Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH2:31])[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH:31][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCOc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 92.7 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-ethoxyphenyl 3-nitrophenyl ketone, 1.16 g of 1-(3,5-difluorophenyl)ethylamine, 2.01 ml of triethylamine, 0.49 ml of titanium tetrachloride, 975 mg of sodium cyanoborohydride and 0.32 ml of acetic acid were reacted, to obtain 1.41 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:17](OC1N=C(NN)C=CC=1)[CH3:18].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](OCC)N=1.IC1C=CC=CC=1C(O)=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:28][C:29]1[C:34]2[C:33](=[CH:32][CH:31]=[CH:17][CH:18]=2)[N:15]=[C:14]2[N:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=3)[N:11]=[C:12]([CH3:16])[C:13]=12
Reactant: CCOc1cccc(Cl)n1
Reactant: CCOc1cccc(NN)n1
Agent: CCOc1cccc(-n2nc(C)cc2N)n1
Agent: O=C(O)c1ccccc1I
Product: CCOc1cccc(-n2nc(C)c3c(Cl)c4ccccc4nc32)n1

Procedure:
Following the procedure described in Reference Example 2-4, 1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine was prepared from 6-ethoxy-2-hydrazinopyridine which was prepared from 2-chloro-6-ethoxypyridine following the method described in Reference Example 2-2. Subsequently, following the methods described in Reference Example 2-5 and Example 2-1, the title compound was prepared from o-iodobenzoic acid and 1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine (36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][N:13]1[C:17](Cl)=[C:16]([Cl:19])[C:15]([Cl:20])=[N:14]1.O>CS(C)=O>[CH3:12][N:13]1[C:17]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:16]([Cl:19])[C:15]([Cl:20])=[N:14]1
Reactant: SCc1ccc(Cl)cc1
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(Cl)c(Cl)c1SCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A stirred mixture of 10.3 g (0.065 moles) 4-chlorobenzyl mercaptan and 3.0 g (0.054 moles) potassium hydroxide in 50 ml dimethylsulfoxide was heated (at about 120° C.) for about 20 minutes. Then 10 g (0.054 moles) 1-methyl-3,4,5-trichloropyrazole were added. Heating (at about 120° C.) of the stirred reaction mixture was continued for about 4 hours. The reaction mixture was allowed to cool. The reaction mixture was added to water (about 50 ml); the resulting mixture was extracted with ether. The etheral phase was separated and dried over magnesium sulfate. The solvent was stripped and the residue was hard-topped. The product was purified by high pressure liquid chromatography to give 6 g.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Br[C:18]1[CH:23]=[CH:22][N:21]=[N:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:20]1[CH:19]=[CH:18][C:23]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccnnc2)cn1
Temperature: 96 °C

Procedure:
To a reaction tube were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1.00 mmol), 4-bromopyridazine (159 mg, 1.00 mmol), Pd(PPh3)4 (57.7 mg, 0.05 mmol) and K3PO4 (424 mg, 2.00 mmol). The tube was subjected to vacuum and back filled with argon. Dioxane (3.0 ml) and water (0.3 ml) were added and the mixture was heated at 96° C. overnight. After cooled to room temperature, the reaction mixture was filtered through celite (washed with ethyl acetate) and concentrated by evaporation. Subsequent silica gel column chromatography with 5% methanol in DCM as eluent gave 5-(pyridazin-4-yl)pyridin-2-amine 134-1 as brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](O)=[O:5].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([N:16]([C:4](=[O:5])[C:3]([CH2:8][OH:9])([CH2:2][OH:1])[CH3:7])[NH2:17])=[CH:12][CH:11]=1
Reactant: CC(CO)(CO)C(=O)O
Reactant: Cc1ccc(NN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(N(N)C(=O)C(C)(CO)CO)cc1
Reaction time: 24 h
Yield: 61.5 %

Procedure:
Sixty-five grams (0.49 m) of 2,2-bis(hydroxymethyl) propionic acid was added to a solution of p-tolylhydrazine (100 g, 0.44 m) and dicyclohexylcarbodiimide (100 g, 0.49 m) in 2,500 ml of tetrahydrofuran. The reaction mixture was stirred under a nitrogen atmosphere for 24 hours. The dicyclohexylurea was removed by filtration and the solution was concentrated under reduced pressure. The residue was recrystallized from 300 ml of isopropyl alcohol. There was obtained 71 g (68 percent) of 2,2-bishydroxymethyl propionic acid p-tolylhydrazide, m.p. 129° to 130° C. ##STR6##
Reaction SMILES: FC1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[N:38]1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[CH:3][N:38]=[CH:7][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccncc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-pyridylboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)ccn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (2.50 g), 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (2.77 g) and ethanol (15 ml) was boiled under reflux for 19 hours and evaporated. The residue was triturated with hot water to leave 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone. A mixture of this pyrimidone (3.04 g), 2N hydrogen chloride in ethanol (20 ml) and ethanol (80 ml) was boiled under reflux for 48 hours and evaporated to dryness. The residue was recrystallised from methanol/ethanol to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 181°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 15.8 parts of β-(2,4-dichlorophenyl)benzene-propanol, 12.15 parts of methanesulfonyl chloride, 50 parts of pyridine and 70 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated. The residue is triturated in methanol. The product is filtered off and crystallized from ethanol, yielding 7.28 parts of β-(2,4-dichlorophenyl)benzenepropanol methanesulfonate; mp. 87.3° C.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.[Br:7][CH:8]([CH:11]=O)[CH:9]=O>C(O)(=O)C.CO>[Br:7][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:11]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1ccn[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Brc1cnc2[nH]ncc2c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
1H-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde (9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated to reflux under N2 for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-1H-pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25%).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][CH:12]([F:15])[CH2:13][OH:14]>>[F:11][CH:12]([F:15])[CH2:13][O:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1OCC(F)F

Procedure:
Prepared analogously to example XII.1 using 2-fluoro-3-nitropyridine (142 mg) and 2,2-difluoroethanol (98 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:23](=[O:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C)CCN(C(=O)Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and phenylacetyl-chloride
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CCCCO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.61 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.71 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[CH2:23]([S:30](Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][S:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NS(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (99.5 mg, 342 μmol) was dissolved in pyridine (1 mL) and cooled to 0° C. To this was added benzylsulfonyl chloride (84.7 mg, 444 μmol) and stirred for an hour after warming to room temperature. To this was added benzylsulfonyl chloride (13.8 mg, 72.3 μmol) and the mixture was stirred for 2.5 h. To this was further added benzylsulfonyl chloride (13.9 mg, 72.9 pimp and the mixture was stirred for 15 h. To this was further added benzylsulfonyl chloride (13.1 mg, 68.7 μmol) and the mixture was stirred for 5.5 h. To this was added 2 M hydrochloric acid to stop the reaction, and after separating the aqueous layer and organic layer, it was extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (7 g, n-hexane/ethyl acetate=7/3→ethyl acetate). The resulting solid was recrystallized from ethyl acetate to give 3-benzyl-2-benzylsulfonylamino-5-(4-methoxyphenyl)pyrazine (c-18) as a colorless solid (56.0 mg, 36.8%). Rf=0.32 (n-hexane/ethyl acetate=7/3). Mp. 213-215° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 334.5 (4.04), 290 (4.21), 276.5 (4.23). UV (pH 7.4 PB, 0.3% DMSO) λmax (log ε) 348.5 (3.90), 293 (3.95). 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 4.22 (s, 2H), 4.91 (s, 2H), 7.02-7.07 (AA′BB′, 2H), 7.14-7.21 (m, 1H), 7.24-7.27 (m, 4H), 7.36 (s, 5H), 7.99 (d, J=7.3 Hz, 2H), 8.88 (s, 1H), 10.46 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 38.0, 55.3, 59.6, 114.4 (2C), 126.3, 127.6 (2C), 128.1, 128.3 (2C), 128.4, 128.5 (2C), 129.0 (2C), 129.9, 130.9 (2C), 136.2, 138.1, 144.6, 145.8, 146.0, 160.3. IR (KBr, cm−1) 459, 538, 586, 698, 748, 785, 831, 893, 912, 926, 1032, 1121, 1132, 1177, 1215, 1256, 1287, 1319, 1395, 1452, 1495, 1516, 1609, 3231. HRMS (FAB+) m/z 446.1548 (M+H, C25H24N3O3S requires 446.1548).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH2:19]>C1COCC1.O.[Ni]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: COC(=O)c1cc(-c2ccoc2)c(C(F)(F)F)cc1N
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1N
Temperature: 60 °C
Reaction time: 624 h
Yield: 46.7 %

Procedure:
2-Amino-5-furan-3-yl-4-trifluoromethyl-benzoic acid methyl ester (110 mg, 0.38 mmol) was dissolved in THF (15 mL) and, after addition of B113 W (Degussa) Ra/Ni (˜200 mg) in H2O the mixture was stirred for 26 d (TLC control) at 60° C. The mixture was filtered over Celite and evaporated under reduced pressure. The crude product was purified by flash chromatography with hexanes to hexanes/EtOAc 80:20 as eluent to furnish the title compound (51.3 mg, 46% yield) (290 [M+H]+, rt 5.52 min.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=2)[CH:10]=1)=[O:27]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
Triethylamine (1.55 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under water. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (4.8 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.96 (s, 6H), 4.84 (s, 2H), 6.9 (d, 1H), 7.26 (m, 3H), 7.5-7.7 (m, 3H), 7.8-8.1 (m, 4H), 9.97 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−H− 420.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[S:11])[NH:8]2)=[CH:4][N:3]=1.[OH-].[K+].I[CH3:15]>CCO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([S:11][CH3:15])=[N:8]2)=[CH:4][N:3]=1
Reactant: CI
Reactant: S=c1[nH]c2cnc(Cl)nc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2nc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of 2-chloro-7H-purine-8(9H)-thione (2.00 g, 10.72 mmol) and potassium hydroxide (722 mg, 12.86 mmol) in anhydrous EtOH (66.4 mL) was added iodomethane (0.67 mL, 10.72 mmol). The reaction solution was stirred under N2 at RT for 4 h, then partitioned between EtOAc (85 mL) and 2N HCl (15 mL) and allowed to settle overnight. To the aqueous layer, which contained solid material, was added more water (60 mL). The mixture was filtered, and dried under vacuum to afford the title compound as a solid. LC-MS: calculated for C6H5ClN4S 199.99 observed m/e: 200.99 (M+H)+ (Rt 0.99/1.8 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: ClCc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2Cl)c(Cl)c1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
To a reaction flask were added 2-chloro-4-nitrophenol (5.205 g, 30 mmol), 2-chlorobenzyl chloride (5.313 g, 33 mmol), potassium carbonate (4.554 g, 33 mmol) and DMF (40 ml). The reaction mixture was heated to the temperature of 100° C. After the reaction finished, the reaction solution was poured into water (400 ml). The mixture was extracted with ethyl acetate (300 ml). The ethyl acetate layer was washed with saturated saline solution (200 ml) once and dried over anhydrous magnesium sulfate. The organic layer was filtered and the solvent was rotary-evaporated to dryness. The resultant substance was recrystallized with ethyl acetate to give 1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene (8.567 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1nccnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C
Temperature: 80 °C
Yield: 73 %

Procedure:
In a 2-L flask, 3-methylpyrazine-2-carboxylic acid (Matrix, 19.95 g, 144 mmol) was suspended in MeOH (500 mL). The suspension was cooled in an ice-water bath, and concentrated sulfuric acid (Fluka, 27.3 mL, 506 mmol) was added over a time period of 5 min. The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM (750 mL). The excess acid was neutralized carefully with aqueous NaOH (5M, 200 mL). The aqueous layer was separated and extracted with DCM (250 mL). The combined organic layers were combined, dried over MgSO4 and concentrated to afford the title compound (16.15 g, 106 mmol, 73%). MS m/z=153 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:25][C@@H:26]2[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1CCc1ccccc1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(Cl)cc1CCc1ccccc1
Yield: 29 %

Procedure:
500 mg of 4-chloro-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 270 mg of potassium t-butoxide and 520 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 260 mg (yield 29%) of the title compound as an oily substance.