Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC(O)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 82.8 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccccc2F)C1
Solvent: C1CCOC1
Product: Fc1ccccc1[C@@H]1CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 75.3 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(2-fluorophenyl)piperidin-1-yl]methanone (25 mg, 0.073 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 18 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[C:4]([N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH3:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:3](=[O:21])[C:4]([NH:9][CH3:10])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccccc(N)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CNc1ccccc(N)c1=O
Temperature: 0 °C

Procedure:
A solution of 2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one [described in Example 9 (b), 2.53 g] in conc. sulfuric acid (25 ml) is heated at 75° C for 1 hour and added to ice. The ice-mixture is neutralized with sat. sodium carbonate solution and extracted with chloroform. The organic extract is dried over sodium sulfate and evaporated to give 2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.C(Cl)[Cl:37]>Cl>[ClH:37].[ClH:37].[ClH:37].[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:14])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(OCCN1CCNCC1)N1CCN(c2ccccc2)CC1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (7.01 g, 17.7 mmol) was dissolved in DMF (150 mL). Phenylpiperazine (2.8 mL, 18.3 mmol) and NEt3 (3.0 mL, 21.5 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (250 mL), washed with 1M aq Na2CO3 solution (5×250 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-phenyl-piperazine-1-carboxylate (5.68 g, 77%) as a yellow oil. 2-(4-(tert-Butoxycarbonyl)-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (0.45 g, 1.07 mmol) was dissolved in a mixture of DCM (30 mL) and 2M HCl in Et2O (4 mL, 8 mmol) and stirred overnight. The supernatant was discarded. The residue washed with DCM (3×15 mL) and dried in vacuo to give 2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate trihydrochloride (0.42 g, 98%) as a pale brown glass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:5]>CN(C)C=O.[Ni]>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(N)cc1
Reaction time: 6 h
Yield: 86.5 %

Procedure:
Method-A Through a mixture of 2-(4-aminophenoxy)-propionic acid 9 (240 g, 1.103 mmol) in methanol (4.8 liters) was passed dry HCl gas at 10° C. for 1 hour followed by reflux for 48 hours. Methanol (2.5 liter) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 10 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 10 (80 g, 37.2%) as a brown syrup. Method-B 2-(4-Nitrophenoxy)-propionic acid methyl ester 14 (20 g, 88.88 mmol) was dissolved in dimethyl formamide (100 ml) in a pressure vessel, Raney nickel (20 grams) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 6 hours. The catalyst was removed by filtration and the dimethyl formamide distilled off under vacuum. Crude 10 was purified by column chromatography on silica gel using chloroform as eluant to get pure 10 (15 g, 86.55%) as a brown syrup.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O1CCCC1.O>[CH2:16]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCON(Cc1ccccc1)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 22.4 g of methyl 3-[N,N-dibenzylaminoxy]propanoate and 4.50 g of potassium hydroxide in 200 ml of tetrahydrofuran and 200 ml of water is heated under reflux for 12 hours under N2. The mixture is concentrated under reduced pressure and the residue is partitioned between water and ether. The combined aqueous extracts are acidified with hydrochloric acid and then extracted with methylene chloride. The combined organic extracts are dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[CH2:24][C:25]1[N:29]2[N:30]=[C:31]([C:34](=O)[CH3:35])[CH:32]=[CH:33][C:28]2=[N:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11]/[N:12]=[C:34](/[C:31]2[CH:32]=[CH:33][C:28]3[N:29]([C:25]([CH2:24][C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][C:14]=4[F:13])[N:21]=[CH:20][CH:19]=[CH:18]5)=[CH:26][N:27]=3)[N:30]=2)\[CH3:35])=[O:10])=[CH:6][CH:7]=1
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\NC(=O)Nc1ccc(Cl)cc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1

Procedure:
The title compound was prepared from N-p-chlorophenylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl-]ethanone in analogy to the synthesis of example 1. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 9.18 (s, 1H), 8.86 (dd, 1H), 8.31 (m, 2H), 8.07 (d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.67 (m, 3H), 7.48 (q, 1H), 7.36 (d, 2H), 4.58 (s, 2H), 2.32 (s, 3H). LCMS (method C): [MH]+=489, tR=4.35 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[OH:6]
Reactant: CCCCCCCCCc1ccccc1Br
Reactant: O=CCCCCl
Product: CCCCCCCCCc1ccccc1C(O)CCCCl

Procedure:
In a manner analogous to that described in Example 17a, but starting from 4-chlorobutyraldehyde, 2-nonylbromobenzene yields the title compound in the form of a colourless oil; IR (CH2Cl2): 3600, 2960, 2930, 2860, 1470, 1055 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][CH2:16][C:17](=[O:20])[CH2:18][F:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][F:19])[CH2:16][F:15]
Reactant: O=C(CF)CF
Reactant: Cc1ccc(I)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)(CF)CF)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 2-bromo-1-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (25 mL) at 0° C. was slowly added i-PrMgCl (24 mL, 24 mmol). After being stirred for 1 h at 0° C., the reaction mixture was cooled to −78° C. Then a solution of 1,3-difluoropropan-2-one (0.85 g, 9.04 mmol) in dry THF (25 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with HCl (2 N) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, eluting with PE:EA (5:1) to give 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, yield 55%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 H), 7.46 (s, 1 H), 7.21 (d, 1 H), 6.21 (s, 1 H), 4.97-4.94 (m, 1 H), 4.85-4.82 (m, 2 H), 4.74-4.71 (m, 1 H), 2.26 (s, 3 H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:30])[C:10]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])C.[OH-].[Na+]>C1COCC1>[CH2:23]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:10]1[N:9]([CH3:30])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnn2C)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 0.799 g (1.862 mmol) of the product of Example 7 in 20 mL of methano/THF (1:1) was added 9.3 mL of 1N sodium hydroxide solution and the resulting mixture was heated to reflux for 18 h. The reaction was then cooled to room temperature and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.697 g (93%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec: 402 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: N#Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: N=C(NO)c1cccnc1
Reaction time: 0.21 h

Procedure:
To a solution of 5.012 g (72.1 mmol) of hydroxylamine hydrochloride in 55 mL of isopropyl alcohol, 8.8 g (105.7 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 5.0 g (48 mmol) of 3-cyanopyridine was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue, which was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1O[N:7]=[CH:8][C:9]1[NH:10][C:11]([CH2:34][F:35])=[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-])=O.[OH-].[K+]>C(O)C>[C:8]([C:9]1[NH:10][C:11]([CH2:34][F:35])=[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:7]
Reactant: CCOC(=O)C1=C(C=NOc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(C#N)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 58.9 %

Procedure:
The product of step (a) (0.45 g, 0.8 mmoles) was dissolved in 95% aqueous ethanol (20 ml) by heating, and then potassium hydroxide (10.16 ml of 0.2M in 95% aqueous ethanol) was added dropwise. The solution was heated at reflux for 3 hours and then the ethanol removed in vacuo. The residue was dissolved in water (75 ml), 5% aqueous sodium hydroxide (6 ml) and chloroform (100 ml). The aqueous layer was separated and extracted several times with chloroform. The combined extracts were washed with water, dried (MgSO4) and the solvent was removed in vacuo. The residue was crystallised from 2-propanol to give the title compound (0.19 g) mp 147°-8° (dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][C:25]=2[F:31])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH:32](N(CC)C(C)C)(C)[CH3:33].C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl.[Cu](I)I>[C:32]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13]([CH2:16][N:17]3[C:21](=[O:22])[CH2:20][CH2:19][O:18]3)=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:25]([F:31])[CH:26]=1)#[CH:33]
Reactant: O=C(NOCCO)c1cc(CN2OCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(CN3OCCC3=O)c(F)c2F)c(F)c1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (36.9 mg, 66.9 μmol) obtained in Example 37, bis(acetonitrile)dichloropalladium (II) (3.5 mg, 13.5 μmol), 3,3′,3″-phosphinidine-tris(benzenesulfonic acid) trisodium salt (19.0 mg, 33.4 μmol), and copper iodide (I) (2.6 mg, 13.6 μmol) were suspended in methanol (2.5 ml) under a nitrogen atmosphere. To this suspension, N,N-diisopropylethylamine (14.0 μl, 80.4 μmol) and trimethylsilylacetylene (47.3 μl, 334.7 μmol) were added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (30 ml), and washed with saturated brine (2×15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was dissolved in THF (2 ml). To this solution, tetrabutylammonium fluoride (1.0 M solution in THF, 0.10 ml, 0.10 mmol) was added, and the mixture was stirred for 1 hour, and then concentrated under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH (8:1)) to give 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (Compound G-5, 11.1 mg, 37%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](N)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:25].[Na+]>COCCOC.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Oc2ccc(I)cc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a stirred solution of 4-(4-fluorophenoxy)benzenamine (3.4 g, 16.73 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (45 mL) was added dropwise a solution of 50% sulfuric acid (7 mL) in water (34 mL) at room temperature. The reaction was cooled to −5° C. and a solution of sodium nitrite (1.73 g, 25.07 mmol, 1.50 equiv) in water (12 mL) was then added dropwise within 30 min. The resulting solution was stirred for 30 min at −5-0° C. then a solution of sodium iodide (12.6 g, 84.00 mmol, 5.02 equiv) in water (34 mL) was added dropwise at −5-0° C. After stirring for 30 min at −5-0° C., the solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of saturated Na2SO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum to give 5.0 g (95%) of 1-fluoro-4-(4-iodophenoxy)benzene as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 7.62-7.57 (m, 2H), 7.08-6.93 (m, 4H), 6.77-6.70 (m, 2H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CCOC(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCSCC2)c(F)c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of thiomorpholine (3.57 g, 34.56 mmol) and Et3N (3.50 g, 34.56 mmol) in EtOAc was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 min in an ice bath. Upon the end of addition the reaction mixture was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (5.50 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[F:20][C:21]([F:37])([F:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.ClCC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:37])([F:20])[F:36])=[CH:27][CH:26]=3)[S:29][CH:30]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(F)c1)OC(C)C

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(3-fluoro-4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester [example 54 c]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (example 18 a]and 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[F:30]C1C=C2C(=CC=1F)N=C(C)NC2=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:30])[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: Cc1nc2cc(F)c(F)cc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3cc(F)ccc3n2)o1
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3cc(F)c(F)cc3n2)o1

Procedure:
This compound was prepared in the same manner as that described in Example I or the synthesis of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)quinazoline, by using 6,7-difluoro-2-methyl-4-(3H)quinazolinone (1 g) as a starting material.
Reaction SMILES: Cl.C(O[C:7](=O)[N:8]([CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([C:34]([C:36]2[S:40][C:39]3[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=3[C:37]=2[Cl:45])=[O:35])[CH2:17][C:18]2[CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:12][CH2:11]1)C)(C)(C)C.C(O)C>C(OC)(C)(C)C>[ClH:45].[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:20]2[C:21]([O:24][CH3:25])=[CH:22][CH:23]=[C:18]([CH2:17][N:16]([CH:13]3[CH2:12][CH2:11][CH:10]([NH:8][CH3:7])[CH2:15][CH2:14]3)[C:34]([C:36]3[S:40][C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[C:37]=3[Cl:45])=[O:35])[CH:19]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: COc1ccc(CN(C(=O)c2sc3ccccc3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: COC(C)(C)C
Product: CNC1CCC(N(Cc2ccc(OC)c(-c3ccc(C#N)cc3)c2)C(=O)c2sc3ccccc3c2Cl)CC1
Yield: 201.5 %

Procedure:
Concentrated hydrochloric acid (27.5 mL) was added to a solution of compound 6 (11.0 g, 17.1 mmol) and ethanol (82.5 mL). The mixture was stirred until reaction was complete as monitored by TLC. The mixture was concentrated in vacuo and dichloromethane added and concentrated again, this was repeated until a solid was obtained. The solid was then slurried with t-butylmethyl ether (30 mL), filtered, and the organic layer dried (MgSO4) and concentrated in vacuo to give the title compound 7 (10.0 g, 99%): δH (360 MHz: DMSO, 70° C.) 1.30-1.50 (m, 2H), 1.85 (br s, 4H), 2.12 (br d, 2H), 2.48 (s, 3H), 2.91 (br t, 1H), 3.81 (s, 3H), 3.87 (br s, 1H), 4.71 (s, 2H), 7.14 (d, 1H), 7.29 (s, 1H), 7.40 (d, 1H), 7.57-7.68 (m, 4H), 7.80-7.90 (m, 3H), 8.09 (d, 1H), 8.82 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[O:29][CH:30]=1.[I-].[K+]>CC(=O)CC>[CH3:1][C:2]1[CH:3]=[C:4]([O:17][CH2:25][C:26]2[N:27]=[C:28]([CH:31]=[CH:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([C:42]([F:45])([F:43])[F:44])(=[O:41])=[O:40])=[CH:37][CH:38]=3)[O:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: O=S(=O)(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Cc1cc(OCc2coc(C=Cc3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 132 mg (0.57 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol and 186 mg (0.57 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 200 mg (0.57 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-oxazole and 95 mg (0.57 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 50 ml water was added and the mixture extracted with two portions of 50 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated. Chromatography on silica, eluent ethyl acetate, returned 150 mg (49%) pure title compound as light yellow crystals melting at 140-142° C.