Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(#N)C>[C:41]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:42])[NH2:40]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(C(N)=O)C1
Reaction time: 4 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) in acetonitrile (1 mL) was added Et3N (79 μL, 0.79 mmol) followed by 85% trimethylsilyl isocyanate (125 μL, 0.784 mmol). After 4 hours, the cloudy mixture was filtered and attempts to crystallize the solid proved unsuccessful. The solid and filtrate was combined and diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[C:12]#[C:11][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C#Cc2cccnc2)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.0 g (3.7 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 494 g (4.79 mmol) 3-ethynylpyridine, 70 mg (0.37 mmol) CuI, 259 mg (0.37 mmol) PdCl2(PPh3)2 and 85 mL triethylamine in 60 mL dry DMF. Yield after purification by chromatography on silica gel: 800 mg (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:48]2[CH2:50][CH2:49]2)[C:36](=[O:47])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N+:44]([O-])=O)[CH:39]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:36](=[O:47])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[CH:39]=2)[CH:48]2[CH2:49][CH2:50]2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc([N+](=O)[O-])c2)C2CC2)C(C)C)ccc1OC
Agent: [Ni]
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc(N)c2)C2CC2)C(C)C)ccc1OC

Procedure:
At RT H2 is passed through a suspension of (3R*,4R*)-3-({cyclopropyl-[2-(3-nitro-phenyl)-acetyl]-amino}-methyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (660 mg, 0.95 mmol) and Raney-Ni (100 mg) for several hours. After completion of the reaction the mixture is filtered over Celite and the solvent is evaporated to give the title compound which is used without further purification. MS (LC-MS): 667.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.33 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ncc(Br)cn2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxetan-3-one (0.452 mL, 7.72 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water and brine, then dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure. The resulting crude brown oily solid was absorbed onto a 25 g KP-Sil Biotage column with minimal DCM, and eluted using a Biotage Isolera 4 with 10-100% ethyl acetate in heptanes, to afford the title compound (687 mg, 42%) as a crystalline yellow solid. δH (500 MHz, DMSO-d6) 9.07 (s, 2H), 6.43 (s, 1H), 4.94 (d, J 6.5 Hz, 2H), 4.67 (d, J 6.5 Hz, 2H).
Reaction SMILES: CO[C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[N:15][C:5]=2[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:30]([NH2:31])=[CH:29][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H-].[Na+].O>CN(C)C=O>[N:22]1([C:25]2[C:30]([NH:31][C:3]3[C:4]4[CH:18]=[CH:17][CH:16]=[N:15][C:5]=4[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:8]=3)=[CH:29][C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:27][N:26]=2)[CH2:21][CH2:20][O:19][CH2:24][CH2:23]1
Reactant: COc1nc(-c2ccccn2)nc2ncccc12
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c3cccnc3n2)nc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-methoxy-2-(pyridin-2-yl)pyrido[2,3-d]pyrimidine (0.050 g, 0.21 mmol) and 2,5-dimorpholinopyridin-3-amine (0.061 g, 0.23 mmol) in N,N-dimethylformamide (2.0 mL) was added 60% sodium hydride (9.23 mg, 0.23 mmol). The reaction was heated to 60° C. Stirring continued overnight. The reaction was cooled to rt and water was added to quench. The reaction was extracted with EtOAc (3×10 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 to 30% MeOH in DCM) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-2-(2-pyridinyl)pyrido[2,3-d]pyrimidin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 9.75 (1H, d, J=2.7 Hz), 9.36 (1H, br. s.), 9.23 (1H, dd, J=4.4, 1.7 Hz), 8.87 (1H, d, J=8.0 Hz), 8.70 (1H, m), 8.30 (1H, dd, J=8.2, 1.8 Hz), 7.91 (1H, m), 7.84 (1H, d, J=2.7 Hz), 7.62 (1H, dd, J=8.2, 4.3 Hz), 7.42-7.49 (1H, m), 3.94-4.04 (8H, m), 3.43-3.55 (4H, br m), 3.09 (4H, br. m.). Mass Spectrum (ESI) m/e=471.3 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3C)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M240) (416 mg, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (246 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:10]=2[C:11]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][CH3:23])[N:16]=[CH:15]2.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][CH3:23])[N:16]=[CH:15]2
Reactant: CNc1ncc2cc(-c3c(C)cnc4c(=O)[nH]ccc34)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CNc1ncc2cc(-c3c(C)cnc4c(Cl)nccc34)ccc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one (0.400 g, 1.26 mmol) and phosphorous oxychloride (5.00 ml, 1.26 mmol) was heated to 100° C. After 3 hours, the volatiles were removed under vacuum. Residual phosphorous oxychloride was azeotroped with toluene. The resulting residue was dissolved in chloroform and washed with cold water. The organic layer was then washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50 to 100% EtOAc in hexanes to give 6-(8-chloro-3-methyl-1,7-naphthyridin-4-yl)-N-methylquinazolin-2-amine as a yellow solid. MS (M+H)+ 336.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Na].Cl[CH2:11][C:12]1[N:16]=[C:15]([CH2:17]Cl)[O:14][N:13]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]2[N:16]=[C:15]([CH2:17][S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCc1noc(CCl)n1
Reactant: Sc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: Brc1ccc(SCc2noc(CSc3ccc(Br)cc3)n2)cc1

Procedure:
4-Bromobenzenethiol (3.78 g, 0.02 mol) was added to a solution of sodium (0.46 g, 0.02 mol) in ethanol (50 ml.) and 3,5-di-(chloromethyl)-1,2,4-oxadiazole (1.67 g, 0.01 mol) was added dropwise. The solution was then filtered and evaporated to give a solid which was recrystallised from isopropanol to give 3,5-di-(4-bromophenylthiomethyl)-1,2,4-oxadiazole, m.p. 80°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[CH3:22]>CO>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Solvent: CO
Product: Cc1c(NCCNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
3.4 g. Phenyl glycidyl ether and 9.6 g. 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione are stirred for about 24 hours at 70° C. The reaction mixture is dissolved in methanol and then separated by column chromatography, using a weakly acidic cation exchanger ("Amberlite" CG 50 II pract. (Serva)). The column is pre-treated with about 1.5 liters 0.1 M methanolic triethylammonium acetate solution. The elution agent used is 0.1 M methanolic triethylammonium acetate solution. The fractions containing the pure substance are evaporated, then rendered alkaline with 2 N aqueous sodium hydroxide solution, extracted with methylene chloride and the extracts dried and evaporated. The light colored oil obtained becomes crystalline upon triturating with diethyl ether. After recrystallized from ethyl acetate, there are obtained 3.6 g. (44% of theory) of the desired product in the form of colorless crystals: m.p. 104°-106° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][OH:13].[I:14]I>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([I:14])[C:3]=1[CH2:12][OH:13]
Reactant: II
Reactant: OCc1ccc2ccccc2c1Br
Solvent: ClC(Cl)(Cl)Cl
Product: OCc1c(I)cc2ccccc2c1Br
Yield: 26.1 %

Procedure:
A suspension of thalium trifluoro acetate (1.37 g, 2.53 mmole) in anhydrous CCl4 containing 24 (0.5 g, 2.1095 mmole) was refluxed under argon. Iodine (0.535 g, 2.1095 mmole) was added dropwise in a solution of CCl4 (10 ml). The mixture was refluxed for another 60 min. The reaction was cooled and quenched with 10% solution of sodium thiosulfate and then extracted with 3×50 ml of methylene chloride. The combined methylene chloride fractions were thoroughly washed several times with H2O, brine, dried with anhydrous magnesium sulfate, and evaporated in vacuo to give a dark brown thick oil. The crude dark brown oil was purified by chromatography (hexane/ ethyl acetate; 80:20) to afford 0.2 g of 25 (7%) as a light cream solid. A single component was detected by TLC (hexane/ethyl acetate; 80:20) Rf, 0.5; NMR (CDCl3). δ4.8-5 (2H, d, CH2 --OH), d 7.4-8.4 (m, 5H, naphthyl). MS (HRFAB) (M+Li)+ calcd for C11H8OBrI, 368.8963 found 368.8978.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1>O>[F:3][C:4]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(Oc2ccc(Br)cc2)c1
Reaction time: 18 h
Yield: 45 %

Procedure:
The reaction is performed in a 1 L 3-necked flask equipped with a mechanical stirrer, a Dean-Stark trap topped with a condenser and a nitrogen bubbler, and a stopper. The flask is flushed with nitrogen and charged firstly with potassium hydroxide (22.4 g, 0.4 mol), α,α,α-trifluoro-m-cresol (64.8 g, 0.4 mol), and toluene (500 mL). The mixture is stirred and heated at reflux for 2 h, during which water collected in the trap (ca. 6 mL). 1,4-Dibromobenzene (94.4 g, 0.42 mol) and cuprous chloride (39.6 g, 0.4 mol) are added, and heating a reflux is continued for another 18 h. The reaction mixture is analyzed by capillary GC which shows ca.45% of the title product along with ca.10% of the dialkylation product, with the rest being starting materials. The mixture is filtered with the aid of ether (200 mL), and washed successively with 2×100 mL portions of 5% HCl (to remove any residual copper impurities), water, and brine. It is then dried (MgSO4) and concentrated on the rotary evaporator to a red oily residue. TLC (silica gel) shows four components (Rf =0.00, 0.15, 0.35, 0.70, CH2Cl2). Fractional distillation afforded 42.9 g (34%) of the title compound, distilling at 112-116° C. @ 1 mm. Also obtained was 12.1 g (10.5%) of the dialkylation product, distilling at 160-165° C. @ 1 mm.
Reaction SMILES: C([O:8][CH2:9][C:10]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:19][CH:18]=2)=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:13]=[C:12]([CH3:37])[N:11]=1)C1C=CC=CC=1>CCO.[Pd]>[CH2:33]([C:14]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:19][CH:18]=2)=[C:10]([CH2:9][OH:8])[N:11]=[C:12]([CH3:37])[N:13]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C)nc(COCc2ccccc2)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc(C)nc(CO)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 92.9 %

Procedure:
A solution containing 0.5 g of 4-benzyloxymethyl-6-butyl -2-methyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) methyl]pyrimidine in 50 ml of EtOH was hydrogenated in presence of 0.1 g of 10% palladium on charcoal at atmospheric pressure and room temperature. After the theoretical hydrogen absorption the reaction mixture was filtered on Celite® and the solvent was evaporated obtaining 0.38 g of a clear oil, which was directly used without further purification (yield 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2[nH]nc(C)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (28.5 g), 3,4-dihydro-2H-pyran (23.7 mL) and p-toluenesulfonic acid monohydrate (6.8 g) in THF (800 mL) was stirred at r.t. until the reaction was complete. The mixture was poured into water (1.5 l) and extracted with ethyle acetate (600 mL). The organic phase was dried over magnesium sulfate and concentrated in a vacuo. The crude product was purified by silica gel chromatography (heptane/ethyl acetate gradient). 37.8 g (98%) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:10]2[C:11](Cl)=[N:12][CH:13]=[N:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[OH:9])=[C:6]([C:21]([F:24])([F:23])[F:22])[N:5]=[CH:4][N:3]=1.[O-2].[Mg+2].[H][H]>CO.[Pd]>[F:24][C:21]([F:22])([F:23])[C:6]1[C:7]([CH:8]([C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[N:14][CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:2][N:3]=[CH:4][N:5]=1
Reactant: [H][H]
Reactant: OC(c1c(Cl)ncnc1C(F)(F)F)c1c(Cl)ncnc1C(F)(F)F
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: OC(c1cncnc1C(F)(F)F)c1cncnc1C(F)(F)F
Yield: 87.6 %

Procedure:
To a solution of 0.44 g of 1,1-bis-(4-chloro-6-trifluoromethylpyrimid-5-yl)methanol in 4.0 ml methanol were added 0.246 g magnesium oxide and 66 mg of 10% Pd/C (50% wet, Degussa). The mixture was then shaken on a Parr hydrogenation apparatus for 6 hours under 50 psi of hydrogen. The palladium catalyst and excess magnesium oxide were removed by filtration through dicalite, and the methanol filtrate was concentrated in vacuo to afford 318 mg of 1,1-bis-(4-trifluoromethylpyrimid-5-yl)methanol as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]O)[CH2:14][C:13]=2[CH:12]=[C:11]([F:20])[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:40]([C:47](OCC)=O)=NC(OCC)=O.OC(C)(C)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][CH2:47][NH2:40])[CH2:14][C:13]=2[CH:12]=[C:11]([F:20])[CH:10]=1
Reactant: OCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Yield: 17.1 %

Procedure:
Treatment of (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.9 mmol) with triphenylphosphine (1.23 g, 4.67 mmol), diethyl azodicarboxylate (0.82 g, 4.68 mmol), and 2-hydroxy-2-methylpropanenitrile (0.40 g, 4.68 mmol) generally according to the procedure described for Example 552 afforded 0.106 g (15%) of (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 212-213° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[I:22]C1C=CC(C=O)=CC=1>>[I:22][C:7]1[CH:6]=[CH:5][C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Reactant: O=Cc1ccc(I)cc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(I)cc2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 4-iodobenzaldehyde in place of 3-iodobenzaldehyde. Solid (12.7 g, 57%);
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:31])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=429.03.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.CON(C)[C:25](=[O:29])[CH2:26][CH2:27][CH3:28].O>C1COCC1.CCCCCC>[C:9]1([C:7]2[O:8][C:4]3[CH:3]=[C:2]([C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:16]=[CH:15][C:5]=3[N:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
10.00 g (36.48 mmol) 6-bromo-2-phenyl-benzoxazole are dissolved in 180 ml THF and cooled to −70° C., and 35.00 ml (56.00 mmol) n-butyl lithium 1.6M in hexane are added dropwise. This solution cooled to −70° C. is added dropwise after 20 min to an equally cold −70° C. solution of 2.5 g (19.1 mmol) N-methoxy-N-methyl-butyramide and 20 ml THF. After 20 min further stirring the mixture is mixed with water and allowed to come up to RT. The reaction mixture is extracted with water and DCM, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([O:21][C:33](=[O:34])[CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:16]1
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1C2CCC3C4CC=C5CC(OC(=O)Cc6ccc(F)cc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of compound 130A (20 mg, 0.06 mmol), 4-fluorophenylacetic acid (14 mg, 0.09 mmol), 1,3-dicyclohexylcarbodiimide (25 mg, 0.12 mmol), 4(dimethylamino) pyridine (2 mg, 0.016 mmol) and THF (1 mL) was stirred at room temperature overnight. The crude reaction mixture was loaded directly onto silica gel column and eluted with 0.2% ammonium hydroxide and 2% methanol in dichloromethane to give the pure desired product (25 mg, 87% yield).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[C:29](O)(=[O:31])[CH3:30]>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 92%), MS (ISP) m/z=385.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and acetic acid.