Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[NH2:25][C:24]1[CH:23]=[C:22]([CH:28]=[CH:27][CH:26]=1)[O:21][C:12]1[C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.64 g, 0.00974 mol) and Pd/C (10%) in ethanol/THF (400 mL, 3/1) was hydrogenated at 1 atm. of H2, at 50-55° C. for 3 h. The mixture was filtered through Celite and the filtrate was concentrated to about 100 mL. The crude was left in the fridge overnight. The solid was filtered and washed with small portion of cold ethanol to afford 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.05 g, 74.3% yield). 1HNMR (DMSO-d6): δ 10.30 (1H, s), 8.49 (1H, s), 7.46 (1H, s), 7.34 (1H, s), 7.07 (1H, m), 6.48 (1H, m), 6.40 (2H, m), 5.29 (2H, s), 3.90 (3H, s). LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.C(Cl)Cl.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 98 %

Procedure:
To 4,5-dimethyl-2-methoxyaniline(4.50 g, 0.03 mol), methylene chloride(100 ml) was added and phenyl chloroformate(4.80 g, 0.03 mol) was added slowly. The resulting solution was stirred for 2 hrs and thereto water(150 ml) was added, and extracted with methylene chloride and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.B(Br)(Br)Br.I.[CH3:22][O:23]COC>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH2:13][O:23][CH3:22])[CH:8]=2)[N:3]=1
Reactant: COCOC
Reactant: COc1cc([N+](=O)[O-])c2nc(C)ccc2c1
Agent: BrB(Br)Br
Agent: I
Product: COCOc1cc([N+](=O)[O-])c2nc(C)ccc2c1

Procedure:
The preparation of chelators where R8 and R9 are part of a quinoline ring and W=OH begins, for example, with 2-methyl-6-methoxy-8-nitroquinoline. The methoxy group could be cleaved with BBr3 or hot HI to yield a 6-hydroxy group, which could then be protected by reaction with dimethoxymethane under acid catalysis to yield 2-methyl-6-methoxymethyloxy-8-nitroquinoline. This can be used as starting material for the synthesis outlined above for 2-methyl-6-W-8-nitroquinoline, leading to chelators with W=OCH2OCH3. Mild acid hydrolysis of this compound gives chelators with W=OH.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[NH:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)[CH:29]=4)=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].Br[C:41]1(CCOCC)C(=O)NC(=O)NC1=O>>[CH2:1]([O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[NH:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)[CH:29]=4)=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9][C:10]1=[O:11])[CH3:41]
Reactant: COCCC1(Oc2ccc(Oc3ccc(-c4cc(-c5cccc(F)c5)n[nH]4)cc3)cc2)C(=O)NC(=O)NC1=O
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4cc(-c5cccc(F)c5)n[nH]4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(3-fluorophenyl)-1H-pyrazol-3-yl]-phenoxy}phenol (from Example 71, Part C) and 5-bromo-5-(2-ethoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+ 545.1 (M+H)+, ESI− 543.3 (M−H)−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]1[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:6]2[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]2)=[CH:12][C:11]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]1[CH3:25]
Reactant: C[C@H]1COCCN1Cc1cc(C=O)ccc1Br
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(Br)c(CN3CCOC[C@@H]3C)c2)C[C@H](C)N1
Temperature: 25 °C

Procedure:
(2S,6R)-2,6-Dimethylpiperazine (0.304 g, 2.67 mmol) and (S)-4-bromo-3-((3-methylmorpholino)methyl)benzaldehyde (0.530 g, 1.78 mmol) in DCM (10 ml) were stirred at RT under nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.565 g, 2.67 mmol) was then added and the resulting solution was stirred at RT over the weekend. The reaction mixture was quenched with saturated NaHCO3. The reaction mixture was extracted with DCM (×3). The organic layer was dried over MgSO4, filtered and evaporated to afford the sub-title compound as a yellow oil. Yield: 0.620 g
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[Br:42]Br>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([Br:42])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: BrBr
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(Br)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with bromine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:18])[NH:13][C:14](=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:14]1[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=[C:12]([CH3:18])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 40 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7(6H)-one (0.40 g, 1.23 mmol) in POCl3 was added diisopropylethylamine (0.13 ml, 0.77 mmol). The reaction mixture was stirred under N2 at 90° C. for 3.5 hours. After cooling down to room temperature, the reaction mixture was poured into ice-water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexane/EtOAc 10:1) to yield the title compound as a white solid (42.8 mg, 40%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O-])(O)=O.[Na+].IC>CN(C=O)C>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C([O-])O
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(SC)cc1
Yield: 97 %

Procedure:
1.82 g (10 mmol) of the 4-methylthiophenylacetic acid were dissolved in 30 mL of DMF and 1.34 g (16 mmol) of NaHCO3 are then added; the agitation mixture is stirred for 15 min approx. Next, 1.9 mL of ICH3 are added while keeping agitation at room temperature for 24 h. Once this time elapsed the mixture is poured on water/ice. As no precipitation occurs ether is added and extracted. The organic phase is washed with water and after drying on sodium sulfate anhydride, the organic phase is concentrated in a rotary evaporator getting 1.92 g (9.7 mmol, 97% yield) of colorless oil which spectroscopic data confirm the expected structure. This product will be used in the next step of the synthesis process without purification as it provides a single stain in TLC (eluting dichloromethane/methanol 9/1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][N:11]([CH3:19])[C:12]([CH:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([NH:8][CH:16]1[CH2:17][CH:14]([C:12]([N:11]([O:10][CH3:9])[CH3:19])=[O:13])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CC(=O)C1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CON(C)C(=O)C1CC(NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Benzylamine (751 mg, 7.02 mmol), N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (423 mg, 2.70 mmol), and sodium cyanoborohydride (237 mg, 3.78 mmol) were dissolved in 25 mL of anhydrous methanol. The pH of the solution was brought to 5 by addition of acetic acid, and the reaction was stirred for 24 hours at room temperature. The pH of the solution then was brought to 8 by addition of 1 M aqueous sodium bicarbonate. The solvents were removed under reduced pressure. The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL). The organic layer was washed with water and brine and dried, purified using flash column chromatography with hexanes/ethyl acetate (2:1) as an eluant to give 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (498 mg, 2.00 mmol, 75% yield) as an oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][C:7](=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>O.C(O)(=O)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Cl:5][CH2:6][C:7](=[O:16])/[C:8](=[N:1]/[OH:3])/[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=N\O)C(=O)CCl
Yield: 91 %

Procedure:
A solution of 35.6 g of sodium nitrite in 100 ml of water was added to a cold solution of t-butyl 4-chloro-3-oxobutanoate (100.9 g, 0.439 moles of 84% material*) in 400 ml of acetic acid containing 50 ml of water over a 0.5 hour period with stirring. The mixture was stirred in the cold for an additional hour, then stored in the cold overnight. The mixture was diluted with 500 ml portions of water, 500 ml of saturated sodium bicarbonate, 500 ml of water and 500 ml of brine, then dried over magnesium sulfate and evaporated to give an amber oil; yield 88.6 g (91% yield). This material was used in the next step without further purification. *This compound was obtained from Lonza Chemical Co., Fair Lawn, N.J.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]=[C:11]=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:16]=1[NH2:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:15]([O:14][CH3:13])[C:16]=1[NH:17][C:11]([NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CC(C)C1CCC(N=C=O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(NC(=O)NC2CCC(C(C)C)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 1.6 g of 4-isopropylcyclohexylisocyanate in chloroform is added a solution of 1.8 g of 2,4,6-trimethoxyaniline in chloroform dropwise in the presence of pyridine. The mixture is stirred at room temperature until starting compounds disappear on TLC. The resultant mixture is concentrated and the residue is dissolved in ethyl acetate. The solution is washed with diluted hydrochloric acid, aqueous sodium hydrogencarbonate solution and brine. The organic layer is dried over magnesium sulfate and filtered off. The filtrate is distilled away and the resulting residue is crystallized to give N-(2,4,6-trimethoxyphenyl)-N'-(4-isopropylcyclohexyl)urea.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])=[O:5])[CH3:2].C(=O)([O-])[OH:41].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:38]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19])=[O:41])=[O:5])[CH3:39]
Reactant: O=C([O-])O
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
10 ml of a methylene cloride solution containing 554 mg (1.00 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 37) were cooled in an ice bath, and then 1.5 ml (1.5 mmol) of a 1M aqueous solution of sodium hydrogencarbonate and then 215 mg (1.00 mmol) of m-chloroperbenzoic acid (80% purity) were added, and the reaction solution was stirred for 90 minutes at the same temperature. At the end of this time, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was stirred for 10 minutes to complete the reaction. The reaction solution was then diluted with methylene chloride, ice-cooled, washed with an aqueous solution of sodium hydrogencarbonate and condensed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel. Elution with ethyl acetate afforded 145 mg (yield 25%) of an isomer of the title compound of lower polarity (the isomer is a result of the configuration of the S-oxide), followed by 96 mg (yield 17%) of a higher polarity isomer of the title compound, both as foam-like solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2(C(=O)O)CC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
In trifluoroacetic acid (5.0 mL) and water (0.5 mL) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (219 mg), and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, a small amount of tetrahydrofuran was added to the residue, and the mixture was neutralized by 1N aqueous sodium hydroxide solution. Several drops of acetic acid was added to the mixture, the mixture was extracted with ethyl acetate, washed with a saturated brine, and the organic layer was separated and concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (95 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][S:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and cyclopropanamine (9.16 uL, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer).The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid 1H NMR (CHLOROFORM-d) δ: 8.42 (br. s., 1H), 7.78 (d, J=1.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.13 (br. s., 1H), 6.85 (d, J=9.1 Hz, 2H), 6.17 (d, J=2.3 Hz, 1H), 5.05 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.42 (dd, J=10.4, 3.5 Hz, 1H), 3.53 (br. s., 2H), 3.34 (br. s., 4H), 3.14 (td, J=12.9, 2.3 Hz, 1H), 2.99 (td, J=12.8, 2.7 Hz, 1H), 2.78-2.93 (m, 3H), 2.68 (br. s., 4H), 2.39 (dd, J=13.6, 1.3 Hz, 1H), 0.80-0.90 (m, 2H), 0.54-0.67 (m, 2H). [M+H] calc'd for C23H28N6O2S, 479; found, 479.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:30][CH3:31]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([CH2:30][CH3:31])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a solution of 10.0 g (0.028 mole) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate [prepared in Example 2] in 75 mL of N,N-dimethylformamide was added 1.2 g of 60% sodium hydride (0.03 mole) in mineral oil was added. After stirring for 0.5 hour, the sodium hydride had dissolved and 8.5 g (0.056 mole) of iodoethane was added. The solution was stirred at room temperature for 16 hours, diluted to 400 mL with water and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo. The residue was triturated with hexane to remove mineral oil. The residue was absorbed onto silica gel by dissolving in CH2Cl2 and adding dry silica gel, then concentrating in vacuo to a dry powder. This material was transferred to the top of a silica gel column and eluted with 10% (v/v) ethyl acetate in hexane to give 4.9 g (45.5%) of the title compound; m.p.= 113°-114.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:25]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH2:20][C:21]([F:22])([F:23])[F:24])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:25]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: Fc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Yield: 55 %

Procedure:
Following the procedure for 203, 10-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 2-fluoropyridin-3-ylboronic acid to give 10-(2-fluoropyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.108 g, 55%), 1H NMR (400 MHz, DMSO) δ 8.71 (t, J=2.0, 1H), 8.57-7.83 (m, 4H), 7.80-7.39 (m, 2H), 7.22 (d, J=8.5, 1H), 5.88 (q, J=8.8, 2H), 4.79-4.38 (m, 4H). MS (ESI(+)): m/z 431.1 (M+H), which was hydrolyzed with HCl to give 218 (0.072 g, 72%). 1H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.78 (d, J=2.3, 1H), 8.09 (d, J=2.8, 2H), 7.69 (ddd, J=8.9, 7.7, 2.2, 2H), 7.36 (t, J=23.8, 1H), 7.08 (d, J=8.6, 1H), 6.30 (t, J=6.7, 1H), 5.91 (q, J=8.8, 2H), 4.56 (dd, J=13.5, 5.5, 4H). MS (ESI(+)): m/z 429.1 (M+H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1
Reactant: COCCO
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture comprising 20 ml of ethylene glycol monomethyl ether and 70 mg of 55% sodium hydride was heated to 100° C., followed by the addition of a mixture comprising 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline and 5 ml of ethylene glycol monomethyl ether. The obtained mixture was heated under reflux for 2 hours and poured into 50 ml of water. The obtained mixture was extracted with 50 ml of ethyl acetate twice. The organic layers were together washed with 70 ml of an aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was reprecipitated from ethyl acetate/n-hexane to give 420 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1.[CH2:16]([C:18]1[CH:23]=[C:22](O)[CH:21]=[CH:20][C:19]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:17].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:22]2[CH:21]=[CH:20][C:19]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:18]([CH2:16][CH3:17])[CH:23]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1CC
Reactant: Cc1ccccc1-c1snc(Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccccc2C)cc1CC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed [3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methanol (80 mg, 0.33 mmol, 1.00 equiv), ethyl 3-(2-ethyl-4-hydroxyphenyl)propanoate (89.17 mg, 0.40 mmol, 1.20 equiv), ADDP (210.87 mg, 0.84 mmol, 2.52 equiv), n-Bu3P (101.42 mg), Tol (1.5 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 123 mg (83%) of ethyl 3-(4-[[3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-ethylphenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H21FO5, 444.1 (M+H). found 444.1.