Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>C(Cl)Cl>[CH3:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
To the tert-butyl 2-hydroxyimino-3-oxobutyrate was added water [6 l ], to which was added 30% sodium hydroxide [800 ml] at 28° C. while stirring to render the pH to 9.0. To the resultant solution was added dimethyl sulfate [1324 g] at 28° to 30° C. in the course of 20 minutes, which was stirred for 4 hours while adding thereto at 25° to 30° C. a 30% aqueous solution of sodium hydroxide [500 ml] to adjust the pH within the range of 8.7 to 9.0. After completion of the reaction, extraction was conducted with methylene chloride [4 l ], and the aqueous layer was subjected to further extraction with methylene chloride [2 l ]. The methylene chloride layers were combined and washed with a 1N aqueous solution of sodium hydroxide, 1N HCl, a 5% aqueous solution of sodium hydrogencarbonate and water, each one litre portion, successively. The resultant solution was dried over anhydrous sodium sulfate [700 g], followed by concentration under reduced pressure to obtain tert-butyl 2-methoxyimino-3-oxobutyrate [1878 g] as an oily product. The yield was 93.3%.
Reaction SMILES: [CH2:1]([C:8]1([CH2:11][C@H:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH:33]([CH2:43][CH3:44])[C@@H:34]([C:36]1[N:40]=[C:39]([CH2:41][CH3:42])[O:38][N:37]=1)[OH:35]>>[CH2:1]([C:8]1([CH2:11][C@H:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([NH:32][C@H:33]([C:34]([C:36]2[N:40]=[C:39]([CH2:41][CH3:42])[O:38][N:37]=2)=[O:35])[CH2:43][CH3:44])=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC2(Cc3ccccc3)CC2)no1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>O1CCCC1>[CH2:1]([N:8]=[C:16]=[S:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=NCc1ccccc1
Temperature: -10 °C
Reaction time: 2.75 h

Procedure:
A solution of benzylamine (5.4 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column using hexane:ethyl acetate (90:10) as the eluant to yield benzyl isothiocyanate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)#[N:2].[OH-:45].[Na+].OO.Cl>CS(C)=O.C(O)C>[CH3:32][O:31][C:9]1[C:8]2[C:3]([C:1]([NH2:2])=[O:45])=[N:4][C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[O:35])=[CH:6][C:7]=2[N:11]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C#N)c12
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(N)=O)c12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(4-cyano-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (70 mg, 0.121 mmol, synthesized from Intermediate 42B following Scheme 3-Step 2/Method A) was taken up in DMSO (605 μl) and Ethanol (605 μl). NaOH (1.8 ml, 1.815 mmol) was added followed by dropwise addition of hydrogen peroxide (180 μl, 2.056 mmol). The reaction was heated to 60° C. and was allowed to stir for 30 minutes. Room temperature was attained and 1N HCl was added and the products were extracted into EtOAc (3×). The organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give (R)-3-methoxy-6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxamide. The products were carried forward without purification. MS: [M+H]+ m/z 597.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:15])([F:16])[F:17])[O:11][C:10]([NH2:18])=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1
Reactant: O=C(NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a 20 mL resealable vial was added N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.500 g, 1.046 mmol), MeOH (10 mL) and finally 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich; 0.312 mL, 2.091 mmol). The vial was sealed and stirred at 75° C. for 2 h. The reaction mixture was poured into sat NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 9.0% MeOH/CH2Cl2) afforded (4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine. The material still contained some impurities. MS m/z=375.8 [M+H]+. Calculated for C11H9BrF5N3O: 375.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)N
Reactant: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Product: CC(C)(C)NCC(O)COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
A mixture of 2,6-dichloro-4-(2,3-epoxypropoxy)-benzaldehyde (3 gm) and tert-butylamine (20 ml) is heated at 45° for 17 hours. The excess tert-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (25 ml) and heated for 1 hour. The acid solution is added to boiling saturated aqueous sodium carbonate with nitrogen ebullition. The basic solution is extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[F:35][C:32]1[CH:33]=[CH:34][C:25]([CH2:24][NH:23][C:20]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13]3)=[O:22])=[C:26]([C:27](=[O:28])[NH:29][CH3:30])[CH:31]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2

Procedure:
The title compound can be prepared from intermediate 7, 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide. White crystals; mp 189–190° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.01 (3H, d, J=4.5 Hz, NCH3), 4.00 (2H, m, CH2), 4.08 (1H, m, CH), 4.50 (2H, d, J=6.6 Hz, NCH2), 4.71 (2H, s, OCH2), 5.38 (2H, s, OCH2), 6.88 (1H, broad q, NH), 7.07 (1H, m, aromatic), 7.16 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.30–7.44 (6H, m, aromatics), 8.55 (1H, broad t, NH). Anal. Calcd for C24H23FN4O5: C, 61.80; H, 4.97; N, 12.01. Found: C, 61.84; H, 4.82; N, 12.00.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=3)=[CH:23][CH:22]=2)[C:15]([F:39])=[CH:14][N:13]=1>CN(C)C=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][O:18][C:16]3[C:15]([F:39])=[CH:14][N:13]=[C:12]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:17]=3)=[CH:26][CH:25]=2)=[CH:29][C:30]=1[C:35]([F:36])([F:38])[F:37]
Reactant: Fc1cnc(Cl)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cnc(OCc2ccccc2)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of phenylmethanol (100 μL, 0.965 mmol) in N,N-dimethylformamide (DMF) (8 mL) was added sodium hydride (232 mg, 5.79 mmol) 0° C., the 2-chloro-4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-fluoropyrimidine (432 mg, 0.965 mmol) was added at 0° C. after 10 min. The reaction mixture was stirred for 30 min, and poured into ice-water (100 mL), extracted with ethyl acetate (50 mL) twice. Combined organic parts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification via ISCO system afforded the title product (370 mg). LC-MS (ESI): m/z 519[M+H]+; 6.26 min (ret time).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:31][CH3:32])=[C:7]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:7]2[CH:8]=[C:9]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[O:31][CH3:32])=[O:30])=[CH:22][CH:23]=1
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1

Procedure:
step 4—To a solution of 102 (0.36 g, 0.82 mmol) in EtOAc/MeOH (2:1, 15 mL) was added 10% Pd/C (0.035 g). A stream of hydrogen gas was bubbled through the solution for 20 min, and the white solid precipitate that formed was recovered by filtration to afford 4-amino-N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]benzamide (104).
Reaction SMILES: COC(CCC([O:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20](OC)=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25])=O)=O.[NH3:28]>CO>[OH:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25]
Reactant: COC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OC)O2
Reactant: N
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(CCC(N)=O)O2

Procedure:
4.9 g of methyl 3-[5-(3-methoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl]propionate (prepared as described in Example 31) was dissolved in 60 ml of methanol, and 17 g of 28% w/v aqueous ammonia was added to the solution. The reaction mixture was then allowed to react for 5 days at room temperature. At the end of this time, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography, and the title compound, melting at 160°-161° C., was obtained from the fraction eluted with a 3:7 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2,3-difluoro-benzoic acid (3 g) was added to a solution of chlorosulfonic acid and the reaction mixture was stirred for 2 hours at room temperature. After such time, the reaction mixture was poured onto ice. The resulting solid precipitate was then filtered off and dried in vacuo to yield the title compound as a light grey solid (4.8 g, mp=109-114° C., MS (EI): 256.0 (M+) and was used directly in the next step without any further purification.
Reaction SMILES: O[C:2]1([C:12]#[N:13])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].S(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[CH3:8][C:6]1([CH3:9])[CH2:5][CH2:4][C:3]([CH3:10])([CH3:11])[C:2]([C:12]#[N:13])=[CH:7]1
Reactant: CC1(C)CCC(C)(C)C(O)(C#N)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)C=C(C#N)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a mixture of the product of Example 10e (2.22 g, 12.3 mmol) in pyridine (40 mL) was added thionyl chloride (4.4 mL, 61.3 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was acidified with 5 N hydrochloric acid to pH=1, then it was poured into ice-water (20 mL). The aqueous mixture was extracted with ethyl acetate (20 ml×3) and the organic phase washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colorless oil (600 mg, Yield: 30%). 1H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 1.56 (t, J=2.8 Hz, 2H), 1.56-1.43 (m, 4H), 1.16 (s, 6H), 1.03 (s, 6H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].C(NCC)C>CN(C=O)C>[CH2:18]([N:20]([CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Reactant: CCN(CC)CC
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc2cc(C(=O)OC)ccc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (160 mg, 0.63 mmol) in DMF (3 mL) was added triethylamine (0.176 mL, 1.27 mmol) and diethylamine (0.33 mL, 3.17 mmol). The reaction mixture was heated to 100° C. and stirred for 3 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% MeOH/DCM) to afford methyl 2-[(diethylamino)methyl]-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.15 g, 81%). LC-MS: (FA) ES+ 290.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(CCN)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
5 ml of ethanol solution of 1.02 g of hydrazine hydrate were added to 35 ml of ethanol solution of 4.36 g of t-butyl 4-[2-(phthalimido)ethyl]-2-nitrophenoxyacetate and heated under reflux for 2 hours at 100° C. in an argon stream. After cooling, the reaction mixture was filtered through celite, and the filtrate concentrated under reduced pressure. The yellow crystals of t-butyl 4-(2-aminoethyl)-2-nitrophenoxyacetate thus obtained were used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[OH:8].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:9]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[C:7]=1[OH:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1c(Br)cncc1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1c(Br)cncc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.1 %

Procedure:
A mixture of 3-bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol (2.55 g, 91 mmol), TFA (16 mL) and Et3SiH in CH2Cl2 (30 mL) was stirred at rt for 10 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc/MeOH//600:300:50 followed by hexane/EtOAc/MeOH 11400:400:50:10 to afford an impure product which was triturated with a small amount of MeOH and Et2O to obtain the desired product (255 mg, 10%) as a white solid. 1H NMR (DMSO-d6) δ 11.75 (br s, 1H), 8.13 (s, 1H), 7.54 (s, 1H), 7.26-7.14 (m, 5H), 2.49 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH2:19][NH2:20])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=2)[C:33](O)=[O:34])[N:24]=1>>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:19][NH:20][C:33](=[O:34])[C:32]1[CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=[N:30][CH:31]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN(C)CCC(CN)c1coc(-c2ccc(F)cc2)n1
Product: CN(C)CCC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
This compound was synthesized from 3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (16 mg, yield 10%). 1H NMR (400 MHz, MeOD) δ 9.39-9.38 (d, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H), 8.85-8.84 (t, J=2.1 Hz, 1H), 8.08-8.05 (m, 2H), 7.84 (s, 1H), 7.26-7.22 (t, J=8.9 Hz, 2H), 3.79-3.66 (m, 2H), 3.18-3.11 (m, 1H), 2.63-2.46 (m, 2H), 2.37 (m, 6H), 2.06-2.00 (m, 2H). MS (ESI) m/z: Calculated for C24H22F4N6O3: 518.17. found: 519.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:13])[CH3:12]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Temperature: 40 °C
Reaction time: 96 h

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40° C. for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:3→6:4) to give the title compound (637 mg) as a white solid.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@@H]21
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(4-bromobutyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 509 [M+H]+, 507 [M−H]−, 1H-NMR (DMSO-d6) δ 1.14 (3H, t, J=7.5 Hz), 2.62 (2H, q, J=7.5 Hz), 2.72 (2H, t, J=7.1 Hz), 3.18-3.30 (2H, m), 6.60 (1H, t, J=5.7 Hz), 7.19 (1H, tt, J=7.3, 1.3 Hz), 7.28-7.38 (6H, m), 7.64-7.70 (2H, m), 7.76-7.80 (2H, m), 7.88 (2H, dt, J=11.2, 2.6 Hz).