Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.832 g) and triphenylphosphine (1.25 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.50 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.09 g). 1H NMR (300 MHz, CDCl3) δ 0.39-0.48 (2H, m), 0.61-0.76 (2H, m), 1.14-1.37 (4H, m), 1.46 (9H, s), 3.90-4.04 (4H, m), 4.03-4.19 (1H, m), 4.77 (1H, brs), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.01 (1H, d, J=8.7 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 8.04 (1H, dd, J=8.5, 2.1 Hz), 8.22 (1H, d, J=1.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:23][CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:23][CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O)OCC
Temperature: 75 °C
Yield: 26.3 %

Procedure:
A solution of 5.02 g (18.00 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 140 ml of DMA was treated at RT with 0.86 g (19.80 mmol) of NaH (55% in oil) in four portions. After 1 h 3.72 ml (21.60 mmol) of 2-bromo-1,1-diethoxy-ethane were added over 30 min. The reaction was stirred over night and heated for 1 h at 75° C. The reaction was cooled and neutralized with cold aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 98:2) to yield 1.87 g (26%) of the title compound as a yellow viscous oil. MS: 395.4 (MH+, Cl).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 53.1 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (89 μL, 1.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (150 mg, 53%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1.[Li]CCCC.[CH3:17][C:18](OC(C)=O)=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[C:18](=[O:19])[CH3:17]
Reactant: COCOc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(Cl)c1C(C)=O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-(methoxymethoxy)benzene (24 g, 136.74 mmol, 1.00 equiv, 98%) in THF (240 mL) was added TMP (21 g, 150.00 mmol, 1.10 equiv). To the above solution was added n-BuLi (61 mL, 1.10 equiv, 2.5 mol/L) dropwise with stirring at −75° C. over 30 min. After stirring for 2 h at −75° C., the resulting mixture was reacted with Ac2O (15.5 g, 148.92 mmol, 1.10 equiv, 98%) via dropwise addition with stirring at −75° C. over 30 min. The mixture was stirred for additional 30 min at room temperature, and then quenched by adding water. The resulting mixture was extracted with 2×300 mL of ethyl acetate. The combined organic layers was washed with H2O, dried over Na2SO4 and concentrated under vacuum to give 1-(2-chloro-6-(methoxymethoxy)phenyl)-ethanone as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:18]1[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:16])[CH:12]=[CH2:13].Cl>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O.C(N(CC)CC)C>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[CH2:19][C@H:18]1[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(=O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of oxalyl chloride (0.18 ml) in dichloromethane (10 ml) was added dropwise a solution of dimethyl sulfoxide (0.3 ml) in dichloromethane (2 ml) at -60° C. After stirring at -70° C. for 30 minutes, to the mixture was added dropwise a solution of (2S,4R)-1-allyloxycarbonyl-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine (0.6 g) in dichloromethane (5 ml) at -60° C. After stirring at -70° C. for 30 minutes, to the mixture was added dropwise triethylamine (1.3 ml) and the resulting mixture was allowed to warm to 0° C. and diluted with ethyl acetate (150 ml) and brine. After adjusting pH to around 3 with 10% hydrochloric acid, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (50 ml) eluting with 15% ethyl acetate in hexane to give (2S)-1-allyloxycarbonyl-2-t-butyldimethylsilyloxymethyl- 4-oxo-pyrrolidine (0.54 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.[CH3:32][O:33][C:34]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:36][C:35]2[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:34]=2[O:33][CH3:32])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1
Reaction time: 0.25 h

Procedure:
A solution of 3.57 g (11.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 12 ml of abs. THF and 2.35 ml of DMPU (1.65 equivalents) is cooled down to -75° C., under argon, and is treated dropwise, at an internal temperature of less than -70° C. and over a period of 30 min, with 22.9 ml (1.96 equivalents) of a 1 M solution of lithium bis(trimetlhylsilyl)amide in THF (Aldrich, Steinheim, FRG). After a further 15 min, 25 ml of a toluene solution containing approximately 1 equivalent of 2,4-dimethoxybenzyl bromide is added dropwise to this mixture, over the space of 20 min, and this mixture is allowed to react at -70° C. for 2 h. 4.36 ml of propionic acid and 4.36 ml of water are then added to this solution and the temperature is allowed to rise to 0° C. The reaction mixture is diluted with 200 ml of (cold) ethyl acetate and stirred up for 5 min with 60 ml of (cold) 10% citric acid. After that, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again, dried over Na2SO4 and concentrated. The title compound is isolated by flash chromatography on silica gel (E). TLC Rf (E)=0.24.-FAB-MS (M+H)+ =455.-HPLC tRet =16.85 min (gradient II). IR(CH2Cl2)=inter alia 3429, 1769, 1712, 1613 and 1506 cm-1.-1H-NMR(CDCl3)=inter alia 7.34-7.10/m (5H); 6.98/d (1H); 6.45-6.29/m (2H); 4.31/txd (1H); 3.78 and 3.71/each s (each 3H); 3.08 and 2.66/each dxd (each 1H); 1.35/s (9H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@H:5]([CH2:21][O:22]S(C1C=CC(C)=CC=1)(=O)=O)[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+]>CN(C=O)C>[CH3:13][C:9]1([CH3:12])[N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@@H:7]([CH2:6][C@H:5]2[CH2:4][CH2:3][CH2:2][O:22][CH2:21]2)[CH2:11][O:10]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCCO)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-hydroxy-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (254 mg, 0.54 mmol) in anhydrous DMF (8 mL) at 0° C. under N2 was added NaH (43 mg, 1.08 mmol). After stirred at this temperature for 1 hr, the reaction was quenched with aq. NH4Cl and then evaporated to dryness. The residue was dissolved in EtOAc and H2O, the separated aqueous phase was extracted with EtOAc. The combined organic phases were washed with H2O, brine, and dried over Na2SO4, filtered, and evaporated. The residue was purified on silica gel column to afford (S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (136 mg, 84%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)(Cl)Cl>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 85 mg, 0.29 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (49 mg, 0.29 mmol) and molecular sieves 3 Å in dry methanol/chloroform (1:1, 10 mL) was heated to 70° C. for 3 hours. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (190 mg, 0.88 mmol) was added. After 30 minutes, the reaction was filtered through celite, the filtrate was concentrated to dryness, taken up in 15% methanol/chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 70 mg (54%) of the title compound as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[C:17]1([CH:12]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:24][CH2:23]3)[C:15](=[O:16])[NH:14][CH2:13]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NCC(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCC(c2ccccc2)C12CCNCC2
Yield: 63.2 %

Procedure:
A suspension of rac-8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (28.8 g, 90 mmol) in MeOH: DCM (4: 1, 500 ml) was hydrogenated in the presence of Pd (10% on C, 14 g, 132 mmol) at 2 bar for 48 h at room temperature. After filtration over celite, the reaction mixture was evaporated and the residue dissolved in NaOH (2 N, 200 mnL). The product was extracted with DCM (3×150 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the title compound (13.1 g, 63%) as a white solid after trituration from diethylether. MS: m/e=231.4 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2)CC1
Yield: 80.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and oxazolidin-2-one (104 mg)), the title compound (327 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:17][CH3:18].[CH3:20]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]([C:14](=[O:16])[CH3:15])[CH3:20])=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COS(C)(=O)=O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetylamino-2-methoxy-5-nitro-benzoic acid methyl ester (4.0 g, 14.9 mmol), methanesulfonic acid methyl ester (1.3 mL, 15.4 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 40 mL DMF was stirred overnight at ambient temperature. The mixture was poured onto ice water and diluted with dichloromethane. The organic phase was separated, dried and concentrated i. vac.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[C:69]([F:72])([F:71])[F:70])[C:63](Cl)=[O:64]>>[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[C:69]([F:70])([F:71])[F:72])[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)c(F)c4)cc3)cc2C1=O
Yield: 78 %

Procedure:
The compound of example 195 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-fluoro-4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [F:1][C:2]([S:5]([O:8]S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6])([F:4])[F:3].O[C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20].CC1C=CC=C(C)N=1>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([O:8][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20])(=[O:7])=[O:6]
Reactant: COCCOc1ccc(O)c(C=O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCOc1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethyl sulphonic anhydride (3.88 ml) was added dropwise over a period of 10 minutes to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (4.11 g) and 2,6-dimethylpyridine (2.67 ml) in dichloromethane (20 ml) at 0° C. under an atmosphere of argon. After stirring at room temperature for 16 hours, the mixture was added to ice (100 g). The organic phase was separated, washed with 5% aqueous sodium carbonate solution (2×10 ml), dried (MgSO4) and evaporated to give an oil which was purified by flash column chromatography on silica gel using dichloromethane as eluent to give 2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxy)benzaldehyde (2.2 g) as an oil; NMR(CDCl3): 3.45(3H,s), 3.78(2H,m), 4.19(2H,m), 7.3(2H,m), 7.48(1H,d) and 10.23(1H,d); m/z 329(M+H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(N)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-methoxyphenol (0.74 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml) was heated at 100° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound (1.1 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(Cl)(Cl)[Cl:13].C(=O)([O-])[O-].[Na+].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=12
Reactant: ClC(Cl)Cl
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C

Procedure:
1.00 g (6.75 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide is suspended in 5 ml of phosphoryl chloride. 2 ml of chloroform are then added, and the mixture is heated at reflux temperature overnight. The mixture is allowed to cool to RT and poured into ethyl acetate/ice-water. Solid sodium carbonate is then added. The phases are separated and the aqueous phase is washed with ethyl acetate. The organic phases are dried with sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/methanol=4:1).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.O[N:9]=[C:10]1[NH:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:12][CH2:11]1.[OH-].[Na+]>C(O)C>[CH3:7][O:6][N:9]=[C:10]1[NH:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:12][CH2:11]1
Reactant: COS(=O)(=O)OC
Reactant: ON=C1CSc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1CSc2ccccc2CN1
Reaction time: 24 h

Procedure:
Dimethylsulphate (1.26 g) was added dropwise to a vigorously stirred suspension of 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared in a similar manner to Example 25 above) in a mixture of a 10% aqueous solution of sodium hydroxide (4 ml) and ethanol (150 ml). The reaction mixture was kept at room temperature for 24 hours and then extracted with dichloromethane. The organic layer was dried and the solvent was removed by evaporation. Purification of the solid residue by flash chromatography using dichloromethane as eluent gave 3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 1.51 g (m.p. 101°-102° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:17][CH3:18])[N:9]=[CH:8][N:7]=[C:6]2[O:5][C:4]1[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=2)=[O:34])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1O
Temperature: 60 °C

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (70 mg, 0.247 mmol) described in Example 107A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (90 mg, 0.287 mmol) and the mixture was heated to 60° C. for 15 h. Concentration in vacuo followed by trituration of the resulting solid with methanol afforded, after filtration and drying, 1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (73 mg, 59%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.75 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 7.55 (dd, J=2.1, 2.1 Hz, 1H), 7.50 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (dd, J=9, 1.2 Hz, 1H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.88 (s, 1H), 4.00 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.