Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1([F:29])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[F:29][C:13]1([CH2:12][NH:11][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH2:18]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(NCC1(F)CCN(C(=O)OCc2ccccc2)CC1)c1ccc(O)cc1

Procedure:
4-Hydroxy benzoic acid was coupled to benzyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate according to the procedure for EXAMPLE 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15]C(=O)OCC1C=CC=CC=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:15]
Reactant: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 99.6 %

Procedure:
Benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.00 g, 5.51 mmol) synthesized as described above, 5% Pd/C (100 mg) as a catalyst, and toluene (15 ml) as a solvent were charged into a 50 cc round-bottom flask, and the inside of the flask was replaced sufficiently with a hydrogen gas. Then, in a hydrogen gas atmosphere, the mixture was thoroughly stirred for 8 hours at 50° C. After completion of the reaction, the catalyst was separated by filtration, the resulting filtrate was dried with anhydrous magnesium sulfate. After separating the drying agent by filtration, the solvent was distilled off under reduced pressure from the filtrate to obtain quantitatively 2-fluoro-4-chloro-5cyclopentyloxyaniline (1.26 g) as a pale brown oily substance. The spectral data and the like are shown in Reference Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:13][S:12][CH2:11][CH:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)CSCC1=Cc1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN1N=C2C(=Cc3ccc(Cl)c(Cl)c3)CSCC2C1c1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 6.5g of tetrahydro-3,5-bis-[(3,4-dichlorophenyl)methylene]-4H-thiopyran-4-one and 1.1g of n-propyl hydrazine in 250ml of methanol/chloroform (1:1) is heated at reflux temperature for about 16 hours. The reaction mixture is allowed to cool slightly. Unreacted starting material precipitates out and is removed by filtration. The filtrate is concentrated in vacuo, added to chloroform and washed with dilute hydrochloric acid and water. The organic layer is dried with magnesium sulfate and concentrated in vacuo to 5g of a semi-solid material. This is applied to a wet-packed (hexane) neutral alumina column (Activity I) and eluted with 0-100% ether/hexane. Elution with 10-40% ether/hexane yields the product as an oil.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[C:13]([CH3:20])[CH:12]=1>C(OCC)(=O)C>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:3]2[S:4][CH:5]=[CH:6][N:7]=2)=[O:16])=[C:13]([CH3:20])[CH:12]=1
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Reactant: C[Si](C)(C)c1nccs1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1C(=O)c1nccs1
Temperature: 80 °C

Procedure:
2.0 g (13 mmol) of 2-trimethylsilylthiazole and 6.1 g (26 mmol) of 4-bromo-2-methyl-benzoic acid chloride are combined while cooling with an ice bath and then are heated to 80° C. for 3 hours. The crude product is taken up in 30 ml of ethyl acetate, washed with H2O, saturated NaHCO3 solution and H2O, dried and purified by flash chromatography (silica gel; methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH3:17]>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH2:17])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(N)c2cc1OC
Reaction time: 48 h

Procedure:
8.6 g of 2.4-Dichloro-6,7-dimethoxy quinazoline was dissolved in 300 ml of tetrahydrofuran and NH3 -gas was introduced to the solution. After saturated with NH3 -gas, the reaction mixture was allow to stand for 2 days and the solvent was removed. The resulting precipitate was collected by filtration and recrystallized from methanol. 2.8 g of desired compound was obtained. m.p. 248° C. (decomp.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:19]([F:22])([F:21])[F:20])=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH4+:23].[OH-]>CS(C)=O>[NH2:23][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([C:19]([F:20])([F:21])[F:22])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11]
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)/C=C(/c2ccc(Br)cc2)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)CC(N)(c2ccc(Br)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of Intermediate 3A (1.53 g, 4.14 mmol) in DMSO (23 mL) was added 15 N aq NH4OH (10 mL). The reaction vessel was sealed and the reaction was stirred at rt for 16 h. Additional DMSO (3 mL) and 15 N aq NH4OH (1 mL) were added and the reaction was stirred at rt for 16 h. Addition of DMSO (4 mL) was repeated and the reaction was stirred for another 16 h. The solution was concentrated in vacuo followed by lyophilization to provide Intermediate 3B (1.8 g, 100%) as a brown oil. LCMS Anal. Calc'd for C17H15BrF3NO 386.21, found [M+H] 388.1.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[CH:8]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:8]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]#[N:6])=[CH:20][CH:21]=1)=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(C=Cc2ccccc2)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: N#[N+]c1ccc(C=Cc2ccccc2)cc1
Temperature: -30 °C
Yield: 324.3 %

Procedure:
To a 25 mL round bottom in a drybox was added nitrosonium tetrafluoroborate (0.11 g, 0.95 mmol). Acetonitrile (2 mL) was added and the flask was cooled down to −30° C. A solution of 4-STYRYLPHENYLAMINE (0.17 g, 0.86 mmol) and BHT (0.19 g, 0.86 mmol) in acetonitrile (5 mL) was added dropwise via syringe. The reaction was allowed to warm to −5° C. over 20 min. Ether (10 mL) was then added and the precipitate was filtered. The title compound was purified by re-precipitating from acetonitrile (3 mL) with ether (15 mL) to yield 0.82 g (34%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:30]([CH3:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29](=[O:38])[NH:28][C:4]=2[N:5]=[C:6]([NH:8]/[N:9]=[C:10](/[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2Br)\[CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[N:7]=1>[Cu]I.CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:30]([CH3:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29](=[O:38])[NH:28][C:4]=2[N:5]=[C:6]([N:8]2[C:21]3[C:20](=[CH:25][C:24]([Cl:26])=[CH:23][CH:22]=3)[C:10]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9]2)[N:7]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(N/N=C(\CCC(F)(F)C(F)(F)F)c3cc(Cl)ccc3Br)nc(N)c21
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)Nc2nc(-n3nc(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
A DMF (2 mL) solution of the crude intermediate from Step D (73 mg, 0.12 mmol), copper (I) iodide (23 mg, 0.12 mmol) and N,N′-dimethylaminocyclohexane (17 mg, 0.12 mmol) was stirred at room temperature for 30 minutes. The DMF reaction mixture was filtered and purified by reverse phase HPLC using a water/acetonitrile (with 0.1% TFA) gradient to give the indicated compound. 1H NMR (500 MHz, CH3CN-d3): δ 9.17 (s, 1H); 8.83-8.78 (m, 1H); 7.84 (d, T=3.7 Hz, 1H); 7.54-7.49 (m, 1H); 7.38-7.28 (m, 5H); 5.38 (s, 2H); 3.31-3.26 (m, 2H); 2.73-2.66 (m, 2H); 1.82 (s, 3H). m/z=537.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 91.8 %

Procedure:
A stirred mixture of o-nitroaniline (82.5 g.), dry sodium thiocyanate (180 g.) and acetic acid (1 liter) was treated at 11°-12° C. with a solution of bromine (96.5 g.) in acetic acid (100 ml.). The stirring was continued for a further hour at 11°-12° C. and the mixture was then allowed to warm to 15° C. and poured into water (3.5 liters). The yellow solid was filtered off, washed with water, and dissolved in acetone (1 liter). The solution was filtered and the filtrate was evaporated to give 2-nitro-4-thiocyanato-aniline (107 g.), m.p. 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:27]CC)[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1.[OH-:32].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([OH:27])[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(OCC)c1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(O)c1cccc(Cn2c(O)nc3c(N)nc(OCCOC)nc32)c1

Procedure:
Diethyl 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (100 mg, 0.194 mmol) was dissolved in methanol (5 mL) and 1 N aqueous NaOH solution was added. The reaction mixture was heated at reflux and progress was monitored by HPLC. As soon as all the starting material had been consumed, the reaction mixture was acidified with conc. HCL. After heating at reflux for 1 h, the mixture was evaporated to dryness under vacuum. The product was purified by preparative reverse phase HPLC, yielding ethyl hydrogen 3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate Example (K) (18 mg, 22%) as a white powder. 1H-NMR (DMSO) δ: 10.0 (s, 1H), 7.65-7.42 (m, 5H), 6.51 (br, 2H), 4.90 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 3.84 (quint, J=7 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 3.26 (s, 3H), 1.13 (t, J=7 Hz, 3H). 31P-NMR (DMSO) δ: 13.04. MS: 424 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>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.CN(C=O)C>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH:20]=[CH2:21])=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 130 °C

Procedure:
A mixture of 0.73 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 209 mg of tetrakis(triphenylphosphine)palladium(0), 587 μl of tributylvinyltin and 17 ml of DMF is heated at 130° C. for 10 minutes in a microwave device and then concentrated to dryness. The residue is taken up in 100 ml of water and extracted with two times 70 ml of ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The solid is triturated from ethyl acetate, filtered off, washed with ethyl acetate and then with isopropyl ether, and taken up in a mixture of methanol and dichloromethane. The insoluble material is filtered off and washed with methanol. The filtrate is concentrated to dryness under reduced pressure to give 0.29 g of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([NH:17][NH2:18])[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:43](OOC)(OOC)OOC.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:30][CH2:31]4)=[CH:23][CH:24]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:43]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: COOC(OOC)OOC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5ccccn5)[nH]4)CC3)cc2)cc1

Procedure:
To a solution of 8-9 (4.5 g, 8.1 mmol) in 20 mL methanol and 60 mL toluene was added trimethoxy orthoformate (3.5 g, 32.5 mmol) and toluenesulfonic acid (0.1 g, 0.8 mmol). The mixture was refluxed for 10 hrs. Upon removal of the solvent, the residue was purified by flash column chromatography (100% CHCl3 to 50% CHCl3 and 50% methanol) to afford the desired product 8-10.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1cccc(F)c1F
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(F)c1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,3-difluorophenol:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH2:24][CH3:25])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CCC(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a mixture of 1.05 g of 4-fluoro-3-nitro-benzo trifluoride and 10 ml of N-methylpyrrolidone was added 1.10 g of sec-butylamine under ice cool, and the mixture was heated up to room temperature and stirred for 1.5 hours. Into the reaction mixture was poured water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 1.16 g of N-sec-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[C:18]1([NH:26][CH2:27][CH2:28][NH2:29])[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:29][CH2:28][CH2:27][NH:26][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccc(C)c1NCCN
Solvent: COCCOC
Product: Cc1cccc(C)c1NCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N-(2,6-xylyl)ethylenediamine in DME. ES-MS m/e (%): 349 (M+H+, 100), 228 ([M+H—C8H11N]+, 65).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([NH:23]C(=O)OCC)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CC(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([NH2:23])[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Nc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Yield: 56.8 %

Procedure:
A solution of ethyl [6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]carbamate (0.175 g, 0.46 mmol), potassium hydroxide (0.17 g, 3.01 mmol) in propan-2-ol (2 mL) was heated at 110° C. for 24 h. The solvent was evaporated and the crude mixture (0.38 g) was purified by reverse phase chromatography (water/acetonitrile) to give the title compound (0.08 g, 57% of yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16](Br)[C:15](=[O:24])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].[Li+].[Br-]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:24])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCCCC1Cc2c(sc(NC(C)=O)c2C(=O)OCC)C(=O)C1Br
Agent: [Br-]
Agent: [Li+]
Product: CCCCc1cc(O)c2sc(NC(C)=O)c(C(=O)OCC)c2c1
Yield: 18.3 %

Procedure:
Compound 03-5 (4.54 g, 10.9 mmol) was converted with LiBr (1.04 g, 12 mmol, 1.1 equiv.), Li2CO3 (886 mg, 12 mmol, 1.1 equiv.) to 03-6 using the procedure for 01-6. The crude product was washed with EtOAc (15 mL) and washed with Et2O (2×15 mL) to give 03-6 (1.8 g, 5.4 mmol 49%) as a brownish solid. The mother liquor was evaporated and treated with Et2O to give a second crop of 03-6 (0.67 g, 2.0 mmol, 18%) as a brownish solid. Total yield of 03-6: 2.47 9, 7.4 mmol, 68%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N+:13]([O-])([O-:15])=[O:14].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1nc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1

Procedure:
Prepared by nitrogenation of 2-methyl-4-phenyl-imidazole (melting point: 154-156° C.)) in concentrated sulphuric acid with ammonium nitrate analogously to Example D.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](=[NH:16])OCC)([O-:4])=[O:3].CO[CH:19](OC)[CH2:20][NH2:21].Cl.[OH-].[Na+]>C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:16][CH:19]=[CH:20][N:21]=1)([O-:4])=[O:3]
Reactant: CCOC(=N)Cc1ccccc1[N+](=O)[O-]
Reactant: COC(CN)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Cc1ncc[nH]1
Temperature: 25 °C

Procedure:
Ethanol (2,200 ml) and 5,156 g (8.81 moles) of ethyl 2-(2-nitrophenyl)acetimidate hydrochloride were charged into a 22 liter flask. The suspension was stirred under nitrogen at room temperature and 1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal were added all at once. The mixture was stirred for 1 hour and 1,693 ml of 12N hydrochloric acid were added all at once to cause a gentle exotherm (to 40°). Heat was then applied and the temperature was maintained at 70°-80° for 30 minutes. The solution was cooled to 20° (ice-water bath) and diluted with 2,700 ml fo 10N sodium hydroxide solution to precipitate the product. The suspension was stirred at 10° for 1 hour under nitrogen atmosphere, the solid collected by filtration and washed with 3×2,000 ml of water to give 2-(2-nitrobenzyl)-imidazole, m.p. 155°-7°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1.CCOCC>[F:13][C:10]1([F:14])[CH2:11][CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20]([OH:22])=[O:21])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C=O
Reactant: FC1(F)CC[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc([C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g (3.8 mmol) of (R)-3-(4-bromophenyl)-1,1-difluorocyclopentane (from Step B) in 15 mL of THF at −78° C. was treated with 1.6 mL (4.0 mmol) of 2.5M BuLi in hexanes. After stirring for 15 min, the reaction mixture was added to a suspension of dry ice in 200 mL of Et2O. The mixture was allowed to warm to rt. The reaction mixture was extracted with 100 mL of 1 N NaOH. After separating phases, the aqueous layer was acidified to pH 1-2 with concentrated HCl. The aqueous phase was extracted with 3×100 mL of CH2Cl2. The combined organic phases were dried and concentrated to give 0.67 g of the title compound: 1H NMR (CD3OD) δ 1.87 (m, 1H), 2.13-2.37 (m, 4H), 2.54 (m, 11H), 3.41 (m, 1H), 7.39 (d, J=8.2, 2H), 7.97 (d, J=8.2, 2H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].Cl.[CH3:6][C:7]1([CH3:15])[CH2:12][O:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>O>[N:1]([N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][O:11][CH2:12][C:7]1([CH3:15])[CH3:6])=[O:3]
Reactant: O=N[O-]
Reactant: CC1(C)COCC(C)(C)N1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)COCC(C)(C)N1N=O
Temperature: 80 °C

Procedure:
15.6 g of sodium nitrite are added to a solution of 27 g of 3,3,5,5-tetramethylmorpholine hydrochloride (prepared in accordance with Synthesis (1984), 122) in 80 ml of water and the mixture is heated at 80° C. for 3 hours. After cooling, the nitroso compound is extracted with diethyl ether. After drying and concentration of the ether phase, 22.2 g of the compound crystallize out. Melting point: 47° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([CH2:22][CH2:23][CH2:24][OH:25])[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30].CO>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([CH2:22][CH2:23][CH2:24][O:25][CH3:30])[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCC1(NC(=O)OC(C)(C)C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 250 mg (0.65 mmol) of [4-(tert-butyl-dimethyl-silanyloxy)-1-(3-hydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (32) in 3 mL of THF was dropped into a suspension of 28.3 mg (0.71 mmol) of sodium hydride (60%) in 8 mL THF at 0° C. 120 μL (1.94 mmol) of iodomethane were added, and after stirring for 1 h at room temperature another 120 μL (1.94 mmol) of iodomethane were added. The reaction mixture was stirred for 14 h at room temperature, then 5 mL of methanol were added and the volatiles were removed in vacuo. Rt=2.32 min, 2.37 min (Method C). Detected mass: 402.3 (M+H+), 302.3 (M-Boc+H+).