Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:33]([C:34]([OH:36])=O)=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.[NH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:33]([C:34]([NH:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:36])=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:2][CH2:3]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)O)n3)c(C)c2C2CC2)c(F)c1
Reactant: CS(=O)(=O)CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)NCCS(C)(=O)=O)n3)c(C)c2C2CC2)c(F)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 147 mg 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid 2-11-1 (0.27 mmol, 1.0 eq) and 67.5 mg 2-aminoethylmethyl sulfone (0.55 mmol, 2.0 eq) in 2.1 mL DMF were added 191 μL N,N-diisopropylethylamine (1.10 mmol, 4.0 eq) and 157 mg (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.30 mmol, 1.1 eq). The resulting solution was stirred over night at rt and afterwards diluted with water. The precipitate was collected by filtration, washed with water and dried. The crude product was purified by preparative HPLC yielding 40 mg of analytically pure target compound (62 μmol, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:23]([C:24]([N:26]=[C:27]=[O:28])=O)=[C:22]([F:29])[C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([F:29])[C:23]=1[C:24]1[NH:26][C:27](=[O:28])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.130 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=6.0 Hz, 2H), 7.24-7.47 (m, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 8.16 (m, 1H), 12.10 (br s, 1H); MS (m/z): 437.16 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32](O)=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)NS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (60 mg, 0.13 mmol), methanesulfonamide (24 mg, 0.26 mmol), HOBt (53 mg, 0.39 mmol), EDCl (75 mg, 0.39 mmol) and DIEA (1 mL) in CH2Cl2 was stirred at rt overnight. The solvent was removed to give the crude product. It was purified by preparative HPLC to give 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-N-(methylsulfonyl)propanamide (7 mg, 10%). 1H NMR (CDCl3): 1.50 (m, 3H), 2.21 (m, 6H), 2.54 (m, 1H), 2.93 (m, 1H), 3.15 (s, 3H), 5.59 (m, 1H), 6.83 (m, 2H), 6.98 (m, 4H), 7.18 (m, 2H), 7.24 (m, 3H), 9.58 (s, 1H). LC-MS Method 3, tR=1.26 min, m/z=561.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1.C(OCC)(=O)C>[CH2:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:1]([OH:3])=[O:2])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of (2S)-2-carboxypyrrolidine (40 g) in a mixture of water (200 ml) and tetrahydrofuran (200 ml) was added a solution of allyl chloroformate (44 ml) in tetrahydrofuran (40 ml) at 0° C. while adjusting pH to around 9 with 4N aqueous sodium hydroxide. After stirring at 0° C. for 1 hour at pH 9, the aqueous layer was saturated with sodium chloride, and the mixture was diluted with ethyl acetate (200 ml). The aqueous layer was separated and washed with ethyl acetate. After adjusting pH to around 2 with 6N hydrochloric acid, the mixture was extracted with two portions of ethyl acetate (200 ml×2). The combined extract was dried over magnesium sulfate and evaporated in vacuo to give (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (72.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[C:22](Cl)(=[O:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[O:25]=[C:24]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22](=[O:27])[CH2:23]1
Reactant: CC(C)N(C(=O)CNc1ccccc1N)c1ccccc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)Nc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirred solution of 10 g (37.14 mmol) of 2-(2-Aminophenylamino)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 45, in 100 mL of THF is added 5.2 g (37.14 mmol, 1 equiv.) of malonyl dichloride. The resulting solution is stirred at RT for 2 h and the solvent removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 6.1 g of the title compound as an oil: 1H NMR (CDCl3, 300 MHz) δ9.65 (s, 1H), 7.4 (bd, 1H, J=9), 7.30-6.93 (m, 7H), 5.09-4.95 (m, 1H), 4.42 (d, 1H, J=16), 3.68 (d, 1H, J=17), 3.36 (d, 2H, J=4), 1.09 (d, 6H, J=7).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH:29]([CH3:31])[CH3:30])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][C:4]=1[OH:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:18][C:4]1[CH:5]=[C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:31]
Reactant: COc1ccc(-c2cc3nccnc3[nH]2)cc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-c2cc3nccnc3[nH]2)ccc1OC
Temperature: 50 °C

Procedure:
To a solution of 2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol [0.5 g, Example 28] in dimethylformamide (10 mL) and cesium carbonate (0.67g) was added ethyl chloroacetate (0.025 g). The reaction mixture was heated at 50° C. overnight. After cooling, the dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic fraction was dried over sodium sulfate, evaporated and subjected to flash column chromatography on silica eluting with 2.5% methanol in dichloromethane. This product was further triturated with a mixture of ethyl acetate and pentane to give the title compound as a white solid, m.p. 183–184° C. MS: 328 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1([F:33])[CH2:28][CH2:27][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][CH:26]2[CH2:27][CH2:28][C:23]([F:33])([F:22])[CH2:24][CH2:25]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CC1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)CC2CCC(F)(F)CC2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-(4,4-difluorocyclohexyl)acetic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.95 (m, 1H), 7.95-7.86 (m, 1H), 7.48-7.37 (m, 1H), 4.48-4.42 (m, 2H), 2.32-2.22 (m, 3H), 2.05-1.70 (m, 6H), 1.39 (s, 9H), 1.35-1.20 (m, 2H); MS (ESI−) M/Z 449 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:19]([O-])=O)[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>CN(C=O)C.[Pd]>[NH2:19][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:2]2[OH:1]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(CN3CCOCC3)cc2c1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Yield: 89.8 %

Procedure:
A solution of ethyl 4-hydroxy-6-(4-morpholinylmethyl)-8-nitro-3-quinolinecarboxylate (Preparation 1, 1.36 g) in DMF (50 mL) is hydrogenated at 50 psi hydrogen pressure in the presence of 10% Pd/C (400 mg) for 15 min. The catalyst is filtered off and the filtrate is evaporated. The residual solid is triturated with methanol to afford 1.12 g of the title compound. Physical characteristics. 1H NMR (DMSO-d6) δ1.28, 2.35, 3.44, 3.57, 4.21, 5.59, 6.98, 7.33, 8.41.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].O=[C:10]([CH:12]=[C:13]([CH3:15])[CH3:14])C.C(Cl)C=C(C)C>CC(C)=O>[CH2:10]([CH2:1][C:2]([CH:3]=[C:4]([CH3:7])[CH3:5])=[O:8])[CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(=O)CC(C)(C)O
Reactant: CC(=O)C=C(C)C
Agent: CC(C)=CCCl
Solvent: CC(C)=O
Product: CC(C)=CCCC(=O)C=C(C)C

Procedure:
Acetone under the reaction conditions forms also some diacetone alcohol and mesityl oxide, and these then react with the prenyl chloride to produce the above isomers of prenyl mesityl oxide, also called prenyl-substituted methyl pentenones, in the same manner as acetone reacts with prenyl chloride to produce methyl heptenone. It is also possible that prenyl chloride reacts with the diacetone alcohol in the same manner to give the corresponding hydroxy derivatives that subsequently dehydrate. The presence of such hydroxy ketones is observed in the residues of the methyl heptenone production by the process of U.S. Pat. No. 3,668,255.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:20]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCCCc1cccs1
Product: O=C(NCCCc1cccs1)n1cc(F)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-Fluorouracil (3.30 g.) was added to the solution of 3-(2-thienyl)propyl isocyanate and stirred at 100° C. for 2 hours. The resultant mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give colorless plate 1-[N-[3-(2-thienyl)propyl]carbamoyl]-5-fluorouracil (2.3 g.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].N1C=CN=C1.CN(C)C=O>O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH2:2][O:1][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[O:12][C:13]=1[CH3:14]
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.40 g), triisopropylsilyl chloride (0.75 g), imidazole (0.27 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as a colorless oil (0.53 g, yield 95%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC[O:30][CH2:31][CH2:32]Br.C(Cl)(Cl)Cl>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH2:32][CH2:31][OH:30])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reactant: COCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: OCCOc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) is suspended in DMF (5 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmol) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-methoxymethoxyethyl bromide (0.32 g, 2.0 mmol) under ice-cooling, and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added chloroform (100 ml), and the mixture is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (20 ml) and a 35% aqueous hydrochloric acid solution (2 ml), and the mixture is stirred at 60° C. for 30 minutes. The pH value of the reaction solution is adjusted to pH 10 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform (50 ml×2), washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.17 g), m.p. 129-132° C. (recrystallized from ethanol/isopropyl ether).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([N:16]([CH3:23])[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:2]1.C=O.[C:26](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:15][C:8]1[C:7]([N:16]([CH3:23])[CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][C:5]([CH:3]2[CH2:2][N:1]([CH3:26])[CH2:4]2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(C2CNC2)cc(N(C)C2CCOCC2)c1C
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cc(C2CN(C)C2)cc(N(C)C2CCOCC2)c1C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 5-(azetidin-3-yl)-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate (320 mg, 1.01 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (151 mg, 5.03 mmol) followed by acetic acid (0.115 ml, 2.01 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (852 mg, 4.02 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (21 mg) and sodium triacetoxyborohydride (98 mg) was added and the reaction was stirred for a further 4 h whereupon distilled water (20 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7. The phases were separated, the aqueous phase was washed with DCM (3×20 ml), the combined organic phases were then washed with brine (50 ml), dried using MgSO4, filtered and evaporated to afford the title compound as an oil (296 mg, 89%). LC-MS 100%, m/z=333.1, 1H NMR (500 MHz, Chloroform-d) δ 7.42 (d, J=1.4 Hz, 1H), 7.09 (s, 1H), 3.96 (d, J=11.2 Hz, 2H), 3.92-3.82 (m, 5H), 3.74 (d, J=7.2 Hz, 1H), 3.30 (dt, J=22.2, 15.0 Hz, 4H), 3.00-2.89 (m, 1H), 2.62 (s, 3H), 2.49-2.39 (m, 6H), 1.75-1.59 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[S:24])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH3:23])=[N:10][CH:9]=1)[NH2:6])C.C(O)C.[OH-].[K+].Cl>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[S:24])[NH2:6])=[CH:9][N:10]=[C:11]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1ncc(C[C@H](N)C(=S)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1ncc(C[C@H](N)C(O)=S)n1Cc1ccccc1Cl
Yield: 79.9 %

Procedure:
A solution of 3-[(2-chlorophenyl)methyl]-2-propylthiohistidine ethyl ester (Example 2 (i) ) (0.48 g, 1.26 mmol), ethanol (4 mL), water (4 mL) and potassium hydroxide (0.111 g, 1.97 mmol) was stirred at 25° C. for 1 hour. The mixture was treated with concentrated hydrochloric acid to pH 4.0 and cooled. The resulting precipitate was collected and triturated with ethanol to give 0.34 g (77%) of 3-[(2-chlorophenyl)methyl]-2-propylthiohistidine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: C1CNCCN1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
55.1 g (200 mmol) of 2-(4-chlorophenyl)-4,5-dichlorpyridazin-3-one are introduced with 41.6 ml (300 mmol) of triethylamine in 400 ml of dimethylformamide. 137.82 g (1600 mmol) of piperazine are added, and the mixture is stirred at 80° C. overnight. The reaction mixture is cooled and then concentrated under high vacuum. The residue is taken up in dichloromethane and washed twice with water, dried over magnesium sulfate and concentrated. The product is isolated by chromatography (gradient: dichloromethane/methanol from 95:5 to 9:1) on silica gel and subsequent crystallization with ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[Cl:19][C:20]1[C:21]2[CH:29]=[C:28]([C:30]3[O:31][C:32]([CH3:35])=[N:33][N:34]=3)[N:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:20]3[C:21]4[CH:29]=[C:28]([C:30]5[O:31][C:32]([CH3:35])=[N:33][N:34]=5)[N:27]=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: Cc1nnc(-c2cc3c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)ncnc3cn2)o1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chioro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.50(1H,s), 9.53(1H,s), 9.41 (1H,s), 8.94(1H,s), 8.30(2H,s), 7.90(1H, d), 7.80(1H,dd), 7.45(1H,d), 7.25(3H,m), 5.80(2H,s), 2.75 (3H,s); m/z (M+1+) 453.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[N:20]O)[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([NH2:20])[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NO)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
A solution of 6-(1-hydroxyimino-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.0 g, 3.44 mmol), dissolved in MeOH (50 mL), was hydrogenated under a pressure of 40 psi in the presence of 50% RaNi/H2O (3 mL) for 5 hours. The catalyst was filtered off and the solvent evaporated. The crude amine was purified by chromatography (SiO2, 15% of 2.0M NH3/MeOH in CH3CN) to give 0.57 g (60%) of the title compound as a white solid. m.p: 73-75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl
Temperature: 25 °C

Procedure:
5.5 g (29 mmol) 3-nitro-quinolin-4-ol (Example 1a) in 25 ml POCl3 are heated for 2 h to keep at 130° C. The mixture is cooled to rt and poured into ice-water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH2Cl2. The organic phase is washed with cold 0.1N NaOH (1×) and with cold water (2×). After drying over MgSO4, the solvent is evaporated to dryness. The residue is stirred in hexane. The title compound is isolated as a powder and is dried at 60° C. under vacuum. mp: 121-122° C.; NMR (CDCl3): 9.26/s (1H), 8.44/d and 8.21/d (2H), 7.95/t and 7.82/t (2H); HPLC: tret=1 1.64 min (Grad 1).