Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccnc2)cc1
Yield: 63.5 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.61 g) and 3-pyridinebutanamine (0.61 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual workup. the crude product was crystallized form ethyl acetate to provide 1.05 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 121°-123° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[OH:15])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:21].C(=O)([O-])[O-].[K+].[K+]>>[CH:10]1([C:6]2[C:5]3[O:15][CH:2]([CH2:3][OH:21])[CH2:1][C:4]=3[CH:9]=[CH:8][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cccc(C2CCCC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2cccc(C3CCCC3)c2O1
Yield: 54.6 %

Procedure:
Treatment of 2-allyl-6-cyclopentylphenol (6.97 g, 0.0344 mol) with 3-chloroperoxybenzoic acid (17.83 g, 0.1033 mol, 77%) and potassium carbonate (14.0 g, 0.1013 mol) generally according to the procedure described for Intermediate 9 afforded 4.1 g (54%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a yellow oil. Rf=0.58 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C14H18O2 C, 77.03; H, 8.31. Found C, 76.5; H, 8.44.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6](Br)[CH:5]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH:5]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc(F)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A total of 2.49 g of 3-bromo-4-fluorobenzaldehyde dimethylacetal produced in Production Example I-4-a was dissolved in 20 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 8.5 ml of a 1.56 M solution of n-butyllithium in hexane was added. After stirring for 30 minutes, 1.0 ml of N,N-dimethylformamide was added and the mixture was heated to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:12.5), to give 1.35 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].Cl>O1CCOCC1>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:8][C:9]=1[NH2:10])=[O:4]
Reactant: CNC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1nc(-c2ccccc2)sc1N
Reaction time: 72 h
Yield: 88588.1 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid methylamide (98 mg, 0.3 mmol) in dioxane (1.7 ml) was treated with HCl (1.7 ml, 4M dioxane solution) at ambient temperature and stirred for 3 days. The solvent was evaporated, and the residue was dissolved in ethyl acetate and extracted with sodium bicarbonate and brine. The organic layer was dried and the solvent was evaporated to yield the product as yellow solid (62 g, 90%) which was used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:35])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:36]>C1COCC1.O1CCOCC1>[ClH:36].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:35])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 9-bromo-5-[(p-tert-butoxycarbonylaminomethylphenyl)carbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (180 mg, 0.3 mmol) in THF (6 mL) was added 4N HCl in dioxane (6 mL). The mixture was stirred for 3 h at room temperature and concentrated. The residue was collected by filtration, washed with diethyl ether, and dried in vacuo to give 140 mg of the title compound (97%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.11 (s, 1H), 10.27 (s, 1H), 8.27 (bs, 2H), 7.61 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 7.23 (bs, 1H), 7.20 (bs, 1H), 5.17~5.26 (m, 1H), 3.96 (br, 2H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.71 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1>CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:4]3[CH:3]=[CH:8][C:7]([C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=4)=[O:37])=[CH:6][C:5]=3[NH2:13])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3N)n2)cc(OC)c1OC
Yield: 46 %

Procedure:
Using Method LL with 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 4-trifluoromethyl-phenylcarbonyl chloride (35 mg, 0.17 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (34 mg). Yield: 46%. 1H NMR (250 MHz, DMSO-d6) δ 3.65 (s, 3H, [CH3O]4), 3.85 (s, 6H, [CH3O]3+5), 7.28 (s, 2H, Harom2′+6′), 7.95 (d, 4H, Harom 3+5 and Harom 2″+6″ J=8.5 Hz), 8.15-8.21 (m, 4H, and Harom 2+6, Harom 3″+5″ and HPz 5), 8.53 (s, 1H, HPz 3), 9.57 (s, 1H, NH), 10.66 (s, 1H, NHamide). m/z 525.2 [(M+H)+ calcd for C27H23F3N4O4 524.2].
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:27])([F:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:11][C@@H:12]([CH2:17][C:18]([F:26])([F:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reaction time: 3 h

Procedure:
3.0 g of methyl (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate (8.0 mmol) were admixed with 8.0 ml (5 eq.) of a 30% HBr solution in glacial acetic acid with ice bath cooling and stirred for 3 h. 100 ml of diethyl ether were added and the resulting precipitate was filtered off with suction. The crude product thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The amorphous solid obtained after freeze-drying was taken up in dichloromethane and washed with sat. NaHCO3 solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Thus, methyl (S)-2-amino-4,4-difluoro-5-phenyl-pentanoate was obtained as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)=[N:19][CH:20]=[N:21]2)=[O:11]>>[OH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:29]([CH3:34])[CH:28]=1)=[N:19][CH:20]=[N:21]2)=[O:11]
Reactant: ClCc1cscn1
Reactant: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1OCc1cscn1
Yield: 21 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide (obtained as described in Example 79, preparation of starting materials) to give the title compound as a yellow solid in 21% yield; NMR spectrum (DMSO-d6) 2.20 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.23 (s, 2H), 5.49 (t, 1H), 7.08 (d, 1H), 7.13 (d, 1H), 7.32 (d, 1H), 7.44 (d, 1H), 7.57 (dd, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 8.17 (t, 1H), 8.42 (s, 1H), 9.14 (d, 1H), 9.77 (s, 1H); Mass spectrum MH+ 466.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C>[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(/C=C/c2ccncc2)cc1

Procedure:
4-Carboxybenzaldehyde (2.03 g, 13.3 mmol, Aldrich) and 4-picoline (1.24 g, 13.3 mmol, Aldrich) were placed in a round-bottomed flask, to which a 20 mL of acetic anhydride was added. The reaction mixture was heated to reflux for 24 h. The solid was filtered and the solid was washed with acetic acid then with water before being dried in vacuo, at 50° C. overnight to give the title compound as an off white solid (426 mg, 14%).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 7.41 mmol) was added DCM (18.5 mL) and TFA (18.5 mL). The resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO3. The aqueous mixture was then extracted with EtOAc. The organic phases were combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol, 90% yield) which crystallizes upon standing. LCMS m/z 228.0 (M+H)+, Rt 0.44 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([C:10]3[N:14]=[CH:13][S:12][CH:11]=3)[NH:7][C:5]=2[CH:6]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23].[K+].[Br-]>C(Cl)(Cl)Cl>[Cl:26][CH2:25][O:24][C:22]([N:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=[C:8]1[C:10]1[N:14]=[CH:13][S:12][CH:11]=1)=[O:23]
Reactant: O=C(Cl)OCCl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCCl)n1c(-c2cscn2)nc2ccccc21

Procedure:
To a suspension of 15.0 g of thiabendazole in 300 ml of chloroform, 6 g of pyridine was added and the suspension cooled in an ice bath. Chloromethyl chloroformate (10.6 g) was added to the reaction mixture dropwise during 10 minutes with stirring. A clear solution was formed which was kept stirred at room temperature for 16 hours. After washing the chloroform solution with water, it was dried over Na2SO4 and evaporated to a light yellow solid weighing 20.4 g. It was crystallized from EtOAc-CHCl3. Obtained in two crops were 15.07 g of compound, m.p. 143°-144° NMR (CDCl3) δ5.9 (2H, s, OCH2Cl), 7.2-8.2 (5H, m, aromatic), 8.93 (1H, d, J=3 Hz, aromatic). IR (KBr) ν3095, 1780, 1460, 1374, 1340, 1194, 1140, 1078 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])=[CH:3][CH:4]=3)[C:16]=12
Reactant: CC(C)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of dichloromethane (5 mL), compound 23 (45 mg, 0.168 mmol) and triethylamine (71 μL, 0.509 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (16 μL, 0.148 mmol) was added and the reaction was allowed to proceed for 1 hour prior to addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (2×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (8.7 mg, 16% yield): 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.36 (s, 1H), 7.60 (d, J=8.5, 2H), 7.31 (d, J=8.6, 2H), 6.86 (dd, J=16.4, 9.9, 1H), 6.21 (d, J=16.4, 1H), 6.09 (d, J=9.9, 1H), 5.08 (hept, J=6.7, 2H), 1.49 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 155.44, 152.03, 151.64, 144.22, 138.54, 136.17, 129.25, 127.98, 127.41, 119.52, 96.95, 48.66, 21.75; [M+H]+ calculated for C16H18N6O2S 359.1, found 359.5.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1.[BH3-]C#N.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CNC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C=O)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(tert-butyldimethylsilyloxy)-2-naphthaldehyde (4.0 g, 14 mmol), AcOH (1.8 g, 28 mmol) and methyl azetidine-3-carboxylate (3.2 g, 28 mmol, 2.0 equiv) in DCE (30 mL) were stirred at 85° C. for 1 h. Then NaBH3CN (1.8 g, 28 mmol, 2.0 equiv) was added to the mixture at 50° C. and stirred for 2 h at 85° C. The reaction mixture was quenched with water, extracted with DCM and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (DCM:MeOH=40:1) to give the title compound (2.7 g, 50%) as a yellow oil. ESI-MS (M+1)+: 386.2. 1H NMR (400 MHz, CDCl3) δ: 7.72-7.68 (m, 3H), 7.37-7.34 (m, 1H), 7.15-7.10 (m, 2H), 3.94 (s, 2H), 3.81-3.76 (m, 4H), 3.74 (s, 3H), 3.50-3.44 (m, 1H), 1.02 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].O=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CO>[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH:3]([OH:14])[CH2:2][N:1]=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:9]
Reactant: N#Cc1ccccc1OCC(O)CN
Reactant: CCOC(=O)CC=O
Solvent: CO
Product: CCOC(=O)CC=NCC(O)COc1ccccc1C#N

Procedure:
In accordance with Example 10 above 2-(3-amino-2-hydroxypropoxy)benzonitrile was prepared. 1.9 g of this compound were dissolved in 30 ml of methanol and 1.16 g of ethyl 3-oxopropanoate were added, wereby ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-iminopropanoate was obtained. Thesolution was cooled to 0° C. and at this temperature 3 g of sodium borohydride were added little by little, whereby the imino compound was reduced. The temperature was then allowed to rise to ambient temperature and after 1 hour 100 ml of H2O were added and the total mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over MgSO4 and filtered. The residue was transformed into its hydrochloride. In this way ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate hydrochloride wasobtained. Melting point 120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Nc2ccccc2Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 1C (236 mg, 1.0 mmol) and 2-phenoxyaniline (370 mg, 2.0 mmol) in THF (10 mL) was treated with 1M lithium hexamethyldisilazide in THF (4 mL, 4.0 mmol), warmed to room temperature over 4 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[CH3:20][C:21]1([CH3:29])[O:25][CH:24]([CH2:26][O:27][NH2:28])[CH2:23][O:22]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:20][C:21]1([CH3:29])[O:25][CH:24]([CH2:26][O:27][NH:28][C:17]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[O:19])[CH2:23][O:22]1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc(Cl)nnc2Nc2ccc(I)cc2F)O1
Reaction time: 5 h

Procedure:
To a mixture of 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (46 mg, 0.12 mmol), O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (18.9 mg, 0.13 mmol) and diisopropyl ethylamine (27.2 mg, 0.21 mmol) in dichloromethane, was added PyBop (36.4 mg, 0.06 mmol). The reaction was carried out at room temperature for 5 hours. The mixture was concentrated and purified by flash chromatography to afford the desired adduct. LC/MS [9.50 min; 523 (M+1)].
Reaction SMILES: C(O[C:6](=[O:26])[CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O)(C)(C)C.Cl.Cl.[NH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>N1C=CC=CC=1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:7]1[C:6](=[O:26])[N:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:8]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1
Reactant: C1CNNC1
Reactant: CSc1nccc(C(=O)C(Cc2ccccc2Cl)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reaction time: 17 h
Yield: 22 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid tert-butyl ester, 6 (2.0 g, 5.7 mmol)) in pyridine (40 mL) is added pyrazolidine-bishydrochloride (1.2 g, 8.1 mmol). After stirring the reaction for 10 min at room temperature, the mixture i stirred at 90° C. for 2.5 hours and then at 60° C. for 17 hours. The solution i concentrated in vacuo and the resulting curd product is purified over silica (EtOAc followed by 20% MeOH/EtOAc) to afford 460 mg (22%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=5.1 Hz, 1H), 7.42-7.2 (m, 4H), 6.96 (d, J=5.1 Hz, 1H), 4.42-4.3 (m, 4H), 4.10 (s, 2H), 2.95-2.75 (m, 2H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 373.0 (100, M++H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg (0.19 mmol) 1-[2-(4-Bromomethyl-phenyl)-ethyl]-4-(2-fluoro-benzyloxy)-1H-pyridin-2-one (example 9.1b) in 1.5 mL DMF is added at RT 63 μL (0.77 mmol) pyrrolidine. The reaction mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
1-Fluoro-4-nitro-benzene (1.00 g, 7.09 mmol) is dissolved in DMF (20 mL), and to this solution, is added 1-methyl-piperazine (0.944 mL, 8.51 mmol) followed by K2CO3 (1.47 g, 10.6 mmol). After stirring the mixture at rt for 18 h, the solvent is removed via high vacuum. The resulting residue is dissolved in EtOAc (100 mL) and washed with H2O (10 mL) and brine (10 mL) and then dried (Na2SO4). The solvent is taken off via high vacuum to afford the product as a solid (1.50 g, 96%); 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37-2.42 (m, 4H), 3.39-3.43 (m, 4H), 6.98 (d, J=9.6 Hz, 2H), 8.00 (d, J=9.5 Hz, 2H); mass spectrum [(+) ESI], m/z 222 (M+H)+.
Reaction SMILES: [C:1]([C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:28]C(OCC1C=CC=CC=1)=O)=[N:17]C(OCC1C=CC=CC=1)=O)([OH:3])=[O:2].[ClH:39]>[Pd].CO.C(OCC)(=O)C>[ClH:39].[C:1]([C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH2:28])=[NH:17])([OH:3])=[O:2]
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=N)N)[C@@H]1C(=O)O
Yield: 33 %

Procedure:
A methanol/ethyl acetate (3 mL/0.5 mL) solution of compound 29 (200 mg, 0.38 mmol) and 1N HCl (0.5 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (15 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 37 mg (33%) of the title compound.