Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].C1(C)C=CC=CC=1>CCCCCC>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Fc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2F)cc1
Reaction time: 24 h
Yield: 68 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (2.34 mL, 0.64 M, 1.5 mmol) and 1-chloro-2-fluorobenzene (130.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours, then at 80° C. for 12 hours in the same manner as in Example 15. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound (0.135 g, yield=68%, purity=>97% (GC analysis)) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[N:10]([CH3:14])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as described above for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate (8.62 g, 62.5 mmol) in dimethylformamide (150 ml) was added methyl iodide (7.81 g, 55.0 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (400 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml) and dried under vacuum to provide 8-bromo-3,7-dimethylxanthine (12.10 g, 93% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:19]=[CH:18]/[CH2:17][CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCCC(=O)OCC
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 82 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/094362 and ethyl pent-4-enoate, the reaction was carried out in the same manner as the method described in Example 3 (3c) to give the title compound as a colorless oily substance (yield 82%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH2:11]Br)[C:4]=1[CH3:13].[C-:14]#[N:15].[K+].C1OCCOCCOCCOCCOCCOC1.[C:35](#[N:37])C>>[C:14]([CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH2:11][C:35]#[N:37])[C:4]=1[CH3:13])#[N:15]
Reactant: Cc1cc(C)c(CBr)c(C)c1CBr
Reactant: CC#N
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: Cc1cc(C)c(CC#N)c(C)c1CC#N
Reaction time: 2 h

Procedure:
In the above reaction scheme, 1,3-bis(bromomethyl)-2,4,6-trimethylbenzene is reacted with KCN in the presence of a phase transfer catalyst, commonly known as 18-crown-6, (from Aldrich) in acetonitrile. The two-phase system is heated to reflux with vigorous stirring. After two hours, the reaction mixture is cooled, filtered, and evaporated to approximately one-third volume. Distilled water is added, and the mixture is extracted with dichloromethane. The dichloromethane solution is dried over sodium sulfate and filtered, and the solvent evaporated under reduced pressure to obtain 1,3-di(cyanomethyl)-2,4,6-trimethylbenzene.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].CO.Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCNC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of diisobutylaluminum hydride (49 mL, 1.5 M in toluene) in THF (150 mL) cooled to −78° C. was added a solution of 6-benzyloxycarbonylamino-hexanoic acid methyl ester (10 g, 37 mmol) in THF (100 mL). The reaction mixture was stirred for 4 h and methanol (2.5 mL) was added carefully at −78 to −75° C. After 2 h, the mixture was poured to 250 mL of 1 N HCl solution cooled in ice-bath, extracted with ethyl acetate (300 mL), washed with brine (3×100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to yield the titled compound (7.1 g, 80%); white solid, mp 67-66° C.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[OH:13][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][N:10]([S:24]([C:23]2[C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=3[S:21][CH:22]=2)(=[O:25])=[O:26])[CH2:9][CH2:8]1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: OC1(c2ccccc2)CCNCC1
Product: O=C1CCCc2c(S(=O)(=O)N3CCC(O)(c4ccccc4)CC3)csc21

Procedure:
From 4-phenyl-piperidine-4-ol (36 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (50 mg), the title compound (72 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].C(N(CC)CC)C.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)CCCCNC(=O)OC(C)(C)C
Yield: 59 %

Procedure:
To a suspension of 7.68 g of β-alanine ethyl ester hydrochloride in 50 ml of methylene chloride there was added, with stirring, 5.56 g of triethyl- amine. 10.86 g of N-t-butoxycarbonyl-5-aminovaleric acid, dissolved in 50 ml of methylene chloride, and portionwise 11.35 g of DCC, in that order. After completion of the addition, the reaction mixture was stirred at room temperature overnight and filtered off from separated urea. The filtrate was washed in succession with 250 ml of sodium bicarbonate solution (5%), water, 250 ml of 0.1M citric acid and, finally, with saturated sodium chloride solution. Thereafter, the solvent was evaporated under reduced pressure and the oily residue was purified by column chromatography on silica gel, to obtain N-[5-(1-t-butoxyformamido)valeryl]-β-alanine ethyl ester in 59% yield, melting point 28° (from hexane).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:19])[NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[C:4](=[O:14])[CH2:3][C:2]([CH3:1])=[N:6]2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(N2N=C(C)CC2=O)cc1

Procedure:
From the reaction of 5-methyl-2-(4-aminophenyl)-2,4-dihydro-pyrazol-3-one and ethylchloroformate (per the reaction in Example 11) yields N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl-carbamic acid ethyl ester. Subsequent reaction with 2-methoxyaniline yields N-(4-(4,5-dihydro-4-(2-methoxyanilinomethylene)-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-carbamic acid ethyl ester, Mp: 212° C.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C@H:1]1[N:14]([CH3:13])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:7][C@H:1]1[C@H:6]([N:14]([CH3:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)N1CCC2OC2C1
Solvent: CCO
Product: CCOC(=O)N1CC[C@@H](N(C)Cc2ccccc2)[C@H](O)C1
Product: CCOC(=O)N1CC[C@@H](O)[C@H](N(C)Cc2ccccc2)C1

Procedure:
(a-1) A mixture of 51.3 parts of ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. 36.4 parts of N-methylbenzenemethanamine and 480 parts of ethanol was stirred and refluxed for 42 hours. The reaction mixture was evaporated and the residue was taken up in a dilute hydrochloric acid solution. The aqueous phase was washed three times with 2,2'-oxybispropane and alkalized with a sodium hydroxide solution 50%. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 45 9 parts (52.3%) of a mixture of ethyl trans-4-hydroxy-3-[methyl(phenylmethyl)amino-]1-piperidinecarboxylate and ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6) in the proportion of 62.3% and 32.9%. Intermediate 6 was also prepared according to the following procedure:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Br:11].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC>CN(C)C=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:19][CH3:15])[CH3:21])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: Nc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask, was placed a solution of 4-amino-3-bromobenzoic acid (50 g, 231.45 mmol, 1.00 equip) in N,N-dimethylformamide (500 mL), TEA (128 mL, 4.00 equip), HATU (106 g, 278.78 mmol, 1.20 equip), and methoxy(methyl)amine hydrochloride (45 g, 461.33 mmol, 2.00 equip). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (1 L). The resulting solution was extracted with ethyl acetate (1 L) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield 4-amino-3-bromo-N-methoxy-N-methylbenzamide as a yellow solid. LCMS (ES, m/z) 259 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-Carboxylate and benzyl bromide in substantially the same manner, as described in step 1 of Example 1. The product was obtained as a light yellow solid. Mass spectrum (ESI, [M+H]+) m/z 358. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.55 (d, 1H, J=9.01 Hz), 7.42 (d, 1H, J=8.85 Hz), 7.34 (s, 1H), 7.30–7.21 (m, 3H), 6.99 (d, 2H, J=7.94 Hz), 5.85 (s, 2H), 4.28 (q, 2H), and 1.28 ppm (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:16])=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19].[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH3:23][O:22][P:21]([CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19])[CH2:10][O:11][C:12]2=[O:16])(=[O:26])[O:24][CH3:25]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Reactant: COP(OC)OC
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(OC)OC)C(=O)OC2
Yield: 55.7 %

Procedure:
A solution of 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (33 mg, 0.097 mmol) in trimethyl phosphite (1.0 mL, 8.5 mmol) was heated to 100° C. for 1 hour, whereupon complete reaction was indicated by LCMS. The reaction was worked up by removal of the excess of trimethyl phosphite under reduced pressure and the residue was purified by silica gel chromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H); MS (m/z) 371 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:15])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(=O)c2cccc(F)c21

Procedure:
7-Fluoro-1H-indole-2,3-dione (5, prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325, 3.00 g, 0.182 mol), iodomethane (3.40 ml, 0.545 mol) and potassium carbonate (4.92 g, 0.0363 mol) in DMF (15 ml) are stirred at room temperature for 1 hour. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as a solid. HPLC r.t. 4.01 min; MS for C9H6FNO2 m/z 180.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[Se](=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:26](C)=[C:25](C)[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1.[Se]>CO.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:5]([CH:6]=[O:1])=[C:25]([CH3:26])[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1
Reactant: C1COCCO1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Agent: O=[Se]=O
Agent: [Se]
Solvent: O
Solvent: CO
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Temperature: 55 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 1 L round-bottom flask equipped with a magnetic stir-bar was added dioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C., and selenium dioxide (8.6 g, 77 mmole) was added. The mixture was stirred at 55° C. for one hour, over which time all the selenium dioxide had dissolved. To the solution was then added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one. The flask was fitted with a reflux condenser and the resulting slurry heated to a bath temperature of 115° C. After 18 hours, additional selenium dioxide (4.0 g, 36 mmole) was added and stirring continued for 6 hours. The reaction mixture was dark red, with gray metallic selenium lining the sides of the flask. The reaction mixture was cooled to room temperature then filtered through a pad of celite and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo to produce a gummy red solid. Methanol (50 mL) was added, and the mixture stirred over an ice bath, during which time a flocculent yellow precipitate formed. The solid was isolated by filtration, and washed sparingly with cold methanol to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (3.90 g, 61%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)+.
Reaction SMILES: C(C[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)=[O:18])[CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.[ClH:30].NO.[OH2:33]>N1C=CC=CC=1>[ClH:30].[C:19]1([CH:17]([OH:33])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)[CH:20]=[CH:21][CH:26]=[CH:27][CH:28]=1
Reactant: O
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(=O)c4ccccc4)CC3)ccc2N1
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: O=C1CCc2cc(C(=O)N3CCN(CC(O)c4ccccc4)CC3)ccc2N1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
20 Grams of 6-[4-(2-benzoylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 5.33 g of hydroxylamine hydrochloride were dispersed in 40 ml of pyridine and the suspension was stirred at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water and then extracted with chloroform, the extract was dried with anhydrous potassium carbonate, then the solvent was removed by evaporation. The thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =50:1), then recrystallized from ethanol to yield 8.79 g of 6[-4-(3-hydroxyimino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril 1/2-hydrate. White powdery substance. Melting point: 167° C.-169° C. (decomp.)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C.C([Cl:24])(=O)C>CO>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CCCC1CCCCN1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-Butyl-2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 89.9 mmol) in Methanol was added dropwise acetyl chloride. The reaction mixture was stirred for 5 h at room temperature. The completion of the reaction was controlled via Thin-layer chromatography. After completion the reaction mixture was evaporated in vacuum to give Methyl 4-(piperidin-2-yl)butanoate hydrochloride (4) (20.14 g, 100%)
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=O)[NH:3][C:2]1=O.C[Si](C)(C)N[Si](C)(C)C.S(=O)(=O)(O)O.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>C1(C)C=CC=CC=1.O1CCOCC1.CO>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[C:29]([CH:38]=[CH:37][CH:36]=1)[CH2:28][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[N:3][CH2:2]1)=[O:33]
Reactant: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN=CC3=C2CCCC3)c1
Temperature: 122.5 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
To a mixture of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione (10.4 g, 62 mmol) and hexamethyldisilazane (HMDS, 33 mL, 158 mmol) in toluene (100 mL) was added concentrated sulfuric acid (0.34 mL, 6.2 mmol) at r.t. The mixture was heated to reflux overnight until a clear solution was obtained. After the removal of toluene and excess HMDS with vacuum evaporation, methyl 3-bromomethylbenzoate (16 g, 70 mmol) was added to the residue. The reaction mixture was heated to 115-130° C. and was stirred at this temperature for 4 h. The reaction mixture was diluted with 1,4-dioxane (6 mL) and methanol (100 mL) at 100° C., and was stirred for 30 min. The reaction mixture was evaporated to remove the solvent. The residue was dissolved in ethyl acetate (EA, 300 mL) and washed by 1N hydrochloric acid (100 mL×1) and water (100 mL×3). The organic layer was dried with anhydrous sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give the title compound (2.3 g, 12% yield) as yellow powder. 1H NMR (DMSO-d6): 11.40 (s, 1H), 7.87 (d, J=7.5 Hz, 1 H), 7.79 (s, 1H), 7.55-7.44 (m, 2H), 5.12 (s, 2H), 3.85 (s, 3H), 2.45-2.35 (m, 2H ), 2.25-2.20 (m, 2H), 1.65-1.40 (m, 4H). MS: m/z 315.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C@H:12]([CH2:13][F:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>CO.[Pd]>[CH2:36]([O:35][C:33]([N:10]1[CH2:11][C@@H:12]([CH2:13][F:14])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:9]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@H]1CF
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CF

Procedure:
A solution of ((3R,4R)-1-Benzyl-4-fluoromethyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (1 g, 3.24 mmol) in methanol (20 mL) was hydrogenated at 1 atm with 10% palladium on carbon (100 mg) for 24 hours. He crude reaction mixture was filter through celite then concentrate to an oil. The crude amine was dissolved in dichloromethane (8 ml) then cooled to 0 C and diisopropylethylamine (619 ul, 3.57 mmol) was added followed by benzyl chloroformate (507 ul, 3.57 mmol, 1.1 equiv.). The crude reaction was concentrated to an oil then purified by silica gel chromatography eluting with 0-20% EtOAc in Heptane which gave the title compound IXa of as a colorless oil (811 mg). 1H NMR (400 MHz, CHLOROFORM-d) 1.45 (s, 9H) 2.67 (br. s., 1H) 3.24-3.49 (m, 2H) 3.63-3.80 (m, 2H) 4.27-4.53 (m, 2H) 4.53-4.66 (m, 1H) 4.70 (dd, J=9.73, 4.93 Hz, 1H) 5.14 (br. s., 2H) 7.37 (br. s., 5H); LCMS: M+1−Boc=253.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[S:15]([F:25])(=[O:24])([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:16]>CN(C)C(=O)C.O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:7])([CH3:8])[C:4]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([S:15]([F:25])(=[O:24])=[O:16])=[CH:18][CH:19]=1)=[O:5]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a cooled (-20° C.) solution of α-trifluoromethyl lactic acid (2.0 g) in dry N,N-dimethylacetamide (15 ml) was added thionyl chloride (0.97 mL) dropwise over 10 minutes. The reaction mixture was stirred at -20° C. for 1 hour, warmed to 0° C. over 1 hour, then treated with sulfanilyl fluoride (2.22 g) in one portion and heated at 100° C. for 24 hours. After cooling to 22° C. the reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×35 ml). The combined organic extracts were washed with water, brine, dried and the solvent removed under reduced pressure. The crude product was purified by chromatography (13:1 CH2Cl2 :Et2 0) and recrystallised from methyl-t-butyl ether to give 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide as colourless crystals, (1.7 g); mp 152°-154° C.; MS: m/z=316(M+1); NMR (CDCl3): 1.78 (s,3), 3.51 (broad s), 7.86-7.89 (m, 2), 7.99-8.03 (m,2), 8.79 (broad s,1). Analysis for C10H9 F4NO4S: Calculated: C, 38.10; H,2.88; N, 4.44; Found: C, 38.21; H, 2.97; N, 4.44.