Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:19]([C:32](O)=[O:33])=[CH:18]2>>[OH:12][CH2:11][C:9]1[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=[C:2]([NH:1][C:32]([C:19]3[N:20]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:21]4[C:17]([CH:18]=3)=[CH:16][C:15]([F:14])=[CH:23][CH:22]=4)=[O:33])[CH:3]=[C:4]2[N:10]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cn1c(CO)nc2cc(N)cnc21
Product: Cn1c(CO)nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21

Procedure:
Compound 6 is synthesized according to a process similar to that described in Example 1.2, starting with 6-amino-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]-pyridine described in the preceding step and 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid described in step 1.1.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:14]2=[O:38])[CH2:9][CH2:8]1)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[OH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:14]2=[O:38])[CH2:9][CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
1-[trans-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (from Example 3b supra) (139 mg, 0.25 mmol) was dissolved at 0° C. in a 50% solution of trifluoroacetic acid in dichloromethane (5 mL) that contained water (330 μL). After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by adding solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated to the crude product. Purification by silica gel column chromatography with 0–100% ethyl acetate in hexanes gradient followed by a precipitation out of tetrahydrofuran with excess of pentane afforded 1-(trans-4-hydroxy-cyclohexyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 72 mg, 65%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.[NH3:29]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 65.8 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (Diastereomer B, 0.056 g, 0.147 mmol), methanol (3 mL) and ammonia (4.2 mL, 7N in methanol, 29.4 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. LCMS analysis of the cooled reaction showed ˜66% conversion. Additional ammonia (1.0 mL, 7N in methanol, 7.0 mmol) was added and the mixture was heated at 100° C. for 2 h. The cooled reaction mixture solution was concentrated under reduced pressure. The residue was absorbed on silica (4 g) then purified by chromatography on silica using dichloromethane/(80:20:1 dichloromethane/methanol/conc. NH4OH) (10:0 to 0:10) as the eluent to afford the title compound (0.034 g, 67%) as an off-white solid. MW=351.44. M.p. 93-95° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.95 (s, 1H), 7.42 (s, 1H), 7.24-7.20 (m, 2H), 7.13-7.09 (m, 2H), 6.85 (br s, 1H), 6.64 (s, 1H), 5.60 (br s, 1H), 4.13-4.07 (m, 1H), 3.33 (s, 2H), 3.03 (quin, J=7.7 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.0 Hz, 2H), 2.09-1.98 (m, 3H), 1.95-1.86 (m, 1H), 1.77-1.56 (m, 4H). MS: APCI, m/z 352 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1-c1ccc(F)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a mixture of ethanol (179 ml) and 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester (41.8 g) was added 2N aqueous sodium hydroxide solution (179 ml), and the mixture was stirred in an oil bath at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (2.5 g) was added and the mixture was stirred for 2.5 hr. The activated carbon was filtered off through celite and washed with 50 v/v % ethanol-water (100 ml). The filtrate was acidified with 2N hydrochloric acid (196 ml). Then, to this mixture was added water (33 ml) and the mixture was stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was air-dried for 2 hr, and dried under reduced pressure at 60° C. to give the title compound (28.6 g, 2 steps 93%).
Reaction SMILES: C(O)(=O)C(C)(C)C.[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:28][C:18]1([CH3:29])[C:17]2=[CH:16][C:15]3[NH:14][C:11]4[C:12]([C:27]=3[CH:26]=[C:25]2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:8]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[CH:9][CH:10]=4
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2ccccc2)cc13
Temperature: 120 °C
Reaction time: 9 h

Procedure:
50 ml of pivalic acid are added to 20 g of biphenyl-4-yl-(9,9-dimethyl-9H-fluoren-2-yl)amine (55.3 mmol), 1.2 g of palladium(II)acetate (5.5 mmol) and 0.8 g of potassium carbonate (5.5 mmol), and the mixture is stirred at 120° C. for 9 h. After this time, 1.2 g of palladium(II)acetate (5.5 mmol) are added, and the mixture is stirred at 120° C. for a further 9 h. 300 ml of dichloromethane and 0.1 M Na2CO3 solution are then added. The mixture is partitioned between water and dichloromethane, the aqueous phase is extracted three times with dichloromethane, and the combined organic phases are dried over Na2SO4 and evaporated in a rotary evaporator. The residue is recrystallised from toluene/heptane. The yield is 10 g (27.7 mmol, 50%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate(10.0 g), 2-methylimidazole(7.20 g), potassium carbonate(12.1 g) and N,N-dimethylformamide(80 ml) was stirred for 2 hours at 120-130° C. Water was added to the reaction mixture to give ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(9.97 g, 88%). This was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms. mp 93-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N:13]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: CNCCC1=CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/N(C)CCC2=CCCCC2)cc1
Yield: 95.3 %

Procedure:
The solution of p-methoxyphenylacetaldehyde in 200 ml of toluene, prepared according to Example la), is added under reflux within one hour to a mixture of 78 g (55.5 mmol) of N-methyl-2-(cyclohexen-1-yl)ethylamine in 20 ml of toluene. After 1 hour under reflux there is obtained N-[(E)-p-methoxystyryl]-N-methyl-2-(cyclohexen-1-yl)ethylamine (yield 95.3%) dissolved in toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:21]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[N:22]2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([N:21]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[N:22]2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 80.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.35 g, 0.8 mmol) was reacted with NBS (0.14 g, 0.81 mmol) in chloroform (15 mL) according to the procedure as described in Example 1, Step B to give the title compound as pale yellow oil (0.33 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(N)nn4c3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.3 (0.10 g, 0.22 mmol) in DCM (4 mL) was added pyridine (0.036 mL, 0.44 mmol, 2 equiv) and acetic anhydride (0.027 mL, 0.29 mmol, 1.3 equiv). The reaction mixture was stirred for 24 h at room temperature, additional acetic anhydride (0.042 mL, 0.44 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for an additional 24 h. The resulting mixture was concentrated under reduced pressure to give tert-butyl {1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.11 g, 100%) which was used without further purification:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:19][C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: Cc1ccc(OCCN)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)cn1
Temperature: 100 °C
Reaction time: 27 h
Yield: 19.8 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(6-methylpyridin-3-yloxy)ethylamine hydrochloride (549 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(6-methylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (88 mg).
Reaction SMILES: BrCCBr.[F:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:31]=2Cl)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:31]=2[CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([F:5])[C:7]=2[CH3:14])=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c(F)cccc1CBr
Reactant: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
To a suspension of zinc (322 mg, 4.92 mmol) in dry THF (770 μl) in a dry flask under argon was added 1,2-dibromoethane (10.6 μl, 0.123 mmol). The mixture was heated three times to reflux with a heat-gun. After 5 min the flask was placed in an ice bath and a solution of 3-fluoro-2-methyl-benzylbromide (500 mg, 2.46 mmol) in dry THF (1.5 ml) was added slowly, so that the temperature remained at 0° C. The mixture was stirred at 0° C. for 3 h. The cooled suspension was added dropwise to a precooled solution (−78° C.) of B-OM-9-BBN (2.45 ml, 2.45 mmol, 1 M in hexane). The mixture was then stirred at room temperature for 30 min. DMF (7 ml) was added, followed by the compound of step 5 (115 mg, 245 μmol), palladium(II) acetate (5.49 mg, 24.5 μmol) and S—PHOS (20.1 mg, 48.9 μmol). The reaction mixture was stirred at 100° C. for 2 h. The cooled mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 72 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)co1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Reaction time: 1 h
Yield: 58.3 %

Procedure:
tert-Butyl 4-((2-isopropyloxazol-4-yl)methyl)piperazine-1-carboxylate (0.400 g, 1.29 mmol, 1.1 eq) was dissolved in DCM (5 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (5 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)oxazole (supposedly 0.270 g, 1.29 mmol, 1 eq) was suspended in iPrOH (2.5 mL) and DIPEA (1.0 mL). To this solution, the 5-bromo-4-chloro-3-nitropyridin-2-amine (0.300 g, 1.17 mmol, 0.91 eq) was added, and the mixture heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), cold H2O (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow solid (0.290 g, 53%); 1H-NMR (500 MHz, DMSO-d6): δ 1.26 (d, J=7.0 Hz, 6H, iPr—CH3), 2.52-2.64 (br s, 4H, piperazine N(CH2)2), 2.98-3.12 (m, 5H, piperazine N(CH2)2 and iPr—CH), 3.40 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.84 (s, 1H, oxazole 5-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.46 min—425/427 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Br:25])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCOCC2)c2nc(Cl)ccc2n1
Reactant: OB(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N2CCOCC2)c2nc(-c3ccccc3Br)ccc2n1
Yield: 25.9 %

Procedure:
A solution of 2-amino-4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine (265 mg, 1 mmol), potassium carbonate (690 mg, 5 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg) in dioxane (10 ml) and water (3 ml) was refluxed. To this refluxing solution was added dropwise (with a speed of 0.25 ml/min) a solution of 2-bromo-phenyl boronic acid (220 mg, 1.1 mmol) in dioxane (2 ml). Once the addition was complete, the reaction mixture was refluxed for another 2 hours. The reaction mixture was cooled down and the solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water. The combined organic layers were dried over Na2SO4 and the crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding the pure title compound (100 mg, yield: 30%) which was characterised as follows: MS (m/z): 386, 388 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:28])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH3:33]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[N:20]([CH3:33])[CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:28])=[CH:4][C:3]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Yield: 14.3 %

Procedure:
The same procedure as E141 from 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (60 mg, 0.126 mmol), DIPEA (0.044 mL, 0.253 mmol) and MeI (0.012 mL, 0.190 mmol) in DCM (2 mL), except that the reaction time was 3 h, to afford the title compound (11 mg, 0.018 mmol, 14.44% yield). LCMS: rt=3.62 min, [M+H+]=489
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Nc1ccccc1C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-Butyryl-4-chloro-7-benzoyloxymethylquinoline (3.68 g, 10 mmol) and o-toluidine (1.61 g, 15 mmol) in dioxan (100 ml) were refluxed for 2.5 hours, then allowed to cool and stand for 16 hours. The solvent was evaporated and the product converted to the free base and recrystallised from ethanol to give the title compound (1.8 g), m.p. 110°-12°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[NH2:20][C:21]([NH2:23])=[NH2+:22]>>[NH2:22][C:21]([NH2:23])=[N:20][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: NC(N)=[NH2+]
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: [Cl-]
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
in stage e) finally, as described in EP 0 758 644 (p.9, lines 10-20), by reaction of 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride with guanidinium chloride to give the end-product N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, the guanidino group is introduced.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][C:22]1=[O:31])[CH3:19].FC(F)(F)C1CCCC(=O)C1.CN(C(Cl)Cl)C.[Cl-].[NH4+]>O1CCCC1.C(#N)C.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22]2([OH:31])[CH2:23][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:25][CH2:26][CH:21]2[CH2:20][N:18]([CH3:17])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CN(C)CC1CCC(C(F)(F)F)CC1=O
Agent: CN(C)C(Cl)Cl
Agent: O=C1CCCC(C(F)(F)F)C1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CC1CCC(C(F)(F)F)CC1(O)c1cccc(OCc2ccccc2)c1
Reaction time: 8 h

Procedure:
43.9 g (167 mmole) 3-benzyloxy-1-bromobenzene, dissolved in 200 ml of dry tetrahydrofuran, were added drop-wise to 4.06 g (167 mmole) magnesium turnings in 40 ml of dry tetrahydrofuran so that the reaction mixture boiled gently. After the addition of 3-benzyloxy-1-bromobenzene was complete, the mixture was heated for one hour under reflux and was thereafter cooled to 5°-10° C. 30.8 g (139 mmole) (2RS,5SR)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanone, prepared from 3-trifluoromethyl-cyclohexanone and dimethylaminomethylene chloride in acetonitrile, dissolved in 80 ml of dry tetrahydrofuran, were added at this temperature. The reaction mixture was allowed to stand overnight and was then cooled to 5°-10° C. again. The Grignard solution was decomposed by the addition of 150 ml of 20% ammonium chloride solution. The reaction mixture was diluted with 200 ml of ether, the organic phase was separated off and the aqueous phase was extracted twice with 100 ml ether. The combined organic phases were dried over sodium sulphate. After removing the solvent by distillation, the residue (60.6 g) was introduced on to an 8×50 cm column packed with silica gel and extracted with ethyl acetate/methanol. 27.8 g (50% theoretical) of base (26) were obtained.