Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:18]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:11]1[S:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][C:34]([S:37]([NH2:39])=[O:38])([CH3:36])[CH3:35]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Si:1]([O:8][CH2:9][CH:10]([N:18]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])[C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[N:39]/[S:37]([C:34]([CH3:36])([CH3:35])[CH3:33])=[O:38])[CH:15]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(C=O)cs1)S(=O)(=O)c1ccccc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(/C=N/S(=O)C(C)(C)C)cs1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-formylthiophen-2-yl)ethyl]-N-(3-methylbutyl)benzenesulfonamide (125 mg, 0.252 mmol) was dissolved in 0.84 mL THF. Titanium(IV) ethoxide (106 μl, 0.504 mmol) and 2-methylpropane-2-sulfinamide (36.7 mg, 0.303 mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was then poured into an equal volume of brine and filtered thru Celite and then washed with EtOAc.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br.[OH-].[K+]>CS(C)=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A mixture of ethyl acetoacetate (13.0 g, 99.9 mmol), 1,2-dibromoethane (13 mL, 151 mmol) and potassium hydroxide (14.0 g, 250 mmol) in dimethylsulfoxide (130 mL) was stirred at ambient temperature overnight. The mixture was poured into ice water and extracted with diethyl ether. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 16.22 g of an oily material, which was purified by column chromatography (silica gel 80 g, 20% ethyl acetate in n-hexane) to give 12.97 g (83.1%) of 1, as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][C:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:3]1.[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:5]1[C:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:3][N:2]([CH3:1])[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1cc(-c2cccs2)nn1C
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(I)c(-c2cccs2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 1-methyl-5-propyl-3-(2-thienyl)-1H-pyrazole (2.5 mmol) in 7 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (2.6 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 720 mg of 4-iodo-1-methyl-5-propyl-3-(2-thienyl)-1H-pyrazole (88% yield) that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[1-(4-acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in methanol (10 mL) was added sodium tetrahydroboron (0.11 g), and the mixture was stirred at 0° C. for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.02 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1O.C(=O)([O-])[O-].[K+].[K+].ClCC([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=O.ClC1C=CC=C(F)C=1OCC(NC1C=CC(C)=CC=1)=O.C[O-].[Na+]>CC(O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Oc1c(F)cccc1Cl
Reactant: Cc1ccc(NC(=O)CCl)cc1
Agent: C[O-]
Agent: Cc1ccc(NC(=O)COc2c(F)cccc2Cl)cc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(C)O
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reaction time: 2 h

Procedure:
14.65 g (100 mmol) of 2-chloro-6-fluorophenol are dissolved in 50 ml of 2-propanol followed by the addition of 15.5 g (112 mmol) of potassium carbonate and 18.9 g (103 mmol) of 2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4 hours. At this time, the formation of 2-(2′-chloro-6′-fluorophenoxy)-N-(4-methylphenyl)acetamide is completed. 20 ml of sodium methylate solution 30% in methanol are slowly added. To maintain a temperature of at least 75° C., about 25 ml of solvent are distilled during the addition. The mixture is boiled 2 hours more to complete the formation of (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][CH3:24])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([NH2:29])=[O:28].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl>C(Cl)Cl>[C:27]([C@@H:26]1[CH2:30][CH2:31][CH2:32][N:25]1[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][CH3:24])=[O:16])(=[O:28])[NH2:29]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.7 %

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-5-((S)-2-methoxymethyl-pyrrolidin-1-yl)-5-oxo-pentanoic acid (0.34 g, 1 mmol), L-prolinamide (0.11 g, 1 mmol), and HOBt hydrate (0.14 g, 1 mmol) in CH2Cl2 (5 mL) was added EDC (0.19 g, 1 mmol). The reaction mixture was stirred at ambient temperature for 12 h, diluted with CH2Cl2 (20 mL), washed sequentially with saturated aqueous sodium bicarbonate (10 mL), 0.5 N aqueous citric acid (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude a viscous oil. The crude oil was purified by flash chromatography (silica gel, 2 to 8% CH3OH/CH2Cl2 gradient) to give the title compound (0.36 g, 81%) as a foamy solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=3[CH3:27])[C:32]([OH:34])=[O:33])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 150 °C
Yield: 99.5 %

Procedure:
To the solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (191 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (197 mg, 0.75 mmol), K2CO3 (415 mg, 3.0 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.025 mmol). The reaction mixture was heated to 150° C. for about 15 minutes with microwave. The reaction mixture was concentrated to dry then was added DMSO (2 mL), water (0.5 mL) and HOAc (1 drop). The solution was filtered and applied to the reverse phase HPLC to afford the titled compound 0.24 g (quantitative). LC-MS m/z 483 (M+H)+; 1H-NMR (CD3OD) 2.36 (s, 3 H), 2.76 (s, 6H), 3.16 (s, 2 H), 3.56 (s, 2 H), 4.13 (s, 2 H), 7.21 (m, 1 H), 7.53 (m, 2 H), 7.95 (s, 1 H), 8.09 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [OH:1][C@H:2]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C@H:3]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH3:17])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C1COCC1.[Pd]>[OH:1][C@H:2]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C@H:3]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH3:17])[C:4]([OH:6])=[O:5]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of (2S,3R)-benzyl 3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholino acetamido)propanamido)propanoate (2.0 g, 4.0 mmol) in THF (40 mL) was added Pd/C (500 mg, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was washed with EtOAc (10 mL) to afford (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (1.30 g, 78% yield) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][OH:18].Cl.C(O)(=O)C>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][OH:18])[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)C[N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[N+](=O)[O-])=NO)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-methanesulfonyl-phenyl)-2-nitro-ethanone (12.5 g, 51.4 mmol) in ethanol (100 mL), was added NH2OH.HCl (3.57 g, 51.4 mmol) and acetic acid (33 mL) at room temperature. The reaction was refluxed for 3 h and cooled to room temperature. The reaction was concentrated under vacuum and extracted with ethyl acetate (200 mL). The reaction was concentrated to afford the crude compound which was recrystallized from petroleum ether/hexane (1/3) as white crystals (10.3 g, 83.4%). 1H NMR (400 Mz, DMSO-d6) δ 12.81 (s, 1H), 8.03 (m, 4H), 5.93 (s, 2H), 3.28 (s, 3H). LCMS 259.2[M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20]O.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1c(-c2cc(CO)c(Cl)cc2F)nn(C)c1C(F)(F)F
Solvent: CCOCC
Product: Cc1c(-c2cc(CBr)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 7.0 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol in 200 mL of diethyl ether was added 30 mL of phosphorus tribromide and the mixture allowed to stir overnight. The reaction mixture was poured into ice water, the ether removed by concd in vacuo and the resultant solid collected by filtration. The solid was washed with water and air dried to give a quantitative yield of 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole: 1HNMR CDCl3) δ2.17 (t. 3H, 2.0 Hz), 4.07 (s, 3H), 4.64 (s, 2H), 7.30 (d, 1H, 9.5 Hz), 7.62 (d, 1H, 7.5 Hz); 19FNMR CDCl3) δ-58.5 (s, 3F), -111.6 (s, 1F).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCN)cc1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.1 g (67%) of the titled product as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][CH:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[NH:26][CH:27]([CH3:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(NC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 25 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and concentrated. The residue was trituated with ether to afford a white crystalline substance which was further purified by flash chromatography(SiO2) using heptane/ethyl acetate (1:1) to yield 85 mg(25%) of the title compound. Mp 80-82 ° C. 1H NMR (200 MHz, CDCl3): δ=0.90 (s, 9H), 1.02 (d, 3H), 3.02 (m, 1H), 7.27 (s, 2H), 7.47 (d, 2H), 7.51 (d,2H), 7.81 (d, 2H);
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH:29]1([C:32]2[N:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:29]1([C:32]2[N:37]=[CH:36][C:35]([CH2:38][N:15]=[N+:16]=[N-:17])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C2CC2)nc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccc(C2CC2)nc1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Diphenylphosphoryl azide (0.49 ml, 2.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 ml, 2.3 mmol) were added dropwise in that order at room temperature to a solution of (6-cyclopropyl-3-pyridyl)methanol (283 mg, 1.90 mmol) in toluene (4 ml) and the mixture was stirred for 3 hours. After confirming completion of the reaction by thin layer chromatography, it was diluted with ethyl acetate and washed with water and brine. Drying was performed with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (330 mg, quant.) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:39])([F:38])[F:37])=[CH:23][CH:22]=1>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[C:36]([F:37])([F:38])[F:39])=[CH:25][CH:26]=2)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: COc1ccc(Nc2ccc(CN)cc2)c(C(F)(F)F)c1
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)cc2)c(C(F)(F)F)c1
Yield: 32 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (1.00 mmol) was reacted with (4-aminomethyl-phenyl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (1.00 mMol, from Example 4b)). The product was obtained in a yield of 32% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: Nc1ccc(-n2cccn2)c(C(F)(F)F)c1

Procedure:
The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and pyrazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 228 (M+H)+; analytical HPLC: tret=4.58 minutes (Grad 2).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][C:10]([C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[C:9]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:8]=2)[CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O.C(OC(C)C)(C)C>C(Cl)(Cl)Cl>[C:31]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][C:10]([C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[C:9]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:8]=2)[CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 72.8 %

Procedure:
In 1 ml of chloroform was dissolved 100 mg of ethyl 2-[6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 26 mg of acetic anhydride was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, the reaction mixture was added to a mixture of 1 ml of water and 1 ml of chloroform, and the organic layer was separated, washed successively with 1 ml of water and 1 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 0.5 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 80 mg (yield 72.8%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 19.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([CH:17]=O)[N:13]3[CH3:16])=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:30]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:16][N:13]1[C:12]([CH2:17][N:29]2[CH2:32][CH:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:30]2)=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:6]1[C:5]3[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=3[N:3]=[C:2]1[CH3:1])=[N:8][C:9]=2[N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.075 g, 0.20 mmol), 2-azetidin-3-ylpropan-2-ol (0.023 g, 0.20 mmol) in DCE (2 mL), trimethoxymethane (0.215 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (0.042 g, 0.2 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, and the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 315 as an off-white solid (0.020 g, 23%). LCMS (Method G): RT=5.61 min, [M+H]+ 477.2. 1H NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 1 H); 7.72-7.69 (m, 1 H); 7.35-7.26 (m, 2 H); 4.42-4.31 (m, 4 H); 3.89-3.82 (m, 11 H); 3.62-3.12 (m, 2H); 2.94 (s, 3 H); 2.70-2.55 (m, 1 H); 1.18 (s, 6 H)
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][OH:13])=[N:9][CH:10]=1)[CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)Cl>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCc1ccc(CCO)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114 %

Procedure:
To a solution of sodium hydroxide (5 g) in water (30 ml), were added methylene chloride (100 ml), 5-ethyl-2-pyridineethanol (15 g) and benzyltributylammonium chloride (50% aqueous solution, 6 g), p-toluenesulfonyl chloride (23 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added p-hydroxybenzaldehyde (12 g), water (100 ml) and sodium hydroxide (8 g) and the mixture was stirred at 40°-50° C. for 12 hours. The reaction mixture was separated into two phases and the methylene chloride layer was dried (MgSO4) and concentrated to give 28.6 g of crude 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. This oil was purified by silica gel chromatography to give 15.8 g (62%) of pure 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil.