Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.CS[C:21](=[NH:26])[NH:22][N+:23]([O-:25])=[O:24]>C(#N)C>[CH3:17][N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:21]([NH:22][N+:23]([O-:25])=[O:24])=[NH:26])[O:7][C:8]=2[CH:14]=1)[CH3:18]
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CC#N
Product: CN(C)Cc1ccc2cc(CSCCNC(=N)N[N+](=O)[O-])oc2c1

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (Example 1, Step E) (2.6 g., 0.01 mole) and S-methyl-N-nitroisothiourea (1.4 g., 0.01 mole) in acetonitrile (15 ml.) is kept at 25°-27° C. for 4 hours. The solvent is evaporated and the residue chromatographed on silica gel (5% methanol in chloroform elution) to yield N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-nitroguanidine.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]([C:20]2([CH2:35][NH:36]C(=O)OC(C)(C)C)[CH2:25][CH2:24][N:23]([C:26]3[C:27]4[CH:34]=[CH:33][NH:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH2:22][CH2:21]2)=[O:19])[CH3:16])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:36][CH2:35][C:20]1([C:18]([NH:17][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH3:16])=[O:19])[CH2:21][CH2:22][N:23]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:24][CH2:25]1
Reactant: C[C@H](NC(=O)C1(CNC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)C1(CN)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Trifluoroacetic acid (2 mL, 25.96 mmol) was added to (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (Intermediate 13) (0.257 g, 0.5 mmol) in DCM (20 mL) at 25° C. The resulting solution was stirred at 25° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 7N ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-4-(aminomethyl)-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.095 g, 46.0%) as a white solid.
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].[CH2:6]([O:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16](Cl)[C:15]=12)=[O:10])C>>[CH3:6][O:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([O:2][CH3:1])[C:15]=12)=[O:10]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Agent: [Na+]
Product: COC(=O)c1ncn2c1c(OC)nc1ccccc12
Yield: 58.9 %

Procedure:
To a methanolic solution (250 ml) of 4-chloroimidazo [1,5-a]quinoxaline 3-carboxylic acid ethyl ester (4 g) was added sodium bicarbonate (10 g) with stirring. The mixture was heated on steam bath for 2 hours. After removal of solvent under vacuum, the residue was taken up in water, then extracted with chloroform several times. The combined chloroform extracts were washed with water, dried by magnesium sulfate and evaporated to give the product as an off-white solid (2.2 g, 55% yield). Recrystallized from acetonitrile, m.p. 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cccc(O)c2n1
Reaction time: 8 h

Procedure:
A mixture of 2-amino-3-hydroxypyridine (1,000 g) and chloroacetone (845 g) in 7.57 liters of ethanol was heated under reflux for 20 hrs. Most of the ethanol was removed by distillation and the residual material was dissolved in 7.57 liters of water. This solution was extracted four times with 1.2 liter portions of dichloromethane. The combined extracts were washed with 1 liter of water and this was combined with the aqueous solution. This solution was then adjusted to pH 11.5-12 with 850 ml of 50%sodium hydroxide. This basic solution was extracted three times with 1.2 liters of dichloromethane. The combined dichloromethane extracts were washed with 1 liter of H2O and this was added to the basic solution.This solution was chilled in an ice bath and the pH adjusted to 7 with 1.45liters of 6 N hydrochloric acid. After standing overnight, the product was collected, washed with water, and dried. The product was recrystallized from dichloromethane/methanol to give the intermediate.
Reaction SMILES: [C:1]1([CH:7]([N:14]=[C:15]=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@:17]12([OH:26])[N:24]([CH3:25])[C@@H:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]=[CH:18]2>C(#N)C>[CH:7]([NH:14][C:15]([O:26][C@@:17]12[N:24]([CH3:25])[C@@H:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]=[CH:18]2)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)NC(c1ccccc1)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 g (0.012 mol) of diphenylmethylisocyanate is placed in 7 mL acetonitrile, a solution of 1.67 g (0.012 mol) of tropenol in 5 mL acetonitrile is added dropwise. The solution is stirred for 24 hours at ambient temperature; after 10 minutes, a white precipitate is formed. After the end of the reaction time, the suspension is cooled and the precipitate is suction filtered. Yield: 2.28 g (55% of theory); melting point: 140° C.-142° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+].[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:14])[CH3:13].O>CO>[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncccc23)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL) were added sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (541, 1.5 g, 0.0039 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (542, 1.0 g, 51%). MS (ESI) [M+H+]+=499.1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:15]2[CH2:16][C:11]3(Br)[CH2:12][C:13](Br)([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)(C)(C)C.[OH-:21].[Na+]>O1CCOCC1>[NH2:7][CH:8]1[CH:15]2[CH2:14][C:13](=[CH2:12])[CH2:17][CH:9]1[CH2:10][C:11](=[O:21])[CH2:16]2
Reactant: CC(C)(C)OC(=O)NC1C2CC3(Br)CC1CC(Br)(C2)C3
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C1CC2CC(=O)CC(C1)C2N
Yield: 163.7 %

Procedure:
(First step: Rohde, J. J. et al. Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-N-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors. J. Med. Chem. 2007, 50, 149-64). A solution of 25 (125 mg, 0.305 mmol) in dioxane (0.80 mL) was treated with 2N NaOH (0.70 mL, 1.37 mmol) and irradiated under microwaves (μw, Biotage) for 15 min at 180° C. The dioxane was removed in vacuo. The residue was dissolved in DCM, washed with water, dried (Na2SO4), filtered and concentrated in vacuo to afford 82.5 mg of crude 9-amino-7-methylene-bicyclo[3.3.1]nonan-3-one as a yellow oil, that was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8][N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH3:14][O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH3:1])=[O:5])[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=1)=[O:12]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 20 ml of DMF and 188 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 1.32 g of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. Then 100 ml water were added and the precipitating product was collected by filtration. Yield: 1.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[S:18][C:19]([CH3:22])=[N:20][N:21]=1)=[N:5]2.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:14])[CH3:15])[C:6]([S:16]([C:17]1[S:18][C:19]([CH3:22])=[N:20][N:21]=1)=[O:31])=[N:5]2
Reactant: Cc1nnc(Sc2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nnc(S(=O)c2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Reaction time: 8.5 h

Procedure:
A solution of 6,7-dichloro-2-isopropyl-3-(5-methyl-1,3,4-thiadiazol-2-ylsulfanyl)quinoxaline (168 mg, 0.45 mmol) prepared as described in example 1 in dichloromethane (6 ml) was stirred in a dry ice/acetone bath at −78° C. while mCPBA (142 mg, 0.45 mmol) was added. After 8.5 hours, the reaction was quenched by addition of a saturated solution of sodium bi-carbonate. The layers were separated and the aqueous layer was extracted twice with chloroform. Evaporation of the solvent yielded a pale yellow solid. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:3 to afford the title compound.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:32]#[C:31][CH2:30][CH:29]([C:25]4[O:24][CH:28]=[CH:27][CH:26]=4)[OH:33])[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCC(O)c1ccco1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccco3)oc21

Procedure:
Analogous to the procedures described in Example 88, 2-bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 79) is treated with 1-(2-furyl)but-3-yn-1-ol (Preparation 74) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)[C:10]#[N:11].Cl[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[OH-].[Na+]>CS(C)=O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)#[N:11]
Reactant: ClCn1cncn1
Reactant: CN1CCCC(CC(C#N)c2ccc(Cl)cc2Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCCC(CC(C#N)(Cn2cncn2)c2ccc(Cl)cc2Cl)C1

Procedure:
This compound (1.8 g.) was prepared using the procedure described in Example 9b except using 3.0 g. (0.010 mole) of 2-(2,4-dichlorophenyl)-3-(1-methylpiperidin-3-yl)propionitrile, 1.7 g. (0.011 mole) of 1-(chloromethyl)-1,2,4-triazole, 2.0 g. (0.025 mole) of 50% aqueous sodium hydroxide, and 30 ml. of DMSO yielding a white solid, melting point 125°-126° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.C(O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
There were dissolved 1.3 g (0.005 mole) of 2-carbamoyl-7-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine in a mixture solvent of 10 ml of dioxane and 10 ml of ethanol, and the resulting mixture was refluxed with heating for 7 hours. After completion of the reaction, 2N-NaOH solution was added to give the free base, which was extracted from chloroform. The extract was dried with magnesium sulfate. Then, the resultant residue obtained by distilling away the solvent under reduced pressure was crystallized from chloroform and petroleum ether.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(N(CC)CC)C>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][CH:2]([C:4]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])=[CH:26][CH:25]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)c2nc3ccccc3c(=O)n2Cc2ccccc2)cc1

Procedure:
2-Ethyl-3-benzyl-quinazolin-4-one is prepared following the procedure set forth in part (A) above, but substituting N-benzyl-2-(propanoylamino)-benzamide for N-(1-benzoylethyl)-2-(formylamino)-benzamide (“Compound E”). Compound E is brominated by heating in acetic acid with bromine to provide 2-(1-bromoethyl)-3-benzyl-quinazolin-4-one (“Compound F”). Compound F is treated with 4-methoxy-aniline in triethylamine to provide 2-(1-(4-methoxyphenylamino)ethyl)-3-benzyl-quinazolin-4-one (“Compound G”). Compound G is then acylated with benzoyl chloride to provide 2-(1-(N-benzoyl-N-(4-methoxyphenyl)-aminoethyl)-3-benzyl-quinazolin-4-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(O)(C(F)(F)F)=O>>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 85 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1.88 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (3.1 g, 86%) as a yellow powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:13]([SH:21])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II>>[CH3:20][N:18]([CH3:19])[C:15]1[N:14]=[C:13]2[S:21][N:9]([CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:10](=[O:11])[C:12]2=[CH:17][N:16]=1
Reactant: CN(C)c1ncc(C(=O)NCCN2CCCCC2)c(S)n1
Agent: II
Product: CN(C)c1ncc2c(=O)n(CCN3CCCCC3)sc2n1
Yield: 85.9 %

Procedure:
Using the procedure of Example 20, 6.2 g (20.1 mmol) of 2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide were treated with 5.08 g (20.0 mmol) of iodine to give 5.31 g of the title compound after recrystallization from ethyl acetate, mp 128°-129° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[NH:28][CH:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[NH:28][CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2cc[nH]c12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), 4-chloro-5H-pyrrolo[3,2-d]pyrimidine from Example 20 (155 mg, 0.99 mmol, 0.99 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.03 mmol, 3.02 equiv, 98%). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The residue was purified by applying onto a C18 column eluted with water/acetonitrile (95:5-20:80) to afford 150 mg (41%) of 147 as a light-yellow solid. LC-MS (ES, m/z): 355 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.49 (s, 1H), 7.85-7.48 (m, 9H), 7.32-7.30 (m, 1H), 6.63 (d, 1H), 5.81-5.74 (m, 1H), 1.89 (d, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>[Na+].[Cl-]>[C:21]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c([N+](=O)[O-])cccc2n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Reaction time: 0.5 h

Procedure:
360 mg (1.9 mmol) of 2-amino-5-nitroquinoline is stirred with 4 ml (50 mmol) of pyridine and 2 ml (21 mmol) of acetic anhydride for 15 hours at room temperature. The batch is poured into saturated NaHCO3 solution, stirred for 30 minutes, diluted with saturated NaCl solution and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation: 410 mg of a yellow solid.
Reaction SMILES: [O:1]=[C:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]1[C:18](O)=[O:19].S(Cl)(Cl)=O.[CH3:37][OH:38]>>[O:1]=[C:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:18]([O:38][CH3:37])=[O:19]
Reactant: CO
Reactant: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: -30 °C

Procedure:
A solution of 19.4 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(t-butyloxycarbonyl)piperidine-3-carboxylic acid (80% content) in 355 cm3 of methanol is cooled to a temperature in the region of −30° C. Thionyl chloride (7.7 cm3)is added with stirring while maintaining the temperature between −25 and −30° C. After the addition, the mixture is maintained in the vicinity of −30° C. for 30 minutes and then the temperature is allowed to return to the vicinity of 20° C. After stirring at ambient temperature for 19 hours, the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 30° C. The residue is taken up in 300 cm3 of water to which 200 cm3 of dichloromethane have been added, and then stirred. The organic phase is separated by settling; the aqueous phase is again extracted with 200 cm3 of dichloromethane. The aqueous solution is brought to pH 8 by gradual addition of solid sodium hydrogen carbonate. After extracting the alkaline solution 3 times with 200 cm3 of dichloromethane, the combined organic extracts are washed 2 times with 200 cm3 of water and then dried over magnesium sulfate. After filtering through a paper filter, the organic solution is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. to afford 4.51 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH3:25][O:26][N:27]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 13.3 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone in 40 ml of ethanol is treated with 10 g of sodium carbonate and 8.3 g of O-methylhydroxylamine hydrochloride; the mixture is subsequently heated at reflux temperature while stirring. After 4 hours, the mixture is poured onto ice and extracted with ethyl acetate. The organic phase is washed, dried over sodium sulfate and concentrated under reduced pressure to yield 2',4'-dichloro-2-(3-pyridyl)-acetophenone O-methyl oxime as the E,Z-isomer mixture in the form of a yellowish oil. Chromatographic separation on silica gel with n-hexane/ethyl acetate (4:1) as the eluant yields firstly the E-isomer (nD20 =1.5845) and then the Z-isomer (nD20 =1.5745).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:5][C:6]1[C:7]([NH:15]C(=O)OC(C)(C)C)=[N:8][N:9]([CH2:12][CH2:13][OH:14])[C:10]=1[CH3:11].Cl>O1CCOCC1>[NH2:15][C:7]1[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:25]=[C:24]([Cl:26])[CH:23]=2)=[C:10]([CH3:11])[N:9]([CH2:12][CH2:13][OH:14])[N:8]=1
Reactant: Cc1c(Cc2cc(Cl)cc(Cl)c2)c(NC(=O)OC(C)(C)C)nn1CCO
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cc2cc(Cl)cc(Cl)c2)c(N)nn1CCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of the protected amine of Example 86 (50 mg, 0.1 3 mmol) in 1,4-dioxan was treated with 4M hydrogen chloride in 1,4-dioxan (320 μL, 1.25 mmol) and stirred at room temperature for 2 days. The solution was concentrated under reduced pressure. The residue was diluted with water (15 ml) and extracted with ethyl acetate (3×10 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound as a white solid and as the hydrochloride salt (19.5 mg).