Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH3:14][C:15](N(C)C)=[O:16].Cl>CCOCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([C:15](=[O:16])[CH3:14])=[CH:11][CH:12]=1
Reactant: CC(=O)N(C)C
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
BuLi (32.8 ml of a 1.6 M solution in hexanes, 53 mmol) was added dropwise over 10 min to a stirred solution of 2,5-dibromopyridine (12.44 g, 52.5 mmol) in Et2O (600 ml) at −78° C. under nitrogen. The resulting suspension was stirred at −78° C. for 1 h and then heated with dimethylacetamide (5.86 ml, 63 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. 1N HCl (100 ml) was added and the organic layer separated. The aqueous layer was extracted with EtOAc (3×100 ml). The combined organic extracts were dried (MgSO4), concentrated under reduced pressure, then taken up in CH2Cl2 (200 ml) and dry loaded onto silica. Column chromatography on silica using 30-40% EtOAc/iso-hexane as eluent gave the ketone (6.0 g, 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2C=O)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate (1.0 g, 3.3 mmol), (2-formyl-4-methoxyphenyl)boronic acid (896 mg, 5.0 mmol), Pd(dppf)Cl2 (364 mg, 0.5 mmol), and K2CO3 (918 mg, 6.6 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4]CO.[C:8]([O:11][C:12](=O)C)(=[O:10])[CH3:9]>>[C:8]([O:11][CH2:12][CH:3]([N:2]([CH3:1])[CH3:7])[CH3:4])(=[O:10])[CH3:9]
Reactant: CN(C)CCCO
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC(C)N(C)C

Procedure:
14.4 g of 3-dimethylamino-1-propanol and 14.3 g of acetic anhydride are reacted and worked up as described in Example 7. Yield: 14.9 g (73.1%) of analytically pure product (analysis by gas chromatography) with a boiling point of 53° C./12 torr.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6](O)[C:5](C)([CH3:18])[C:4]=2[CH:3]=1.II.Br.[C:23](O)(=O)C>>[Br:16][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:4](=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[C:5]([CH3:18])=[C:6]([CH3:23])[C:7]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc2C1O
Agent: Br
Agent: II
Product: Cc1c(C)c2cc(Br)ccc2c2ccc(Br)cc12

Procedure:
43.4 g (113 mmol) of 2,7-dibromo-9-hydroxy-10,10-dimethyl-9,10-dihydrophenanthrene were suspended in 610 ml of acetic acid. 780 mg of iodine and 3.5 ml of HBr in acetic acid were added, and the suspension was heated to reflux. The mixture was allowed to cool overnight with stirring. The residue was filtered off with suction and washed with water and methanol, giving 35.8 g (87.0% of theory) of the product.
Reaction SMILES: [CH2:1](OCC1C=CC=CC=1)C1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([N:28]3[C:32]([C:33]4[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42]CC5C=CC=CC=5)=[CH:35][C:34]=4[O:50]CC4C=CC=CC=4)=[N:31][N:30]=[C:29]3[OH:58])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[OH:58][C:29]1[N:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][CH2:17][NH:16][CH3:1])[CH:20]=[CH:21]3)[C:32]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[C:36]([OH:42])=[CH:35][C:34]=2[OH:50])=[N:31][N:30]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(ccn3CCN)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(O)cc3O)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The benzylether [4-(1-(2-aminoethyl)-1H-indol-5-yl)-5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4H-1,2,4-triazol-3-ol; 188 mg, 0.33 mmol) was dissolved in 6 ml degassed THF/methanol (1:1). 50 mg Pd/C (10%) was added and the mixture stirred under hydrogen (balloon) at rt for 5 h. After filtration the solvent was removed and the crude purified by chromatography on silica with DCM/MeOH (5-20%)/NH4OH (0.5%) to yield 71 mg (0.18 mmol) 4-(5-hydroxy-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol. This amine (50 mg, 0.125) was added to 4-(2,5-dioxopyrrolidin-1-yl)butanoic acid (26 mg, 0.14 mmol), EDC (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) in 1.5 ml DMF at rt. The mixture was stirred for 12 h and then ethyl acetate and water added. The aq. Phase was extracted twice with ethyl acetate and the combined organic extracts washed with brine and dried over MgSO4. The crude was purified by chromatography on silica with DCM/MeOH (3-10%) to yield 34 mg (0.061 mmol) product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(CO)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of DMSO (1.7 eq.) in DCM (0.5 M) was treated at −78° C. with a 2 M solution of oxalyl chloride in DCM (1.4 eq.). The reaction was stirred for 5 min, and a solution of 2-(4-fluorophenyl)-2-methylpropan-1-ol (1 eq.) in DCM (3 M) added to the reaction mixture. After stirring for 10 min, NEt3 (2.4 eq.) was added and the reaction mixture warmed to 0° C., stirred one hour, removed the cooling bath and stirred for one additional hour. The mixture was diluted with DCM, extracted with bleach/water, 1 M citric acid, water, dried (Na2SO4), concentrated.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 4 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 551.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][N:13]([C:14]([C:16]5[C:17]([CH3:21])=[N:18][O:19][CH:20]=5)=[O:15])[C:7]4([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:6][N:5]3[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C23Cn4cc(NC5CCCCC5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1

Procedure:
To a solution of 7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (33 mg, 0.081 mmol) in CH2Cl2 (0.5 mL) was added cyclohexanone (9 μL, 0.081 mmol), acetic acid (7 μL, 0.12 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). After stirring the mixture for three further hours, cyclohexanone (20 μL, 0.18 mmol) was added followed by the addition of additional acetic acid (20 μL, 0.34 mmol). The mixture was quenched with a saturated aqueous solution of NaHCO3. Additional CH2Cl2 (3 mL) was added and the organic layer separated, the aqueous layer was further extracted with CH2Cl2 (3 mL). The organic layers were combined dried (Na2SO4), filtrated, concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient 0-10% MeOH in EtOAc) and reverse phase chromatography (Biotage SP4, 12 g C18 cartridge; gradient ACN in water). The compound 7-(cyclohexylamino)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (112) was isolated as a solid (1.6 mg, yield 1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21].[H][H]>C(O)C.C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Br)ccc1C=Cc1cccc(OC)c1C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1CCc1cccc(OC)c1C
Temperature: 38 °C

Procedure:
To 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-vinyl]-benzoic acid methyl ester (5) (4.99 g; 13.8 mmol), stirring in ethyl alcohol (70 mL) and acetic acid (23 mL), was added PtO2 (0.075 g; 2.4%). The solution was stirred in a hydrogen atmosphere (balloon pressure) and the temperature of the solution was raised to 38° C. The reaction was monitored closely by TLC and the mixture was cooled after three hours. The reaction mixture was filtered and evaporated to give compound 6 as a residue. The residue was carried on to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][C:12]([C:20](O)=O)=[N:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:20]([C:12]3[CH2:13][C:14]4([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[O:10][N:11]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Product: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 4-bromo-benzene-1,2-diamine and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedures described in Example 1, steps F and G. 1H-NMR (400 MHz, d4-MeOH) δ: 7.74 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.8 Hz, 1H), 3.25 (s, 2H), 1.69-1.87 (m, 6H), 1.45-1.63 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2].Cl.[NH2:28][OH:29].[F-].[K+]>C(O)C>[CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13](/[C:15](=[N:28]/[OH:29])/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(CC(=O)O)Cc1cc(C(=O)c2ccc(C)cc2)ccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC(=O)O)Cc1cc(/C(=N/O)c2ccc(C)cc2)ccc1[N+](=O)[O-]
Reaction time: 22 h
Yield: 19 %

Procedure:
A mixture of 26.7 parts of ethyl N-[[5-(4-methylbenzoyl)-2-nitrophenyl]methyl]glycine (which is a precursor to intermediate 50 in Example 9), 6.25 parts of hydroxylamine monohydrochloride, 5.25 parts of potassium fluoride and 395 parts of ethanol was stirred for 22 hours at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate. The whole was washed with sodium hydrogen carbonate solution 10% and with water. The organic layer was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the E- and Z-isomer fractions was evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 3.7 parts of product. The mother liquor was evaporated and the residue was isomerized in a mixture of 1,4-dioxane and 2-propanol, saturated with HCl, by stirring overnight. The solvent was evaporated and the residue was stirred in water. After neutralizing with NaHCO3 10%, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 2 additional fractions of resp. 3.6 parts and 1.2 parts of product. The three fractions were recrystallized from a mixture of ethyl acetate and 2,2'-oxybispropane, yielding 5.3 parts (19%) of ethyl (E)-N-[[5-[(hydroxyimino) (4-methylphenyl)methyl]-2-nitrophenyl]methyl]glycine (interm. 57).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].CN1CCCC1=O.Cl[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[CH3:36].C(N(C(C)C)CC)(C)C>O>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:47][CH:46]=5)=[CH:39][CH:38]=4)[CH3:36])[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Reactant: CC(Cl)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.56 g) was added to an N-methylpyrrolidone solution (5 ml) of 1-(1-chloroethyl)-4-(4-trifluoromethylbenzyloxy)benzene (0.54 g). Subsequently, diisopropylethylamine (0.54 ml) was added thereto, and the mixture was stirred at room temperature for 12 hours. Thereafter, the mixture was heated to 60° C. and stirred for 7 hours. Water was added to the reaction mixture and the precipitated solid was collected by filtration. The solid thus obtained was purified by basic silica gel column chromatography (methylene chloride) and recrystallized from acetone-water to afford the title compound as a slightly yellow powder (0.15 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:35]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:35])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCCCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 48.4 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and azepan-2-one (119 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (234 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:5]([C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])=[O:7])[C:4]([N:3]([CH2:1][CH3:2])[CH2:33][CH3:34])=[O:32])=[CH:24][CH:25]=1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(Cc1ccc(N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a mixed suspension of the compound (2.53 g) obtained in Example 6 in ethanol (200 mL)/ethyl acetate (100 mL) was added 10% palladium/carbon (500 mg), and the mixture was heated under reflux under hydrogen atmosphere for 6 hr. After allowing to cool to room temperature, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.37 g) as a white powder. In some cases, the compound was further converted to a hydrochloride salt with 4 mol/L hydrochloric acid/ethyl acetate and used.
Reaction SMILES: [Br-:1].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.[C:34]([C:37]1[O:38][C:39]2[C:45]([CH:46]([O:48][C:49](=[O:51])[CH3:50])[CH3:47])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[C:49]([O:48][CH:46]([C:45]1[C:39]2[O:38][C:37]([C:34](=[O:36])[CH2:35][Br:1])=[CH:41][C:40]=2[CH:42]=[CH:43][CH:44]=1)[CH3:47])(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)c1cccc2cc(C(C)=O)oc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1cccc2cc(C(=O)CBr)oc12
Reaction time: 6 h
Yield: 69.1 %

Procedure:
25.1 g of trimethylphenylammonium tribromide were added at 20°-25°C to a stirred solution of 16.4 g of 2-acetyl-7-(1'-acetoxyethyl)benzofuran in 250 ml of dry tetrahydrofuran. The resulting solution was stirred for 6 hours in order to complete the precipitation of trimethylphenylammonium monobromide. The mixture was poured into 1000 ml of water to which sodium chloride was added to saturation. The product was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and with brine and dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated to dryness. The residual solid was crystallized from diethyl ether to give 8.7 g of 7-(1'-acetoxyethyl)-2-bromoacetylbenzofuran in the form of pale yellow crystals of melting point 86°-88°C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[N:30](COC(=O)C(C)(C)C)[CH:31]=[N:32]2)=[C:27]([OH:44])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[NH:30][CH:31]=[N:32]2)=[C:27]([O:44][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC1CCOCC1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Di-tert-butyl azodicarboxylate (16.3 g) was added portionwise to a stirred mixture of 7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (17 g), 4-hydroxytetrahydropyran (5.4 g) and methylene chloride (200 ml) that had been cooled to 5° C. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated and the residue was dissolved in a saturated methanolic ammonia solution. The resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was dried under vacuum to give 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (12.5 g); NMR Spectrum: (DMSOd6) 1.6–1.7 (m, 2H), 1.85–1.95 (m, 2H), 3.5 (m, 2H), 3.9 (m, 2H), 4.75 (m, 1H), 5.22 (s, 2H), 6.7 (d, 1H), 6.8 (d, 1H), 7.3–7.5 (m, 5H), 7.9 (s, 1H); Mass Spectrum: M+H+ 353.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-])=O)=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([NH:14][C:15]1[CH:20]=[C:19]([OH:21])[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][C:16]=1[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:13])[C:7]2=[O:30].Cl>[Pd].CCOC(C)=O>[NH2:31][C:5]1[CH:4]=[CH:3][CH:2]=[C:11]2[C:6]=1[C:7](=[O:30])[C:8]([C:12]([NH:14][C:15]1[CH:20]=[C:19]([OH:21])[C:18]([C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][C:16]=1[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:13])=[CH:9][NH:10]2
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3c(Br)ccc([N+](=O)[O-])c3c2=O)cc1O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3cccc(N)c3c2=O)cc1O
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A flask charged with 8-bromo-N-(2,4-di-tert-butyl-5-hydroxyphenyl)-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxamide (430 mg, 0.83 mmol)) and Pd/C (60 mg, 0.56 mmol) was evacuated under vacuum, followed by purging with N2. EtOAc (4 mL) and HCl (1 mL of 1 M, 1.000 mmol) were added followed by evacuating under vacuum. The reaction was stirred overnight under an atmosphere of hydrogen, filtered through a plug of celite and concentrated to get 5-amino-N-(2,4-ditert-butyl-5-hydroxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (164 mg, 48%). LC/MS: m/z 408.5 (M+H)+ at 1.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].O>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C@H:3]([CH3:4])[O:5][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
36.0 g (316 mmol) of (S)-1,1,1-trifluoro-propan-2-ol (CAS: 3539-97-7) was added to a cold (0 to 5° C.) suspension of 17.0 g (425 mmol) of NaH (pract., 60%) in 200 ml of dioxane. The suspension was stirred at room temperature during 0.5 h then cooled (0 to 5° C.) and a solution of 20.0 g (143 mmol) of 2-fluoro-benzoic acid in 100 ml of dioxane was added. The mixture was stirred during 0.5 h at room temperature and during 140 h under reflux. The mixture was poured into 800 ml of water, washed with 300 ml of MTBE, then acidified to pH 2 with hydrochloric acid and the product was extracted with MTBE. The solvent was concentrated in vacuo and the residue was crystallized from ethanol/water to provide 27.3 g (82%) of the title compound as a white solid. MS (m/e): 234.1 [M]+.