Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[CH:5]=1.C([N-]C(C)C)(C)C.[Li+].[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[CH:5]=1
Reactant: CCCCCCCCCC(Br)Br
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(-c2cc(CCCCCCCCCCCBr)ccn2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
100 ml abs. tetrahydrofurane (THF) are cooled to 0° C. in an inert gas atmosphere (N2) and mixed with 2.00 g (10.9 mmol) of 4,4′-dimethyl-2,2′-bipyridine. After stirring for 15 min at 0° C. 5.45 ml (10.9 mmol) of a 2 M solution of lithium diisopropylamide (LDA) are added to the THF which is then reacted for 2 hr with cooling. The reaction solution is added dropwise over a period of 30 min to a solution of 3.30 g (11.0 mmol) of 1.10 dibromodecane in 30 ml abs. THF at 0° C. The brownish clear solution is stirred for a further 2 hr at 0° C. and for 16 hr at RT before being quenched with 10 ml H2O. The suspension is then concentrated under a reduced pressure almost until dry. The aqueous residue is taken up in 25 ml of water, and 25 ml brine is added and the mixture extracted three times with 75 ml CHCl3 each. The organic phases are dried over Na2SO4, filtered and concentrated until dry under a reduced pressure. Purifying of the product mixture is achieved on silica gel with ethyl acetate (EtOAc). The product A is obtained in the form of a beige crystalline powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[S:13]([Cl:16])(=[O:15])=[O:14])([CH3:3])[CH3:2].[Sb](Cl)(Cl)(Cl)(Cl)[Cl:18].ClCl>C(Cl)(Cl)(Cl)Cl>[Cl:18][C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([S:13]([Cl:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:10]([CH3:11])[CH3:12])[CH:8]=1
Reactant: Cl[Sb](Cl)(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(C(C)C)c(S(=O)(=O)Cl)c1
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(Cl)c(C(C)C)c(S(=O)(=O)Cl)c1
Reaction time: 6 h

Procedure:
A sealed autoclave, charged with 288 parts of 2,5-diisopropylbenzenesulfonyl chloride, 5 parts of antimony pentachloride and 600 parts carbon tetrachloride and 36 parts chlorine, is shaken at 150° for 6 hr. The reaction solution is washed with sodium bisulfite and water. The washed solution is dried and the solvent distilled under reduced pressure. The crude residue can be recrystallized from a suitable solvent to give 3-chloro-2,5-diisopropylbenzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH3:16].[OH2:18]>O1CCOCC1.C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:13]=[CH:14][C:4](/[CH:3]=[C:2](\[CH3:1])/[CH:17]=[O:18])=[C:5]([O:15][CH3:16])[CH:6]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(C=C(C)C)c(OC)c1
Reactant: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(/C=C(\C)C=O)c(OC)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 1.0 g (4.3 mmol) of ethyl 4-(2,2-dimethylvinyl)-3-methoxybenzoate, 1.24 g (11.2 mmol); of SeO2, and 0.2 mL of water in 15 mL of dioxane was heated in a 110° C. oil bath for 1.5 h. After cooling to room temperature, the reaction mixture was filtered through Celite (Et2O rinse) to remove excess SeO2. Concentration afforded an orange semisolid residue, which was dissolved in a small amount of toluene and chromatographed on 25 g of silica gel using 30% Et2O/hexane to afford a small amount of a yellow oil (Rf 0.64, Z-isomer) followed by 0.60 g of a yellow solid (Rf 0.56, E-isomer). This solid was rechromatographed on 20 g of silica gel (toluene) to remove colored byproducts (Rf 0.0, 0.38) and to isolate the aldehyde (Rf 0.18), which was submitted to evaporative distillation at 110°- 120° C. (0.005 mm) to afford 0.45 g (42% yield) of very pale yellow solid. The 1H NMR spectrum indicated none of the Z-isomer was present. A sample was purified by crystallization from EtOAc/hexane: white prisms, mp 59°-61° C.; IR (CHCl3) 2840, 1705, 1675, 1410, 1290, 1110, 1010 cm-1 ; 1H NMR (CDCl3) δ 1.42 (t, J=7 Hz, 3, CO2CH2CH3), 2.0 (d, J=0.5 Hz, 3, C=CCH3), 3.95 (s, 3, OCH3), 4.42 (q, J=7 Hz, 2 CO2CH2CH3), 7.3-7.85 (m, 4, C=CH, 3', 5', 6' H), 9.67 (s, 1, CHO); MS calcd for C14H16O4 248.1049, found 248.1058.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[Br:25][CH2:26][C:27]([C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)=[O:28]>C1COCC1>[Br:25][CH2:26][CH:27]([C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[OH:28]
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Product: OC(CBr)c1ccc2c(c1)OCCO2

Procedure:
(R)-2-Methyl-CBS-oxazaborolidine (1M in toluene, 1.95 ml, 1.95 mmol) was added to a flask containing 20 ml dry THF under Ar2(g) at 0° C. BH3.SMe2 (2M in THF, 6.0 ml, 12.0 mmol) was added over 5 min. 2-Bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (4.7 g) was dissolved in 30 ml dry THF, added to a dropping funnel and added to the above solution slowly (ca 4 h) at 0° C. The mixture was stirred over night. The reaction was quenched by addition of 0.4 ml MeOH. The mixture was concentrated under reduced pressure, diethyl ether (200 ml) was added and the solution was extracted with 0.5M HCl (pH=1). The aq-phase was extracted with 100 ml diethyl ether and the combined organic phases were washed with ca 2% NaHCO3 followed by brine. The organic phase was dried with MgSO4 and concentrated to yield the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; mp >160° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.60 (m, 2H), 1.85-2.05 (m, 2H), 2.60-3.50 (m, 7H), 3.67 (brd, J=12.1 Hz, 2H), 3.75-3.95 (m, 3H), 4.57 (dd, J=9.6, 3.8 Hz, 1H), 6.66 (d, J=8.9 Hz, 2H), 6.77 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 8.92 (brs, 1H); MS (ES) m/z: 472.0 (MH+); HRMS Calcd. for C24H30N3O5S(MH+): 472.1906. Found: 472.1898.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1>>[N:14]1[CH:13]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[N:16][CH:15]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Brc1cncnc1
Product: CC(=O)N(c1ccccc1)c1cncnc1
Yield: 61 %

Procedure:
Using acetanilide (8.25 g) and 5-bromopyrimidine, a reaction was made in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:1 to 3:1) produced N-(5-pyrimidinyl)acetanilide (7.98 g; yield, 61%) as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)C1C=CC=CC=1>C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:22])[C:13]=2[CH:23]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Solvent: CCO
Product: Cc1c(C(=O)C(C)C)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 99.6 %

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (4.0 g) synthesized in Example A85(1) was dissolved in ethanol (80 mL), and palladium carbon-ethylenediamine complex (400 mg) was added to the solution at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 9.5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.82 g, 100%) as a colorless solid.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[C:18]1([C:24]2[O:40][C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:32][C:33]4[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=4)[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]3[C:26]4[CH:25]=[C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[O:40][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:38][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.03 ml) to 4-(6-phenyl-furo[2.3-d]pyrimidin-4-yloxy)phenylamine (40 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered out and washed with toluene to obtain the title compound (42 mg) as light yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COCCOCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)COCCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a mixture of diisopropylamine (2.1 ml, 15 mmol) and tetrahydrofuran (30 ml) was added dropwise n-butyllithium (2.4M n-hexane solution, 5.0 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred for 30 minutes. To the mixture was added dropwise tributyltin hydride (3.3 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred at 0° C. (external temperature) for 40 minutes. After the reaction mixture was cooled at −78° C. (external temperature), to the reaction mixture was added dropwise 2-methoxyethoxymethyl chloride (1.4 ml, 12 mmol). After a temperature was raised to room temperature, to the reaction mixture were added diethyl ether and an aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (2.6 g, 6.9 mmol, 57%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[K+]>C1COCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:8]2[S:9][C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nc(Nc2ccc(Cl)cc2)sc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(Nc2ccc(Cl)cc2)nc1C(=O)O
Temperature: 50 °C
Yield: 44.7 %

Procedure:
A mixture of 5.1 g (18 mmol) 2-(4-Chloro-phenylamino)-5-methyl-thiazole-4-carboxylic acid ethyl ester and 10.8 ml 5M aq. KOH in 50 ml THF was heated to 50° C. for 16 h. After evaporation of the volatiles 100 ml water and 6 ml HOAc was added and the mixture was extracted 3× with 500 ml ethyl acetate. The combined organic layers were washed 3× with 200 ml water and concentrated at 40° C. under reduced pressure until precipitation started. After cooling to room temperature the crystals were filtered off, washed 3× with 10 ml ethyl acetate and dried to yield 2.16 g (44.5%) of the title compound. MS (m/e): 453.0 (MH+, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10]>>[NH2:1][C:2]1[C:3]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: Nc1cccnc1Nc1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 3.1 %

Procedure:
A mixture of 3-amino-2-chloropyridine (2.57 g) and 3-nitroaniline (2.76 g) was heated at 200° C. for 1 hour. The mixture was cooled and partitioned between aqueous sodium bicarbonate solution and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (chloroform-methanol, 40:1) to afford 3-amino-2-(3-nitrophenylamino)pyridine (141 mg) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 25.3 %

Procedure:
A solution of (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1), phenylboronic acid (73 mg, 0.6 mmol), (Ph3P)4Pd (20 mg, 0.02 mmol) and K2CO3 (80 mg, 0.6 mmol) in a mixture of DME (1.5 ml) and water (50 μl) was heated at 80° C. for 12 h. The insoluble material was filtered off and the filtrate concentrated. After chromatography, (5R*,6S*)-6-biphenyl-4-yl-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (20 mg) was obtained as a white solid. 1H NMR (CDCl3): 7.5-7.6 (4H, m), 7.3-7.5 (3H, m), 7.15-7.3 (3H, m), 6.64 (2H, m), 3.45 (1H, dd, J1=12.4 Hz, J2=6.1 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.8-2.45 (5H, m).
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:15]([NH2:25])(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:12]([O:11][C:9]([C:8]1[N:25]=[C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][CH:7]=1)=[O:10])[CH3:13]
Reactant: NC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
Synthesis was performed as described by Panek et al. (J. Org. Chem., vol. 61, p. 6496 (1996)). Sodium hydrogencarbonate (22.8 g) and ethyl bromopyruvate (10.5 mL) were added to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 mL) at room temperature, and the mixture was heated under reflux for 48 hours. After the reaction mixture was left to cool to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and trifluoroacetic acid anhydride (30 mL) was added to the solution at 0° C. The mixture was gradually heated to room temperature, and was stirred for 63 hours. Saturated aqueous sodium hydrogencarbonate (500 mL) and ethyl acetate (150 mL) were added to the reaction mixture to partition the mixture. The aqueous layer was extracted with ethyl acetate (150 mL), and the organic layers were combined. The combined organic layer was washed with saturated brine (150 mL), dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→3:1), to thereby give the title compound (10.9 g).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[F:26][C:27]1[CH:28]=[C:29]([CH:51]=[CH:52][C:53]=1[F:54])[CH2:30][N:31]1[C:36](=[O:37])[C:35]([C:38]([O:40]C)=[O:39])=[CH:34][C:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=2)=[N:32]1>>[C:38]([C:35]1[C:36](=[O:37])[N:31]([CH2:30][C:29]2[CH:51]=[CH:52][C:53]([F:54])=[C:27]([F:26])[CH:28]=2)[N:32]=[C:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=2)[CH:34]=1)([OH:40])=[O:39]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 97.6 %

Procedure:
Following the procedure of Example 1 (7), 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow crystalline powder (yield: 97.6%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1>CN(C=O)C.O>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC1CCCCN1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCCCC2C)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech, 1 g; 4.69 mmol) and 2-methylpiperidine (1.39 g; 14.07 mmol) in DMF (4 mL) was heated to 50° C. for 3 hours. The reaction was then allowed to return to RT and diluted with water. It was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo, affording ethyl 4-(2-methylpiperidin-1-yl)-3-nitrobenzoate as a yellow oil. The residue was taken up in THF (10 mL) and lithium hydroxide (561.73 mg; 23.46 mmol) was added followed by water (10 mL). The reaction mixture was stirred at RT for 16 hours. It was concentrated and the residue was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 5 with acetic acid. It was extracted with Et2O and the organic phase was dried over magnesium sulfate and concentrated, affording the title compound as a yellow solid (1.17 g, 94%). 1H NMR (DMSO-d6) δ 13.07 (s, 1H), 8.23-8.22 (d, J=2.13 Hz, 1H), 8.04-8 (dd, J=8.96, 2.28 Hz, 1H), 7.44-7.41 (d, J=8.88 Hz, 1H), 3.64-3.60 (m, 1H), 3.25-3.17 (m, 1H), 2.90-2.84 (m, 1H), 1.82-1.43 (m, 6H), 1.06-1.04 (d, J=6.43 Hz, 3H). LC/MS (Method A): 265.0 (M+H)+; 263.0 (M−H)−.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([Cl:22])[CH:18]=1)=[O:12]
Reactant: Clc1ccccc1Cl
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.31 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in 1,2-dichlorobenzene (20 ml) under ice-cooling and the mixture was stirred at 60°-70° C. for 1.5 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.47 g of 6-bromo-1-(3,4-dichlorophenyl)-1-hexanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](C=O)[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:3]=1.[C:26]([CH:31]=[C:32]1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](/[CH:32]=[CH:31]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(-n3ncc(C=O)c3C)nc(N)n2)cc1
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/c1cnn(-c2cc(NCc3ccc(OC)cc3)nc(N)n2)c1C

Procedure:
The compound obtained in (2) above weighing 3.50 g and 4.3 g of (carboethoxymethylene)triphenylphospholane were allowed to react and worked up in the same manner as in Example 57-(3) to give 3.22 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[CH:14][CH2:15][Si](C)(C)C)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:23])[CH:14]=[CH2:15])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=CC[Si](C)(C)C)COC1(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a solution of the compound produced in Example 47 (0.196 g, 0.63 mmol) in acetonitrile (6 ml), was added Selectfluor™ (0.33 g, 1.5 eq.) and NaHCO3 (0.105 g, 2 eq.). The reaction mixture was stirred under an atmosphere of nitrogen for 20 hours before concentrating under reduced pressure. Purification by flash chromatography (diethyl ether:hexane 1:19) afforded the product (0.116 g, 72%). de=33%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Br:3][C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1cccc(N)c1Br
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(NCCO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.25 h

Procedure:
To a stirred slurry of NaH (60% in mineral oil) (0.435 mL, 10.00 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-3-methylaniline (0.625 mL, 5 mmol) in THF (1 ml). After 15 min, (2-bromoethoxy)-tert-butyldimethylsilane (1.07 mL, 5 mmol) was added and the reaction mixture was stirred for 48 h. The reaction was quenched with water, partitioned between EtOAc and aqueous saturated ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-10% EtOAc/hexanes). 2-Bromo-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methylaniline was isolated as a yellow oil.