Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH:27]=C)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.C1C[O:36]CC1>O.[Os](=O)(=O)(=O)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[O:36])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: C=Cc1ccc(NC(=O)Nc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1C(F)(F)F
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1ccc(NC(=O)Nc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
1-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-vinylphenyl)urea (300 mg, 0.68 mmol) was dissolved in a solution mixture of THF (100 mL) and water (50 mL), and an osmium tetraoxide aqueous solution (0.1 M, 300 μL) and sodium periodide (590 mg, 2.76 mmol) were added thereto. The resulting mixture was stirred at room temperature for 17 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product of 1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-formylphenyl)urea (229 mg, 76%). Then, this crude formyl compound (59.4 mg, 0.14 mmol) was dissolved in methanol (3 mL), and sodium borohydride (15.5 mg, 0.41 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product of 1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-hydroxymethylphenyl)urea (50.9 mg, 85%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([CH3:34])[C:25]=1OS(C(F)(F)F)(=O)=O)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:25]2[C:24]([CH3:34])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[CH3:15])[CH:6]=1
Reactant: COCOc1ccc(C)c(B(O)O)c1
Reactant: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c1
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: CO
Product: COC(=O)c1cc(C)c(-c2cc(O)ccc2C)c(C)c1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid (described in Example 16(c)) with 5.3 g (17 mmol) of methyl 3,5-dimethyl-4-trifluoromethanesulphonyloxybenzoate, 17 mL of 2.0M potassium carbonate solution and 1 g (0.82 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a yellow oil (m=3.0 g; Y=65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[I-].[NH2:17][N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O.ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: N[n+]1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a two-phase mixture of 6-chloro-3-(2-phenylethynyl)pyridazine (2.3 g), N-aminopyridinium iodide (90% purity; 5.3 g), benzyltrimethylammonium chloride (0.20 g), dichloromethane (23 ml), and water (23 ml) was added sodium hydroxide (3.4 g) in one portion. After stirring at ambient temperature overnight, the reaction mixture was treated with concentrated hydrochloric acid followed by dilution with dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted once with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 25:1 dichloromethane--ethyl acetate) to give 3-(3-chloropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.92 g).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]([O:27][C:28]([NH:30][C@@H:31]([C:40]([OH:42])=O)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:29])([CH3:26])[CH3:25].Cl.Cl.[Br:45][C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[CH:51][N:50]=[C:49]2[N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:24]([O:27][C:28](=[O:29])[NH:30][CH:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:40]([N:59]1[CH2:60][CH2:61][N:56]([C:49]2[C:48]3[C:53](=[CH:54][CH:55]=[C:46]([Br:45])[CH:47]=3)[N:52]=[CH:51][N:50]=2)[CH2:57][CH2:58]1)=[O:42])([CH3:23])([CH3:25])[CH3:26]
Reactant: Brc1ccc2ncnc(N3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDCI.HCl (230 mg, 1.2 mmol), HOBt (160 mg, 1.2 mmol) and Boc-D-4-chlorophenylalanine (240 mg, 1.2 mmol) were added to a stirred solution of 6-bromo-4-piperazin-1-yl-quinazoline bis-hydrochloride (360 mg, 0.98 mmol) and triethylamine (0.30 mL, 1.2 mmol) in DMF (8 mL) at room temperature under nitrogen. Stirred at room temperature overnight. Diluted with EtOAc (100 mL) and washed with water (3×50 mL.) Dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (100% EtOAc) to give [2-[4-(6-bromoquinazolin-4-yl)-piperazin-1-yl]-1-(4-chlorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester as a yellow solid (320 mg, 57%.) MS (APCI+) [M+H]+ 575.9. 1H NMR (CDCl3, 400 MHz) δ 8.75 (1H, s), 7.95 (1H, s), 7.85-7.79 (2H, m), 7.30-7.27 (2H, m), 7.17 (2H, d, J7.1 Hz), 5.39 (1H, app. d, J8.2 Hz), 4.86 (1H, app. d, J 7.3 Hz), 3.83-3.60 (6H, m), 3.36-3.26 (2H, m), 3.04-2.96 (2H, m), 1.43 (9H, s).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]>CCO>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19]3[CH2:20][CH2:21][N:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:17][C:18]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCc2[nH]c3ccc(C)cc3c2C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Following a literature procedure (Harbert, C. A.; Plattner, J. J.; Welch, W. M.; Weissman, A.; Koe, B. K. J. Med. Chem. 1980, 23, 635-643) p-tolylhydrazine hydrochloride (0.500 g, 3.15 mmol) and 1-carbethoxy-4-piperidone (0.18 mL, 1.17 mmol) were suspended in EtOH (0.880 mL) and heated to reflux for 2 hours. The reaction mixture was removed from heat and allowed to stand overnight at ambient temperature. The resulting mixture was filtered and washed with 50% aqueous EtOH to afford the desired product as a beige powder (259 mg, 86%).
Reaction SMILES: [Cl-].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][NH2+:13]3)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:29]1[N:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][N:30]=1)(=O)=O>CN(C=O)C.O.C(OCC)(=O)C>[F:18][C:3]([F:2])([F:17])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:29]2[N:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][N:34]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: FC(F)(F)c1cccc(N2C[C@@H]3C[C@H]2C[NH2+]3)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
Compound 558 (500 mg, 1.794 mmol) and cesium carbonate (1461 mg, 4.49 mmol) were suspended in DMF (5 mL) to give a yellow suspension. Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (496 mg, 2.153 mmol) was then added and the reaction was stirred at room temperature for 3 days. The mixture was diluted with water and ethyl acetate. The organic layer was washed twice with water then brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (25-50% EtOAc in Hexanes) to obtain compound 559 as a white solid (313 mg, 45%). LRMS: 392.1 (found) 393.2 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[O:21]C(C)(C)C)=[CH:15][CH:14]=3)[C:5]=2[N:4]=[CH:3]1.[C:27]([C:31]1[CH:35]=[C:34]([N:36]=C=O)[N:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:35]=[C:34]([NH:36][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[C:5]4[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=4[N:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)=[O:21])[N:33]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2)cc1
Yield: 55 %

Procedure:
Method F1 was used with Tert-butyl 4-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to obtain the title compound (yield 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21]([NH2:23])=[S:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C[Si](C)(C)Cl.C(N(CC)CC)C>C(#N)C.O>[CH:36]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:43])=[CH:26][N:35]=3)[C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[C:32]2[N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21]([NH2:23])=[S:22])[O:16][C:15]4=[O:24])=[CH:3][C:2]=3[F:1])[CH2:9][CH2:10]2)[CH2:37][CH2:38]1
Reactant: NC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC(=S)NC[C@H]1CN(c2ccc(N3CCN(c4c(C(=O)O)c(=O)c5cc(F)cnc5n4C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 29.8 %

Procedure:
A mixture of 100 mg [(5S)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-thiourea (0.28 mmol), 87.98 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.31 mmol), 71.57 μl trimethylchlorosilane (0.56 mmol) and 118.31 μl triethylamine (1.4 mmol) in acetonitrile was stirred in a micro wave oven for 8 min at 150° C. The reaction mixture was diluted with water and the solid filtered. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture with 1% acetic acid as eluent to leave 50 mg of an oily residue which was crystallized from a ETOAC/hexane mixture.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N:9]([C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-])=O)=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:17]=1)=[N+:10]=[N-:11].[C:27]([C:29]1[O:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1)#[N:28].CCN(C(C)C)C(C)C>O.C1COCC1.[Cl-].[Na+].O>[N:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:24][C:34]([C:32]2[O:33][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[O:35])=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:17]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(N=[N+]=[N-])cc2N2CCCCC2)o1
Yield: 12 %

Procedure:
To a solution of sodium hydrosulfite (936 mg, 5.30 mmol) in 8 mL of water was added 1-(5-azido-2-nitro-phenyl)-piperidine (133 mg, 0.530 mmol, as prepared in the previous step) in 4 mL of THF dropwise. After 25 min the reaction was poured into 50 mL of brine, extracted with EtOAc (3×30 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was then allowed to react in a manner similar to Example 4, step (c), with 5-cyano-furan-2-carbonyl chloride (31 mg, 0.20 mmol) in the presence of DIEA (203 μL, 1.16 mmol) to afford 8 mg (12%) of the title compound as an amber solid. 1H-NMR (CDCl3; 400 MHz): δ 9.58 (s, 1H), 8.44 (d, 1H, J=7.8 Hz), 7.22-7.30 (m, 2H), 6.81-6.89 (m, 2H), 2.81-2.86 (m, 4H), 1.79-1.82 (m, 4H), 1.62-1.65 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C17H16N6O2, 337.1 (M+H), found 337.0.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[F-].[K+].[C:25]([O:31][CH2:32]Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][C@H:8]1[C:9]([O:11][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[O:6])[CH3:1]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of (cis)-1-[(1,1-dimethylethoxy)carbonyl]-4-(phenylmethyl)-L-proline (3.4 g) in dry dimethylformamide (3.0 ml) is added solid potassium fluoride (1.5 g), followed by chloromethyl pivalate (2.0 g). After stirring for 16 hours at ambient temperature the mixture is diluted with water (100 ml) and extracted with ethyl acetate. The ethyl acetate solution is washed with 5% sodium bicarbonate, water, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue (5 g). The oil is chromatographed on silica gel (120 g) eluting with ether/hexane (1:3) to give the product (4.4 g) as an oil that solidifies on standing, melting point 60°-62° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2C=N[N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C(OC)=O.I[C:39]1C=NC=C[N:40]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[N:15][CH:17]=[CH:39][N:40]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: Ic1cnccn1
Agent: COC(=O)c1cc(C)ccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(C)ccc1-c1cnccn1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and using 2-iodopyrazine. ESI-MS (m/z): 229 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22].C([OH:25])C>>[ClH:22].[C:7]([O:8][CH2:9][CH:10]([NH2:11])[CH2:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14])(=[O:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=S(CC1COC(c2ccccc2)=N1)c1ccc(O)cc1
Agent: Cl
Product: NC(COC(=O)c1ccccc1)CS(=O)c1ccc(O)cc1

Procedure:
1.3 g (4.3 mM) of the oxazoline from Example 2 was dissolved in 30 mL ethanol and treated with 8 mL lN HCl for 3 hours. The solvents were removed under reduced pressure and the resulting foam was dried under high vacuum for 18 hours at 50° C. to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[N:24]=[C:23]([NH2:34])[N:22]=4)=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:35][N:36]1CCCC1=O.N>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[NH2:34][C:23]1[N:22]=[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([CH2:19][CH2:20][N:11]([C:9](=[O:10])[CH2:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=4)[C:35]#[N:36])[CH2:12]3)=[CH:17][CH:16]=2)[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:24]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3cncc(Br)c3)CC4)nc(N)n2)CC1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: N
Agent: [C-]#N
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3cncc(C#N)c3)CC4)nc(N)n2)CC1
Temperature: 135 °C

Procedure:
A degassed mixture of 4-{2-[(5-bromopyridin-3-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20 mg, 0.04 mmol), zinc cyanide (7 mg, 0.06 mmol), bis(tri-t-butylphosphine)palladium (1 mg, 0.002 mmol) and zinc (0.4 mg, 0.006 mmol) powder in anhydrous N-methylpyrrolidinone (0.1 mL, 1 mmol) was heated at 135° C. for 18 h. The mixture was adjusted to pH=10 with aqueous NH3, filtered, washed with MeOH, and purified by RP-LCMS (pH=10) to afford the desire product. Analytic LCMS (M+H)+: m/z=469.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-hydroxy-phenol (1.5 g, 13.6 mmol) in acetonitrile (50 mL) is added methyl 2-(bromomethyl)-6-methyl-benzoate (0.82 g, 3.4 mmol, example 2) followed by K2CO3 (3.76 g, 27.2 mmol). The resulting mixture is heated to 50° C. and stirred at this temperature for 90 min. then cooled, filtered and the filtrate concentrated under vacuum. The residue is purified by flash chromatography (silica, 5% ethyl acetate in dichloromethane) to give the title compound as a white solid. MS (EI) 272 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([OH:28])=O)([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:28])[N:33]([CH3:34])[CH3:32])([CH3:24])[CH3:25])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N(C)C)c1)N2
Yield: 91.4 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), dimethylamine hydrochloride (490 mg, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H35N3O3 (M+H)+: 438.59, observed: 438.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][NH:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a suspension of (4-fluorophenyl)hydrazine•hydrochloride (3 g, 18 mmol) and water (75 mL) were added potassium carbonate (5.6 g, 40 mmol) and diethyl ethoxymethylenemalonate (4.8 g, 22 mmol), and the mixture was heated under reflux for 7 hr. After cooling to room temperature, the mixture was washed with ethyl acetate. 6N Aqueous hydrochloric acid solution was added to the separated aqueous layer under ice-cooling. The precipitated solid was collected by filtration, washed with water and ethyl acetate/hexane (1/10), and dried under reduced pressure to give the title compound (2.2 g, 48%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])C.[K+].[Br-]>>[C:21]1([NH:20][C:18](=[O:19])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=3)=[CH:16][CH:15]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3)cc2)no1
Agent: [Br-]
Agent: [K+]
Product: O=C(Nc1ccccc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Yield: 95.6 %

Procedure:
The title compound was prepared from 3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid ethyl ester as set forth in example 8 and was obtained in 95.6% yield. Mass (ES+): 324 (M++1); IR (KBr): 3312, 1711, 1645, 1599, 1461; 1H NMR (DMSO-d6) δ: 6.97 (t, 1H), 7.28 (t, 2H), 7.45 (d, 2H), 7.59 (d, 2H), 7.71 (s, 1H), 7.87 (d, 2H), 8.76 (s, 1H), 8.96 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[CH2:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH3:16]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: C=C(C)c1cc(C(=O)OC)c(OC)cc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(C)C)c(OC)cc1OC

Procedure:
A solution of 5-isopropenyl-2,4-dimethoxy-benzoic acid methyl ester (6.0 g, 25.4 mmol) in MeOH (85 ml) was shaken with 10% Pd/C under an atmosphere of H2 at room temperature for 3 hours. The catalyst was filtered through GF/A paper but a little fine powder passed through. The filtrate was passed through a small pad of silica and evaporated to dryness to yield a colourless solid. The product was purified by flash column chromatography (DCM:Petrol gradient elution) to yield 5-isopropyl-2,4-dimethoxy-benzoic acid methyl ester a colourless solid (5.5 g). 1H NMR (Me-d3-OD) 7.68 (1H, s), 6.64 (1H, s), 3.94 (3H, s), 3.91 (3H, s), 3.84 (3H, s), 3.23 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 239.