Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH:17]1([OH:23])[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29](O)[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[C:27]([CH:26]=1)[O:22][CH:19]1[CH2:20][CH2:21][CH:17]([OH:23])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1CCC(O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC(O)C1
Temperature: 25 °C

Procedure:
Di-tert-butyl azodicarboxylate was added at 0° C. to a mixture of 1,3-cyclopentandiol (1.02 g), 5-fluoro-2-nitrophenol (0.79 g) and triphenylphosphine (1.97 g) in THF (15.0 ml). After stirring at room temperature over weekend the mixture was treated with 2 M aq. HCl (20.0 ml) and refluxed for 30 min. The reaction mixture was diluted with methylene chloride. The layers were separated. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The crude was purified by chromatography to yield the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[N:7]=2)[CH:3]=[N:2]1.[CH:21]1([CH:24]=[CH:25][C:26]#[N:27])[CH2:23][CH2:22]1.CN(C=O)C.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[CH:21]1([CH:24]([N:2]2[CH:3]=[C:4]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[CH:9]=[C:8]([C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[N:7]=3)[CH:5]=[N:1]2)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22]1
Reactant: Cc1nnc(-c2cc3nccn3c(-c3cn[nH]c3)n2)s1
Reactant: N#CC=CC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)s1
Temperature: 25 °C
Reaction time: 40 h
Yield: 31.2 %

Procedure:
In a 20 mL flask, 2-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)-5-methyl-1,3,4-thiadiazole (17.4 mg, 0.0614 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 17.2 mg, 0.184 mmol) were dissolved in DMF (614 μL, 0.0614 mmol). To this was added DBU (23.0 μA, 0.154 mmol) and stirred at ambient temperature for 40 h. The reaction was incomplete, so another portion of DBU (23.0 μA, 0.154 mmol) and 3-cyclopropylacrylonitrile (17.2 mg, 0.184 mmol) were added. After 4 hours, the reaction mixture was diluted in EtOAc, and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to a yellow oil. The crude material was purified by silica chromatography using a 0-10% MeOH/EtOAc gradient to afford 3-cyclopropyl-3-(4-(7-(5-methyl-1,3,4-thiadiazol-2-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (7.2 mg, 31% yield). MS (apci) m/z=377.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 116.5 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)aniline (1.0 g, 4.85 mmol) in CH2Cl2 (15 mL) and TEA (2.95 g, 4.1 mL, 29.11 mmol) in a round-bottom flask at 0° C. was added trimethylacetyl chloride (1.75 g, 1.8 mL, 14.55 mmol) dropwise. The reaction mixture was warmed to room temperature and was quenched by pouring into water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel column chromatography using (0-100% EtOAc/Hex.) to obtain N-(4-nitro-3-(trifluoromethyl)phenyl)pivalamide (1.64 g, 81%). LC/MS: m/z 291.1 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:11]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][N:5]=3)=[N:17][CH:16]=[CH:15][CH:14]=2)=[O:13])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.24 g), 4-benzyl-4-hydroxypiperidine (0.20 g), HATU (0.50 g) and triethylamine (0.74 mL) in DMF (6 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.085 g).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:24]=C([Mg]Br)[CH:26]=[CH:27][CH:28]=1.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccc(F)c1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (23.45 g, 104 mmol) in abs. THF (100 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of 3-fluorophenylmagnesium bromide in THF (208 ml, 208 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[N:7]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:13][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:12])=[N:9][CH:10]=1
Reactant: Nc1nccc(-c2ccco2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Br)c(-c2ccco2)n1
Reaction time: 6 h
Yield: 83.6 %

Procedure:
To a solution of 4-(2-furyl)-2-pyrimidinylamine (4.10 g, 25.4 mmol) in N,N-dimethylformamide (40 ml) was added N-bromosuccinimide (4.53 g, 25.5 mmol) at 2° C., followed by stirring as it was. After 6 hours, the reaction mixture was diluted with an aqueous saturated sodium bicarbonate solution (240 ml). The mixture was ice-cooled, and then the crystals were collected by filtration and washed with water, to give the title compound (5.10 g, 84%) as a pale brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=2)OC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1
Reactant: Cc1cncc(B2OCC(C)(C)CO2)c1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1
Temperature: 70 °C
Yield: 35 %

Procedure:
To a mixture of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150 mg, 0.42 mmol) and 3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5-methylpyridine in 1,4-dioxane (5 ml) was added a solution of caesium carbonate (340 mg, 1.04 mmol) in water (0.5 ml). The reaction was degassed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) was added and the mixture heated at 70° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous phase was re-extracted with dichloromethane and the combined organic layers dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified using a short silica gel column eluting with 2% diethyl ether in dichloromethane followed by 15% diethyl ether in dichloromethane to give a yellow solid. This was purified further by loading as a solution in methanol onto a cartridge of strong cation-exchange resin, eluting with methanol then with 2M ammonia in methanol. The basic fractions were concentrated in vacuo to give a dark cream solid. The solid was triturated with diethyl ether to give 3-[4-fluoro-3-(5-methylpyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid (55 mg, 35%): δH (360 MHz, d6-DMSO) 2.39 (3H, s), 7.51 (1H, d, J 7), 7.60 (1H, dd, J 11 and 9), 7.85 (1H, ddd, J 9, 5 and 2), 7.91-7.94 (1H, m), 8.00 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.49 (2H, d, J 2), 8.68-8.71 (1H, m), 9.36 (1H, d, J 7); m/z (ES+) 373 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1C=O
Reactant: Nc1cccnc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1CNc1cccnc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.4 %

Procedure:
Molecular Sieves (16 g) was added to a solution of 2,3-diaminopyridine (8 g), 2-methylbenzaldehyde (8.81 g), and acetic acid (4.2 ml) in methanol (160 ml) and the mixture was stirred for 96 hours at room temperature. Sodium cyanoborohydride (4.61 g) was added portionwise to the mixture with stirring under ice-cooling over a period of 20 minutes. After being stirred for 3 hours, the mixture was made alkaline with aqueous sodium bicarbonate solution and filtered by suction. The filtrate was evaporated in vacuo, and to the residue was added water and then extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-amino-3-(2-methylbenzylamino)pyridine (5.38 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.030 mL (0.36 mmol) of 2-pyridine carboxaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. A recrystallization in isopropanol gives 0.042 g (35%) of pure product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].N1C=CNC1=[O:16].COC1C=C(CC[N:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[C:30]2=[O:46])C=CC=1OC.[CH2:47]([C:51](C)=O)[CH:48](C)[CH3:49].O>CN(C=O)C>[CH:45]1([O:44][C:38]2[CH:37]=[C:36]([C:35](=[O:16])[CH2:34][N:31]3[CH:32]=[CH:33][NH:29][C:30]3=[O:46])[CH:41]=[CH:40][C:39]=2[O:42][CH3:43])[CH2:49][CH2:48][CH2:47][CH2:51]1
Reactant: O=c1[nH]cc[nH]1
Reactant: CC(=O)CC(C)C
Reactant: COc1ccc(CCN2CCN(CCc3ccc(OC)c(OC)c3)C2=O)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cn2cc[nH]c2=O)cc1OC1CCCC1
Reaction time: 2 h
Yield: 12.6 %

Procedure:
Sodium bis(trimethylsilyl)amide (5 ml) was added to a solution of 1,3-dihydro-2H-imidazol-2-one (0.84 g) in DMF (50 ml), stirred under a N2 flow and cooled in an ice-bath. The reaction mixture was stirred for 30 minutes. Intermediate 1 (2.69 g) was added portionwise and the resulting reaction mixture was stirred for 16 hours at RT, then for 2 hours at 50° C. The reaction mixture was stirred in methyl isobutyl ketone/water (200 ml/50 ml). The solvent was evaporated and methyl isobutyl ketone (100 ml) was added and azeotroped on the rotary evaporator. The mixture was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 97/3). The desired fractions were collected and the solvent was evaporated. The white solid was stirred in diisopropyl ether, filtered off, washed with DIPE and dried, yielding 0.4 g (12.6%) of 1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-ethyl]-1,3-dihydro-2H-imidazol-2-one (interm. 2; mp. 201.1° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:25][S:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([CH2:25][S:26][C:27]2[NH:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CN(CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCCN(CC(=O)O)Cc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-((3-Methyl-4-(2-(N-benzyl-N-ethoxycarbonylmethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (1.0 g) was dissolved in ethanol (10 ml) and thereto was added an aqueous solution (3 ml) of 1N sodium hydroxide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and adjusted to pH 4 with an aqueous solution of dilute acetic acid. The resultant crystals were collected by filtration to give 2-((3-methyl-4-(2-(N-benzyl-N-carboxymethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[N:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:41][C:42]=2[CH3:43])=[CH:31][CH:30]=1)([C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([O:3][C:4]([CH2:6][C:7]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[N:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:41][C:42]=2[CH3:43])=[CH:31][CH:30]=1)([C:18]([OH:20])=[O:19])[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
Dibenzyl 2-ethoxycarbonylmethyl-2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (29.5 g, 44.6 mmol) obtained in Example 9 was dissolved in methanol (150 ml) and tetrahydrofuran (150 ml), and 5% palladium carbon (2.0 g) was added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere (3.3-3.4 atm) for 6 hr. After stirring, the catalyst was removed with celite and the solvent was evaporated to give the title compound (21.0 g, yield 98%) as an orange-yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:22][C:23]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:22][C:23]1([F:29])[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25][CH2:24]1
Reactant: FC1(F)CCNCC1
Reactant: Nc1nnc(Cl)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nnc(N2CCC(F)(F)CC2)c(-c2ccccc2)n1
Yield: 13.9 %

Procedure:
6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 14%) was prepared from 6-chloro-5-phenyl-1,2,4-triazin-3-amine (0.20 g, 0.96 mmol), K2CO3 (0.23 g, 1.67 mmol) and 4,4-difluoropiperidine hydrochloride (0.22 g, 1.45 mmol) according to the general procedure of Example 2.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:33]1[N:38]=[C:37]([CH2:39][NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])[CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.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.CO>[CH:50]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([CH:47]([CH3:49])[CH3:48])[C:41]=1[NH:40][CH2:39][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][C:10]2[CH:28]=[CH:29][CH:30]=[CH:31][C:9]=2[CH3:8])[N:38]=1)([CH3:52])[CH3:51]
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1NCc1ccccc1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 4.00 g (14 mmol) of Na2CO3×10H2O, 60 ml of water and 20 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 1.82 g (5.6 mmol) of 2-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]aniline, 1.95 g (6.7 mmol) of N-[(6-Bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 0.32 g (0.28 mmol) of Pd(PPh3)4 in 75 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was re-crystallized from 15 ml of diethyl ether. Yield 1.79 g (69%) of white crystalline powder. Anal. calc. for C32H37N3: C, 82.89; H, 8.04; N, 9.04. Found: C, 82.68; H, 7.98; N, 8.80. 1H NMR (CDCl3): δ 7.70 (m, 1H), 7.49-7.55 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.37-7.40 (m, 2H), 7.28 (m, 1H), 6.99-7.11 (m, 5H), 6.60 (m, 1H), 6.55 (m, 1H), 4.48 (d, J=4.6 Hz, 2H), 4.21 (s, 2H), 4.07 (br.s, 1H), 3.98 (br.s, 1H), 3.33 (sept, J=6.8 Hz, 2H), 2.04 (s, 3H), 1.19 (d, J=6.8 Hz, 12H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]([NH2:26])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(N)=Nc1cccc(-c2ncccc2C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N-bis(tert-butoxycarbonyl)-N″-(3-(3-carboxypyridin-2-yl)phenyl)guanidine (220 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-carboxypyridin-2-yl)phenylguanidine dihydrochloride (144 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:19]=[CH:18][C:17]=1[NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:31][C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=3)=[CH:21][C:16]=2[F:15])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CSc1nccc(Oc2ccc(N)c(F)c2)n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)n1
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A solution of 162 mg (0.732 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 5 min. drop by drop at 0° C. to a solution of 184 mg (0.732 mmol) 2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and treated with 10 ml ether. Isolation of the precipitate gave 140 mg (40%) 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: [F:1][C:2]([F:12])([CH3:11])[CH:3](O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1COCC1>[F:1][C:2]([F:12])([CH3:11])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)C(C)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/C(C)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4,4-difluoro-3-hydroxy-pentanoate (3.39 g, 0.0186 mol) was dissolved in THF (20 ml). Diphenyl-2-pyridylphosphin (7.37 g, 0.028 mol) was added followed after five minutes by di-tertbutylazodicarboxylate (2.83 g, 0.028 mol). The mixture was stirred for one hour at room temperature and left standing overnight. The mixture was acidified with trifluoroacetic acid (2 ml) and stirred for one hour at room temperature. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 4N HCl. The phases were separated, the organic phase was washed with 1M HCl (4×), dried over magnesium sulfate and evaporated to dryness. After distillation at 2 mbar 5.99 g were obtained which still contained some solvent but were used directly in the next step.