5 g of thionyl chloride (0.58 mol, 1.17 equivalents) are added at 110° C. in the course of 2 hours to a solution of 88 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.5 mol) in 440 g of chlorobenzene. The reaction mixture is stirred for 1 hour at 110° C. The reaction mixture is concentrated to a crude product solution. 190 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (50% in chlorobenzene, yield: 98%) is obtained. The crude product solution is used without being further purified.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4].C1N2CN3CN(C2)C[N:15]1C3>ClC1C=CC=CC=1.C(OCC)C>[NH2:15][CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])nc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: NCC(=O)c1ccc([N+](=O)[O-])nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 1.549 g (6.322 mmol) of 2-bromo-1-(6-nitropyridin-3-yl)ethanone in 25 cm3 of chlorobenzene is added at a temperature in the region of 20° C. to a solution of 0.975 g (6.954 mmol) of hexamethylenetetraamine in 10 cm3 of chlorobenzene. After stirring for 1 hour at this temperature, the suspension is heated for 18 hours at 50° C. The reaction medium is then cooled to 5° C. and then diluted with 200 cm3 of ethyl ether. The precipitate thus obtained is filtered and washed with three times 50 cm3 of ethyl ether. The resulting ammonium salt is stirred in 20 cm3 of ethanol and then 8 cm3 of 37% hydrochloric acid are added at a temperature in the region of 20° C. The solution is then stirred for 16 hours at this temperature. The precipitate formed is filtered, washed with three times 50 cm3 of water, drained and dried to give 1.05 g of 2-amino-1-(6-nitropyridin-3-yl)ethanone in the form of a cream powder. ES+: m/z=182 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34]OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34][N:5]3[C:4]([CH3:3])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=[CH:6]3)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](COS(=O)(=O)c3cccc([N+](=O)[O-])c3)CC[C@H]2CN1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
Sodium hydride (0.24 g, 1.2 eq) was washed with hexanes (3×10 ml) and suspended in dry THF (10 ml). To this was added a solution of 0.848 g of ethyl 4-methyl-5-imidazolecarboxylate in THF (5 ml) dropwise. The reaction mixture was stirred at 20° C. for 1.5 h and DMF (10 ml) was added. To the resulting solution was slowly added a solution of 2.43 g of [3S,4aR,6S,8aR]-ethyl-6-((3-nitrophenylsulfonyloxy)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate in THF (10 ml). The reaction was stirred at ambient temperature over night under N2. The reaction was quenched with saturated aqueous sodium bicarbonate. The resulting white solid was removed by filtration and the filtrate was extracted with ethyl acetate (3×10 ml). The combined organic extract was washed with brine, dried (MgSO4), filtered, and evaporated to a light brown oil. The crude product was chromatographed over silica gel eluting with ethyl acetate to give 1.09 g of the intermediate title compound: MS m/z: 456.3 (m++1);
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: Cc1cccc(C(O)CN)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(O)CNC2=NCCN2)c1

Procedure:
A mixture of 8.2 parts of α-(aminomethyl)-m-methylbenzyl alcohol, 6,1 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C, while almost all xylene is distilled off. The residue is diluted with a few parts of acetone and allowed to crystallize. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding α-(2-imidazolin-2-ylaminomethyl)-m-methylbenzyl alcohol; m.p. 121°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([C:19]3[NH:23][CH:22]=[CH:21][N:20]=3)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[O:31])[N:10]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(NCCNC(=O)c3cccc([N+](=O)[O-])c3)ncc2-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzene-carbonitrile (30 mg, 0.098 mmol), 3-nitrobenzoic acid (17 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (19 mg, 0.1 mmol), 1-bydroxybenzotriazole hydrate (HOBT) (14 mg, 0.1 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in DMA (500 uL) were stirred at room temperature. After 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)(3-nitrophenyl)carboxamide weighing 32 mg (70% yield) was approximately 95% pure by LCMS and HPLC.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH2:20][C:21](OCC)=[O:22])[N:19]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH2:20][CH2:21][OH:22])[N:19]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
Ethyl 2-(2-(4-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)acetate (1.20 g, 3.23 mmol) in THF was added to a solution of 1.0 M lithium aluminum hydride (9.69 mL, 9.69 mmol) in ether and THF (50 mL) at 0° C. The reaction mixture was stirred for 40 minutes, and cooled while carefully quenching with an excess of sodium sulfate decahydrate. A small amount of anhydrous magnesium sulfate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered, and the cake was washed with THF several times. The combined filtrates were concentrated and the residue was recrystallized from 3:1 ethyl acetate:hexanes (50 mL). The crystals were filtered, washed with hexanes and dried to afford 2-(2-(4-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)ethanol (0.501 g, 47.1% yield) as light pink crystals/needles. 1H NMR (d6-DMSO) δ 11.11 (s, 1H), 8.08 (d, 1H), 7.53-7.61 (t, 6H), 6.73 (s, 1H), 6.57 (s, 1H), 6.56 (m, 1H), 4.58 (t, 1H), 3.65 (m, 2H), 2.69 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])O1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[C:31]([F:32])([F:34])[F:33])[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C(F)(F)F)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(C(F)(F)F)c1

Procedure:
Followed Scheme 3: starting with 2-chloroquinolin-6-ol and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (Intermediate 5).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:12]C1CC(C(C)C)CCC1=O>>[Br:12][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][C:7]1=[O:11]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CCCCC1CCCC(=O)C1
Product: CCCCC1CCC(Br)C(=O)C1

Procedure:
The bromination of 3-butylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.