Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]=[CH2:35]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH2:35][CH:34]=[CH2:33])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2O)Cc2ccccc2C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1c(Cl)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a suspension of 2-(3-chloro-2-hydroxy-benzoylamino)-indan-2-carboxylic acid ethyl ester (14) (250 mg, 0.69 mmol), anhydrous Cs2CO3 (453 mg, 1.39 mmol), and KI (23 mg, 0.14 mmol) in DMF (10 mL) is added 3-bromo-propene (70 μL, 0.83 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (80 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (17) as white solid (160 mg, 58%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:10])[CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:20][C:21]1[C:26]([F:27])=[C:25](Cl)[N:24]=[C:23]([CH3:29])[N:22]=1>ClCCl>[Cl:20][C:21]1[C:26]([F:27])=[C:25]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[CH3:10])[N:24]=[C:23]([CH3:29])[N:22]=1
Reactant: C[C@@H]1CN(C)CCN1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 35 °C
Reaction time: 72 h
Yield: 118.2 %

Procedure:
To a solution of (3R)-1,3-dimethylpiperazine dihydrochloride (Example 63) (5.88 g, 31.4 mmol) in dichloromethane (126 mL) was added N,N-diisopropylethylamine (18.11 mL, 104 mmol), and 4,6-dichloro-5-fluoro-2-methylpyrimidine (5.69 g, 31.4 mmol). The solution was heated at 35° C. and stirred for 3 days. The solution was cooled to room temperature, diluted with DCM (100 mL), and washed with sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.60 g, >100% yield) as a brown oil that was used without further purification. LCMS: (M+H)+: 258.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCCSCCCOc1cccc2c(Cl)c(C(=O)CC)cnc12
Solvent: CC#N
Product: CCCSCCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Yield: 54 %

Procedure:
3-Propanoyl-4-chloro-8-(3-propylthiopropoxy)quinoline (2.0 g, 5.7 mmol) and o-toluidine (0.7 g, 6.5 mmol) was refluxed in acetonitrile (10 ml) for 2 h. The solvent was evaporated and the residue was partitioned between methylene chloride and 10% Na2CO3 solution. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (methylene chloride: ethyl acetate 70:30). 1.3 g (54%) of the title compound was obtained. (1H-NMR, 300 MHz, CDCl3) 0.94 (t, 3H), 1.26 (t, 3H), 1.57 (m, 2H), 2.25 (m, 2H), 2.34 (s, 3H), 2.49 (t, 2H), 2.75 (t, 2H), 3.15 (q, 2H), 4.27 (t, 2H) 6.83-7.23 (m, 7H), 9.22 (s, 1H), 11.73 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](=[NH:12])OC)=[CH:5][CH:4]=1.[NH3:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([NH2:12])=[NH:15])=[CH:13][CH:14]=1
Reactant: N
Reactant: COC(=N)COc1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(OCC(=N)N)cc1
Reaction time: 48 h

Procedure:
23.9 g (0.122 mole) of methyl 2-(4-methoxyphenoxy)acetimidate are added to a solution, maintained at 10° C., of 10.4 g (0.61 mole) of ammonia in 480 ml of absolute ethanol. The reaction mixture is left for 2 days at room temperature and the excess ammonia is then driven off with a stream of nitrogen. The solution obtained is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethyl sulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 80 ml methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 189°-191° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(NC)c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of the above ester (10.5 g, 32.5 mmol) in EtOAc (130 mL) was hydrogenated over 10% palladium on carbon (0.5 g) at 50 psi for 24 h. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated. A mixture of EtOAc/hexane (1:1, 10 mL) was added to the residue and the resulting mixture was stirred for 0.5 h. The crystals were filtered and washed with hexane to give 2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester (7.74 g, 81%), mp 118-123° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([OH:25])=O)[C:21]([OH:22])=[C:16]2[CH:15]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CC(O)=O>CN(C=O)C>[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=3)=[O:25])[C:21]([OH:22])=[C:16]2[CH:15]=1
Reactant: O=C(O)c1cnc2sc(Br)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(Br)cc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (1.00 g) in CHCl3 (26 mL) is added bromine (0.23 mL) dropwise. The reaction is stirred at rt for 2 h. The reaction mixture is poured into 2N HCl (30 mL), and the aqueous layer is extracted with CHCl3 (3×30 mL). The combined organic layers are washed with H2O (100 mL), dried with MgSO4, filtered and concentrated in vacuo to yield 0.840 g (62%) of the bromide as a yellow solid. This material (0.757 g) is suspended in 10% aqueous NaOH (7 mL) and heated to reflux. The reaction is stirred at reflux for 1 h. The reaction mixture is cooled to rt, and H2O (26 mL) is added. Conc. HCl is added until a precipitate forms. The precipitate is filtered off to yield 0.597 (87%) of the acid as a brown solid. Carbonyldiimidazole (0.530 g) is added to a solution of 2-bromo-4-hydroxy-thieno-[2,3-b]pyridine-5-carboxylic acid (0.597 g) in DMF (20 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To 130 ml of toluene was added, with stirring, 24.0 g (0.0.165 mole) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mole) of pyridine. The resulting solution was cooled to ca. 0° C. and 13.2 ml (0.166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml of 1N hydrochloric acid, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate, and then it was concentrated in vacuo to give 32.6 g (88% yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:45])[CH2:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:45])[CH2:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)[CH3:23]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Yield: 15 %

Procedure:
Title compound was prepared according to the procedure described in example G from N-Boc-piperazine and 2-Chloro-5-trifluoromethylbenzonitrile (CAS: 328-87-0)(15% yield, yellow oil, MS (m/e): 373.1 (M+NH4+, 100%).
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:26][OH:27]>>[CH3:26][O:27][C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reactant: CO
Solvent: CCN(CC)CC
Product: COc1cc2nc(OC)n3cnnc3c2cc1OC

Procedure:
A mixture of 500 mg 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline and 25 ml triethylamine in 25 ml. methanol is stirred at 40° C. for 24 hrs. The solution is then evaporated in vacuo to dryness, treated with water, and the aqueous layer extracted several times with chloroform. The combined chloroform extracts, after washing with H2O, is dried over sodium sulfate and evaporated in vacuo to dryness. The residue is dissolved in minimum chloroform and chromotrographed on silica gel, elution being carried out with chloroform and then with chloroform containing increasing concentrations of methanol. The desired fractions are collected, evaporated to dryness in vacuo and the residue crystallized from methylene chloride/diethyl ether to obtain 5,8,9-Trimethoxy-1,2,4-triazolo-[4,3-c]quinazoline, m.p. 245°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1CBr
Yield: 73.5 %

Procedure:
A mixture of 5-bromo-1-cyclohexylmethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.95 g, 14.5 mmol), N-bromosuccinimide (2.83 g, 15.9 mmol), and benzoyl peroxide (0.35 g, 1.45 mmol) in CCl4 (140 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (10% EtOAc/hexanes) to give 4.49 g of the title compound as a white solid. MS: (+) m/z 422.09 (M+1).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:7][CH:6]=1)#[N:4].CCN(CC)CC.[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([N:22]2[CH2:23][CH2:24][CH2:25][C@H:20]([C:18](=[O:19])[NH:17][CH2:16][CH2:15][C:14]3[N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=4)[CH:11]=[N:12][CH:13]=3)[CH2:21]2)=[O:43])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCN(C(=O)N(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3(S)-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine dihydrochloride (Example 11, Step E) (0.346 g, 0.843 mmol) was dissolved in CH2Cl2 (10 mL), treated with Et3N (0.587 mL, 4.2 mmol) and diphenylcarbamoyl chloride (0.390 g, 1.686 mmol) and stirred at ambient temperature for 1 hr. The reaction mixture was concentrated to dryness, partitioned between EtOAc and satd NaHCO3 soln, the organic layer separated, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on a silica gel column eluting with 0-2% MeOH/CH2Cl2. Anal. calculated for C32H32N6O2.0.95 H2O: C, 69.91; H, 6.22; N, 15.29; Found C, 69.97; H, 6.15; N, 14.80.
Reaction SMILES: N.C([O:5][CH2:6][CH2:7][CH2:8][CH:9]([F:17])[CH2:10][CH2:11][CH2:12][O:13]C(=O)C)(=O)C>CO>[F:17][CH:9]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7][CH2:6][OH:5]
Reactant: CC(=O)OCCCC(F)CCCOC(C)=O
Agent: N
Solvent: CO
Product: OCCCC(F)CCCO
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.8 %

Procedure:
Methanol (15 ml) saturated with anhydrous NH3 gas was added to acetic acid, 7-acetoxy-4-fluoro-heptyl ester (500 mg, 2.13 mg) contained in round-bottomed flask closed by glass stopper. The mixture was allowed to stir for over 28 hours at room temperature and then concentrated. Purification of the residue by column chromatography on silica gel, using 5% methanol in CH2Cl2, gave the title compound (320 mg, 100%) as pure colorless oil. 1H NMR (CDCl3) δ 1.59-1.83 (m, 8H), 3.67 (t, 4H, J=5.7 Hz), 4.47-4.67 (m, 1H); 13C NMR (CDCl3) δ 28.73, 28.75, 31.78, 32.06, 62.88, 93.56, 95.98; ES-MS m/z 173.2 (M+Na).
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:14]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)=[CH:11][O:12][CH3:13].[O:20]([C:27]1[C:32]([F:33])=[C:31](F)[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[O:20]([C:27]1[C:32]([F:33])=[C:31]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:14]2[O:19][CH2:18][CH2:17][O:16][N:15]=2)=[CH:11][O:12][CH3:13])[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC=C(C1=NOCCO1)c1ccccc1O
Reactant: Fc1ncnc(Oc2ccccc2)c1F
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC=C(C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2)c1F
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
0.119 g of potassium hydride (60% suspension in mineral oil) is added to a solution of 0.7 g (0.00298 mol) of 3-[1-(2-hydroxyphenyl)-2-methoxyethen-1-yl]-5,6-dihydro-1,4,2-dioxazine and 0.6 g (0.00288 mol) of 4-phenoxy-5,6-difluoro-pyrimidine in 10 ml of dimethylformamide at 0° C., and the mixture is then stirred for 12 hours at 20° C. The reaction mixture is poured into water and extracted using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 0.4 g (82% of theory) of 3-{1-[2-(4-phenoxy-5-fluoropyrimid-6-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCc1ccccc1
Temperature: -4 °C
Reaction time: 0.5 h

Procedure:
To a chilled (-4° C.) solution of 19.4 g. of 6-phenylhexanol (prepared as described in Example 46) and 15.1 g. of triethylamine in 500 ml. of dichloromethane is added dropwise, over 5 minutes, 12.6 g. of methanesulfonyl chloride. The mixture is stirred at -10° C. for 30 minutes and the solution washed successively with 200 ml. of cold water, 200 ml. of cold 10% hydrochloric acid, 200 ml. of cold saturated sodium bicarbonate and 200 ml. of cold saturated sodium chloride solution. The organic layer is dried over magnesium sulfate and the solvent removed under reduced pressure to give 6-phenylhexanol O-methanesulfonate as an oil.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: COC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with methyl 4-(bromomethyl)benzoate to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 60% yield: mp 174-175° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, 2H), 4.53 (s, 2H), 4.12-4.03 (m, 2H), 3.96 (s, 3H), 3.49-3.44 (m, 2H), 2.60 (s, 3H), 2.39 (s, 3H); MS (ES+) m/z 374.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1.[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1
Reactant: CCOC(=O)c1cccc2c1OC(C)(C)C2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (1 g, 4.54 mmol) in trifluoroacetic acid (7 mL) at 0° C. was slowly added nitric acid (1.36 mL). The reaction was stirred at 0° C. for one hour and then at room temperature for 30 minutes. The reaction was added to ice and the resultant solid was collected by filtration, and washed with water to provide ethyl 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate (674) as a yellow solid (1.02 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([NH:17][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CNC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclobutane amine 52a (0.68 g, 0.0027 mole) and ethyl glyoxylate (50% solution in toluene) (1.02 g, 0.01 mole) in 20 mL of a mixture of solvents DMF and acetic acid (ratio, 99:1) was added sodium triacetoxyborohydride (2.11 g, 0.01 mole) portion-wise over a period of 15 minutes at room temperature. The resulting mixture was stirred for 8 hours at room temperature and the progress of the reaction was monitored by TLC. The reaction mixture was poured in to saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined extract was washed with water (50 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluents to give pure 54a as colorless liquid in 45% (0.41 g) yield. The 1H NMR and mass spectral data are identical to the compound synthesized using the protocol described for the synthesis of 54a-e (Example 3, Scheme 7).