Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])C(O)=O.[Br:29]Br.FF>C(O)CO.O>[F:1][C:2]([Br:29])([F:28])[C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: BrBr
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FF
Solvent: OCCO
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Temperature: 30 °C
Yield: 93.2 %

Procedure:
Perfluorononanoic acid 100 g (0.215 mole), bromine 41 g (0.258 mole) and Freon 113 (500 ml) were mixed in a 2-liter Teflon plastic bottle. This plastic reactor was equipped with a Teflon-coated magnetic stir bar, inlet and outlet tubes made of Teflon-FEP, and a thermocouple coated with Teflon-FEP. The outlet tube was connected to a condensor which was chilled with an ethylene glycol-water mixture. The acid solution was warmed to 30 ° C. through agitation while the reactor was purged of air by flushing it with an inert gas, such as nitrogen, through the inlet tube; The nitrogen flow was terminated and fluorine gas was bubbled into the mixture at 30 cc/min. The fluorine, supplied by Air Products, was used without further purification. The fluorine flow rate was controlled with a Monel needle valve and monitored with a Hastings mass flow transducer. Despite an exothermic reaction occurring immediately, the reaction temperature was kept at 30°-40° C. throughout the reactor by external cooling. The fluorine flow was maintained until the color of the solution turned from deep red to light yellow. Approximately 2.2 fold excess of fluorine (based on the initial amount of acid used) was required to produce this result. After the fluorine gas was terminated, the reactor was again purged with nitrogen and the mixture was carefully poured into water. The organic precipitate was washed with water containing a small amount of sodium thiosulfite, and then dried over magnesium sulfate. Fractional distillation of the precipitate produced 100 grams of perfluorooctyl bromide (97% yield) having a boiling point between 142°-144° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:41]=[CH:40][C:23]([CH2:24][N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][NH2:25])=[CH:40][CH:41]=3)[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)no3)cc2C)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred solution of di-tert-butyl (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)imidodicarbonate (Example 98, 2.73 g, 4.88 mmol) in dichloromethane (37 mL) was added trifluoroacetic acid (3.7 mL, 48.8 mmol). After the reaction mixture had been stirred at rt for 3 h, water (50 mL) was added, and it was extracted with dichloromethane (3×30 mL). The aqueous phase was then made alkaline (pH 10) by addition of potassium carbonate. It was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the title compound was obtained (1.28 g, 73%): 1H NMR (400 MHz, DMSO-d6) 8.02 (d, 2H), 7.55 (d, 2H), 7.18 (d, 2H), 7.11 (d, 2H), 6.90 (s, 1H), 5.43 (s, 2H), 3.85 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 360, HPLC RT (Method D) 1.56 min.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[C:9]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:26])[CH2:16][CH2:17]1)(=[O:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution (667 ml, 2 mole) phenylmagnesium bromide* (3 molar in ethyl ether) was diluted with 2 liters of anhydrous ethyl ether, cooled to 0°-10° C., and treated with a solution of 148 g (0.6 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 1.5 liters of anhydrous tetrahydrofuran dropwise over a 1.5 hr period. The mixture was stirred at ambient temperature overnight and then poured into a solution of 107 g (2 mole) of ammonium chloride in 2 liters of cold water. The mixture was extracted thrice with 1 liter portions of benzene. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give a semi-solid as residue. The semi-solid was triturated with isopropyl ether and the mass crystallized. The solid was collected by filtration and dried to yield 87.8 g (45%) of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([Br:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2ccc(=O)n(Cc3ccccc3)c2c1O
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (50 mg, 0.16 mmol) and N-bromosuccinimide (30 mg, 0.17 mmol) in 0.5 mL of CH2Cl2 was refluxed for 3 h. Solvent was evaporated, and the residue was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 26 mg of the title compound as a pale yellow solid. MS: (+) m/z 387.14, 389.13 (M−1, 79/81Br).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:15][O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)[C:3]=1[CH3:16]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 55 %

Procedure:
By using 5-bromo-7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (1.80 g, 6.31 mmol) synthesized in Reference example 94 and 1-(4-methylphenyl)piperazine (2.22 g, 12.6 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 1.32 g (yield 55%).
Reaction SMILES: [CH3:1][C:2]([Mg]Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[Mg].ClC(C)(C)CCCC.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>CCOCC>[Cl:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCCCC(C)(C)[Mg]Cl
Agent: CCCCC(C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)CCCCl
Reaction time: 12 h

Procedure:
Four hundred ml. of a solution in ether of 1,1-dimethylpentylmagnesium chloride prepared from magnesium (24.3 g., 1.0 mole) and 1-chloro-1,1-dimethylpentane (134.5 g., 1.0 mole) according to the procedure of Whitmore and Badertscher [J. Am. Chem. Soc., 55, 1559 (1933)] is added dropwise with stirring to 4-chlorobutyryl chloride (197 g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an additional 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column to yield the product as a colorless oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br-].[PH4+].[CH3:8][C:9]1([CH3:16])[CH2:14][CH:13]=[CH:12][C:11](=O)[CH2:10]1.[CH2:17](OCC)C>>[CH3:8][C:9]1([CH3:16])[CH2:14][CH:13]=[CH:12][C:11](=[CH:4][CH2:3][CH2:2][CH:1]=[CH2:17])[CH2:10]1
Reactant: CC1(C)CC=CC(=O)C1
Reactant: CCOCC
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [PH4+]
Product: C=CCCC=C1C=CCC(C)(C)C1
Reaction time: 3 h
Yield: 50 %

Procedure:
8 g of a 14% solution of butyl-lithium in diethylether were added under nitrogen within 15 min. to a suspension of 7 g of the above said phosphonium bromide in 80 ml ether. To the red resulting solution, cooled to 5°-10°, 2.1 g of 3,3-dimethyl-cyclohex-5-en-1-one in 10 ml ether, were added, whereupon, the reaction mixture was stirred for 3 h, filtered and the clear filtrate was washed with water until neutrality. On evaporation and distillation in a bulb apparatus, 1.5 g (50% yield) of (3,3-dimethyl-cyclohex-5-en-1-yliden-)-pent-4-ene were obtained.
Reaction SMILES: O=C1C2C3C(C(OC)=O)=CC=CC=3NC=2CNC1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C[N:27]1[CH2:39][C:38]2[NH:37][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:40](=[O:43])[NH:41][N:42]=[C:29]([C:30]=2[C:31]=34)[CH2:28]1>>[CH:19]1([N:27]2[CH2:39][C:38]3[NH:37][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:40](=[O:43])[NH:41][N:42]=[C:29]([C:30]=3[C:31]=45)[CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: O=C1CCCCC1
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Product: O=C1NN=C2CN(C3CCCCC3)Cc3[nH]c4cccc1c4c32

Procedure:
Compound 53 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclohexanone according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.42 (d, 1H, J=7.8 Hz), 7.12 (t, 1H, J=7.8 Hz), 3.91 (s, 2H), 3.38 (s, 2H), 2.50-2.56 (m, 1H), 1.58-1.84 (m, 4H), and 1.11-1.31 (m, 6H). MS (ESI) m/e [M+1]+ 309.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:53])([CH3:52])[CH2:48][C:49]([NH2:51])=[O:50].NC(C)(C)C(NCCO)=O>>[C:49]([CH2:48][C:47]([NH:46][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[C:32]([CH3:42])[CH:33]=1)([CH3:53])[CH3:52])(=[O:50])[NH2:51]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(N)CC(N)=O
Agent: CC(C)(N)C(=O)NCCO
Product: Cc1cc(OCCCNC(C)(C)CC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 72 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 3-amino-3-methylbutyramide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-[2-amino-2-(methyl)-propionylamino]ethanol, respectively.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.BrCCBr.[OH-:35].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[P:7]([CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: BrCCBr
Product: O=P(CCCCP(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of palladium acetate (10 mg; 4.45×10-2 mmol), dppb (4.00 g; 9.4 mmol), 1,2-dibromoethane (3.6 g; 19.15 mmol), and dichloromethane (10 mL) was stirred for 30 minutes. To this suspension, aqueous NaOH (20% by weight; 10 mL) was added and the mixture was vigorously stirred at room temperature for 3 days. Dichloromethane (30 mL) was added, the organic phase was filtered through a silica plug which was then washed with 80 mL of CH2Cl2 /AcOEt (5:3 by volume). The combined organic solutions were evaporated to dryness. The solid residue was dissolved in boiling CH2Cl2 (ca. 30 mL) and the solution was treated with ether (100 mL; portionwise) and left at room temperature for 2 hours. Well-shaped, colorless crystals were separated, washed with ether, and dried under vacuum. The yield was 3.33 g (80%). 1H NMR (CDCl3, 20° C.), δ: 1.5 (m, 2H, CH2); 1.7 (m, 2H, CH2); 2.0 (m, 2H, CH2); 2.2 (m, 2H, CH2); 7.2-7.8 (m, 20H, Ph). 31P NMR (CDCl3, 20° C.), δ: -15.5 (s, 1P, PPh2); 32.2 (s, 1P, P(O)Ph2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[C:21]([C@@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)[CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:27][C@H:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:20]=1)[CH3:26])=[O:12]
Reactant: C[C@H](N)c1cccc(-c2cccnc2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-c2cccnc2)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-fluoro-phenyl)-acrylic acid (0.083 mmol), (S)-1-(3-pyridin-3-yl-phenyl)ethylamine (12.7 mg, 0.064 mmol), EDC (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol), DMF (2 mL) and diisopropylethylamine (33 μL, 0.192 mmol) was stirred at 23° C., 18 hours. The residue was purified by preparative HPLC (Primeshere C18-HC 21.2×100 mm; (5 mM NH4OAc) 0-100% gradient over 5 minutes 20 mL/min flow rate) to afford the title product.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH2:1]1[N:6]([S:40]([C:37]2[CH:38]=[CH:39][C:32]3[O:31][CH2:30][CH2:29][N:28]4[CH:27]=[C:26]([C:25]5[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][N:24]=5)[N:35]=[C:34]4[C:33]=3[CH:36]=2)(=[O:42])=[O:41])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: C1CCN2CCNCC2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN4CCCCC4C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of octahydropyrido[1,2-a]pyrazine (50 mg, 0.38 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 132 (36 mg, 62%) as a white solid. LCMS: RT 2.90 min [M+H]+ 498.3. 1H NMR (DMSO, 400 MHz): δ 8.78 (1H, d, J=2.41 Hz), 8.01 (1H, s), 7.94 (1H, s), 7.63 (1H, dd, J=8.63, 2.42 Hz), 7.28 (1H, d, J=8.62 Hz), 5.73-5.72 (1H, m), 4.63-4.59 (4H, m), 3.53 (1H, d, J=11.02 Hz), 3.43 (1H, d, J=9.07 Hz), 2.70-2.68 (2H, m), 2.33-2.32 (1H, m), 2.19-2.11 (1H, m), 1.93-1.92 (3H, m), 1.62 (1H, d, J=12.59 Hz), 1.57-1.52 (2H, m), 1.49 (6H, t, J=6.30 Hz), 1.38-1.16 (2H, m), 1.01-0.87 (1H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl-].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](O)=[O:19])[CH3:14]>C1C=CC=CC=1>[CH2:13]([O:15][C:16]([CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18](=[O:19])[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])=[O:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=O)O
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)Nc1ccc(NC(=O)CC(=O)OCC)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated in 160 ml of absolute benzene together with 30.1 gm (0.2 mol) of malonic acid monoethylester chloride for 31/2 hours at refluxing. After cooling the precipitate was suctioned off and recrystallized twice from isopropanol. The product had a melting point of 96°-97°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:6](=[O:20])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]=1[CH3:9])#[N:2].Cl.[NH2:36]O.C[C:39]([O-:41])=O.[Na+].C(O)C>O>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:5]2[C:6](=[O:20])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=3)[C:8]([CH3:9])=[C:3]([C:1]3[N:36]=[CH:39][O:41][N:2]=3)[CH:4]=2)=[O:22])=[CH:30][CH:29]=1)(=[O:32])=[O:33]
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ncon2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 57 (a), 0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (90° C.) overnight. The solvents were evaporated in vacuo. The residue was dissolved in triethyl-orthoformate (3 ml) in a vial and a magnetic stirrer bar was added. The vial was sealed and heated (130° C.) with stirring for 2 h. LC-MS confirmed formation of a product with the expected MW. The volatiles were removed in vacuo, and the residue was purified on preparative HPLC giving the title compound (0.012 g, 27%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Cl)c(CNc2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2,5-dichlorobenzylbromide (528 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5. Yield: 0.045 g (15.4%); MS m/z: 292.2/294.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.32 (d, 2H, 3J=6.1 Hz); 6.20 (br s, 1H); 6.43 (br s, 1H); 6.60 (dd, 1H, 4J=1.6 Hz, 3J=8.8 Hz); 7.30-7.33 (m, 2H); 7.40 (d, 1H, 4J=2.6 Hz); 7.49 (d, 1H, 3J=8.5 Hz); 7.86 (s, 1H), 11.83 (br s, 1H); HPLC (METHOD [A]): rt 12.97 min (100%)
Reaction SMILES: [C:1]1([S:7][CH2:8][Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:13])C1>CO.O>[C:1]1([S:7]([CH2:8][Cl:9])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: O=S(CCl)c1ccccc1
Yield: 41.8 %

Procedure:
Chloromethyl phenyl sulfide (3 g, 18.9 mmol) was dissolved in a mixture of methanol (15 mL) and water (3 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (4.04 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 solution (10%, 15 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was dried with anhydrous MgSO4 and concentrated. The crude product was purified by medium pressure chromatography (Ethyl Acetate/Hexane 2:8) to give 1.381 g (42%) of the desired product as a colourless liquid. 1H NMR (CDCl3, 400 MHz): δ 7.71-7.69 (2H, m), 7.57-7.56 (3H, m), 4.41 (2H, ABQ, J=10.8 Hz). 13C NMR (CDCl3, 100 MHz): δ 140.8, 132.1, 126.3, 124.8, 61.3. FT-IR (NaCl): 3058, 3004, 2935, 1472, 1444, 1384, 1218, 1085, 1052 cm−1.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=O)[CH3:10].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>[Cu]>[N:13]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][O:8][CH2:9][CH3:10])[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: CC(=O)Cl
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccccc1
Agent: [Cu]
Product: CCOCc1ccccc1-n1cncn1

Procedure:
The diethyl acetal of benzaldehyde (3.6 g) and acetyl chloride (2.5 g) were reacted in the presence of a trace of copper bronze. The product was reacted with 1,2,4-triazole (2.8 g) to give the title compound as a viscous oil which GLC showed to be about 95% pure. Analysis:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:32]([OH:34])=[O:33])[CH:7]=1
Reactant: O=C=O
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
3.00 g (0.0086 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 5.9 ml of a 1.6M-hexane solution of BuLi (0.0086×1.1 mol) was added thereto, followed by stirring the obtained solution for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.