Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)N(C)c2ccccc2)c1
Yield: 27.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.440 g, 1.68 mmol) in dichloromethane (2 ml) was added to a mixture of N-methylaniline (0.364 g, 3.40 mmol) and pyridine (0.5 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (15:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.155 g, 28%). 1H NMR (CDCl3, HMDSO), δ: 3.12 (3H, s); 3.74 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.97–7.74 (10H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9](C)[CH3:10])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH3:10])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1cc(Br)cnc1C

Procedure:
To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 3.81 mmol) in THF (25 ml) cooled with an ice-bath was added 1 M bis(trimethylsilyl)amide in THF (4.38 mmol). The RM was stirred for 1 h at rt then was added iodomethane (4.38 mmol). The RM was stirred for 1 h at rt. The RM was cooled with an ice-bath and was added 1 M bis(trimethylsilyl)amide in THF (1.9 mmol). The RM was stirred for 30 min at it then was added iodomethane (1.9 mmol). The RM was stirred for 1 h at it then was diluted with EtOAc and washed with aqueous Na2CO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in MeOH and separated by preparative HPLC. The first eluting pure fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (HPLC: tR 1.88 min (Method A); M+H=201, 203 MS-ES). The second eluting pure fractions, that contained (5-bromo-2-methyl-pyridin-3-yl)-dimethyl-amine side product, were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (HPLC: tR 2.01 min (Method A); M+H=215, 217 MS-ES).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(O)c1
Yield: 90 %

Procedure:
To a stirred solution of 3-hydroxy-4-methoxyphenyl acetic acid (24.8 g, 136 mmol) in 200 mL of MeOH was added 1 mL of H2SO4 and the reaction mixture was heated at reflux overnight. The methanol was removed by evaporation in vacuo and the residue was poured into saturated NaHCO3 solution and extracted with EtOAc (3×150 mL). Combined organic extracts were then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 23.9 g (90% yield) of 3-hydroxy-4-methoxyphenyl acetic acid methyl ester as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH:20]=[CH:19][C:18]4C(OC(=O)[C:16]5[C:17]=4[C:12]=3[C:13](=[CH:14][CH:15]=5)[C:8]3[C:9]=2[C:4]2[C:5](C(OC(=O)[C:3]=2[CH:2]=1)=O)=[CH:6][CH:7]=3)=O.N1C=CN=C1.O.C(C1C=CC(C(C)(C)C)=CC=1N)(C)(C)C>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH:14]1[C:13]2=[C:12]3[C:11]([C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][C:8]2=5)[CH:3]=[CH:2][CH:1]=4)=[CH:20][CH:19]=[CH:18][C:17]3=[CH:16][CH:15]=1
Reactant: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Agent: [Zn+2]
Solvent: O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Temperature: 210 °C
Reaction time: 1 h

Procedure:
In an autoclave of capacity 100 ml, a mixture of 3.66 g (9.34 mmol) of perylene-3,4,9,10-tetracarboxylic dianhydride, 18.7 g of imidazole, 1.32 g of zinc acetate dihydrate, 8.0 ml (450 mmol) of water and 1.05 g (5.12 mmol) of 2,5-di-tert-butylaniline (prepared according to Rec. Trav. Chim. Pays-Bas, 1958, 77, 491) is heated at 210° C. for 23 h. After the end of the reaction, the mixture is removed from the autoclave by rinsing with ethanol, treated with water and concentrated hydrochloric acid and boiled until all the ethanol has evaporated. The brown-red residue is filtered off with suction and boiled in 10 per cent potassium carbonate solution for 1 h. The residue is filtered off with suction, dried at 120° C. in a drying cabinet and chromatographed on silica gel using chloroform. This gives a forerun (yellow, blue fluorescence) of perylene, followed by N-(2,5-di-tert-butylphenyl)perylene-3,4-dicarboximide (2b) and then by N,N'-bis(2,5-di-tert-butylphenyl)perylene-3,4,9,10-tetracarboximide (1b). Yield 2.40 g (50.5%), m.p. >300° C. Rf (CHCl3 /silica gel)=0.85. UV (CHCl3): λmax (ε)=489 nm (35300), 512 (33590). Fluorescence (CHCl3,exc. 489 nm) λmax (Irel)=535 nm (1), 576 nm (0.36).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([NH:21]CC4C=CC=CC=4)[C:14]([F:20])=[C:15]([F:19])[C:16]=3[F:18])[C:11](=[O:29])[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:9]2)[C:5]([F:35])=[CH:4][C:3]=1[F:36]>[Pd].C(O)(=O)C>[NH2:21][C:13]1[C:14]([F:20])=[C:15]([F:19])[C:16]([F:18])=[C:17]2[C:12]=1[C:11](=[O:29])[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:9][N:8]2[C:6]1[C:5]([F:35])=[CH:4][C:3]([F:36])=[C:2]([NH2:1])[N:7]=1
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(N)c2c1=O
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To 5 ml of acetic acid was added 260 mg of ethyl 1-(6-amino-3,5-difluoropyridine-2-yl)-5-benzylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate together with 50 mg of 10% palladium on carbon, and the mixture was hydrogenated at room temperature for 4 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. The procedure of adding 10 ml of ethanol to the residue and concentrating under reduced pressure was repeated twice. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 160 mg of the title compound as a pale yellow powder.
Reaction SMILES: [OH:1][C@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CP(C)(=O)OCC(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COP(C)(=O)C[C@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 4.3g of isobutyl P-[2(R)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.5 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(R)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: a δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =-15.8(0.51% in ethanol).
Reaction SMILES: [N+](C1C=CC(C2SC=CC=2)=CC=1NC(=O)C1C=CC(C2NN=NN=2)=CC=1)([O-])=O.[CH3:29][O:30][C:31]1[CH:53]=[CH:52][C:34]([C:35]([NH:37][C:38]2[CH:43]=[C:42]([C:44]3[NH:45][N:46]=[N:47][CH:48]=3)[CH:41]=[CH:40][C:39]=2[N+:49]([O-])=O)=[O:36])=[CH:33][CH:32]=1.CO>C(OCC)(=O)C>[NH2:49][C:39]1[CH:40]=[CH:41][C:42]([C:44]2[NH:45][N:46]=[N:47][CH:48]=2)=[CH:43][C:38]=1[NH:37][C:35](=[O:36])[C:34]1[CH:52]=[CH:53][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3cnn[nH]3)ccc2[N+](=O)[O-])cc1
Agent: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc(-c3cnn[nH]3)ccc2N)cc1
Yield: 25 %

Procedure:
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 272 and using ethyl acetate as a solvent instead of methanol, the title compound 273 was obtained in 25% yield (over two steps). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.62 (s, 1H); 8.08 (bs, 2H); 7.97 (d, J=8.5 Hz; 2H); 7.62 (s, 1H); 7.45 (d, J=8.2 Hz; 1H); 7.03 (d, J=8.5 Hz; 2H); 6.82 (d, J=8.2 Hz; 1H); 5.11 (bs, 2H); 3.83 (s, 3H). MS: calc: 309.3; found: 310.1 (M+H)
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]([CH3:26])([CH3:25])[CH2:15][CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([NH2:24])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:13][C:14]([CH3:26])([CH3:25])[CH2:15][CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH2:22][NH2:24]
Reactant: CC(C)(C)CCc1ccsc1C(N)=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCc1ccsc1CN
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 17.0 ml of Vitride® T [sodium dihydrobis(2-methoxyethoxy)aluminate (70% solution in toluene)] in 50 ml of toluene, was added dropwise a solution of 5.0 g of 3,3-dimethylbutyl-2-thiophene carboxamide in 50 ml of dried tetrahydrofuran. The resulting mixture was heated at reflux for 2 hours, then cooled. The complex was decomposed by adding dropwise 30 ml of 2.5N sodium hydroxide. The mixture was stirred for one hour. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a light brown liquid. Kugelrohr distillation (75° C./0.15 mm of mercury) gave 4.0 g (82% yield) of the desired product.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[C:10]([CH:28]=1)[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:29][CH2:2][CH2:3][CH3:4])=[C:10]([CH:28]=1)[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CCCI
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCC)nn1

Procedure:
The title compound was prepared by reacting 1-iodopropane and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) using a similar method to that of reference example 4.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1Cl

Procedure:
To a solution of 2,6-dichloronicotinic acid (52 g, 0.27 mol) in benzene: MeOH (7:1, 1.0 L) was added dropwise a solution of (trimethylsilyl)diazomethane (1 M in heptane) until gas evolution ceased and the yellow color persisted (ca. 320 mL, 1.2 equiv.). The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to give the product as a white solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.[O-]CC.[Na+].Br[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[O:18]1[CH2:3][CH2:2][S:1][CH:10]=[C:11]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: OCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=CSCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A solution of 2-mercaptoethanol (58.5 g.) in anhydrous ethanol (220 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (17.2 g.) with anhydrous ethanol (570 cc.)]. After having heated the reaction mixture to 45°-50° C., ethyl γ-bromoacetoacetate (157 g.) is added over the course of 45 minutes, and then the reaction mixture is stirred for 2 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (1,000 cc.) and, after filtration of the resulting solution, toluene-p-sulphonic acid monohydrate (1.5 g.) is added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then toluene (200 cc.) is distilled. After cooling, the toluene solution is filtered and washed twice with a saturated aqueous solution of sodium bicarbonate (200 cc.) and then with water (2 × 200 cc.); it is then dried over sodium sulphate, treated with decolourizing charcoal, filtered and evaporated under reduced pressure (20 mm.Hg). A residue (131.9 g.) is obtained and is chromatographed on alumina (550 g.). Elution is effected using a mixture (2.5 liters) of ethyl acetate and cyclohexane (1-19 by volume) and the eluates are concentrated to dryness under reduced pressure (20 mm.Hg). Ethyl (5,6-dihydro-1,4-oxathiin-2-yl )acetate (75.7 g.) is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](O)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([Cl:24])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc(C)nc(O)c1Cc1ccc([N+](=O)[O-])cc1
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc([N+](=O)[O-])cc1

Procedure:
32 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-hydroxypyrimidine, prepared in Example 6, are suspended in 45 ml of phosphorus oxychloride. The mixture is brought to reflux for 6 hours and then concentrated under vacuum. The residue is taken up with water and extracted with dichloromethane. The organic phase is washed with potassium carbonate solution, then dried over magnesium sulphate and evaporated to dryness to give 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine in the form of crystals of melting point 65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.C([N:32](CC)CC)C.N.O>CN(C)C=O.O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:32])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Reactant: CCN(CC)CC
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(-c3cccc(S(N)(=O)=O)c3)nc(OC)n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.2 g, Intermediate (10)] and triethylamine (0.3 mL) in dimethylformamide (5 mL) is cooled to 0° C. and treated with a solution of ammonia in 1,4-dioxane (5 mL, 0.5M). The solution is allowed to reach room temperature overnight and poured into water (100 mL). The mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [140 mg, Example 3]. MS: 415 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.9 (1H, d, J=3 Hz); 7.7 (1H, m); 7.4 (2H, m); 7.1 (2H, d, J=7 Hz); 6.8 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (2H, t). IC50=2.9 nM
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:15])([F:14])[CH2:12]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:15])([F:14])[F:10]
Reactant: FC(F)(F)CI
Reactant: Oc1cc(F)ccc1Br
Product: Fc1ccc(Br)c(OCC(F)(F)F)c1

Procedure:
2-Bromo-5-fluoro-phenol was reacted with 1,1,1-trifluoro-2-iodo-ethane according to the method of Example 108A to provide the title compound. MS (DCI/NH3) m/z 273 (M)+, 275 (M+2)+.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(O)CCC>[N+:10]([C:6]1[C:5]2[NH:23][CH2:22][CH2:21][NH:24][C:3](=[O:14])[C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: NCCN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Yield: 46.7 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (2.00 g, 9.3 mmol) was dissolved in n-butanol (10 ml). Na2CO3 (986 mg, 9.3 mmol) was added followed by ethylenediamine (622 μL, 9.3 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, filtered, and washed with water (200 ml) to afford 9-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a bright orange solid (900 mg, 46%). mp 196-197° C.; LCMS: m/z=208.22 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.70 (m, 1H), 8.39 (m, 1H), 8.22 (dd, J=8.3 Hz, 1.8 Hz, 1H), 8.14 (dd, J=7.8 Hz, 1.8 Hz, 1H), 6.75 (t, J=7.8 Hz, 1H), 3.65 (m, 2H), 3.35 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:26])[C:16]2([CH3:28])[CH3:27])=[O:14])=[C:8]([N+:10]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl>CO>[NH2:10][C:8]1[CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:17](=[O:26])[C:16]1([CH3:27])[CH3:28])=[O:14]
Reactant: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2[N+](=O)[O-])C(C)(C)C1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: O
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2N)C(C)(C)C1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of 4-(2-tert-butyl-4-nitrothiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.200 g, 0.49 mmol) and tin chloride dihydrate (0.55 g, 2.4 mmol) dissolved in 4 mL MeOH was stirred at 70° C. overnight. The reaction mixture was cooled down to room temperature, quenched with saturated NaHCO3 (40 mL), and extracted with ethyl acetate. The combined organic layers was dried, the solvent eliminated under vacuum and the residue purified by chromatographic column (silica gel, dichloromethane) to afford 0.090 g of 4-(4-amino-2-tert-butylthiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one as a tan solid.
Reaction SMILES: [N+](C1C=CC([C:10]2[C:15]3[C:16]4[C:22]([C:23]([O-:25])=O)=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[C:17]=4[O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)=CC=1)([O-])=O.[NH2:28][C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[CH:31][C:30]=1[Cl:36].[H-].[Na+].C(O)(=O)C>CN(C=O)C.O>[Cl:36][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Cl:35])[C:29]=1[NH:28][C:23]([C:22]1[C:16]2[C:15]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[O:18][C:17]=2[C:19]([O:26][CH3:27])=[CH:20][CH:21]=1)=[O:25]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)[O-])c2c1oc1ccnc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccncc12
Reaction time: 50.67 h
Yield: 46.4 %

Procedure:
To a well stirred solution of 4-nitrophenyl-6-methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 14) (55 mg, 0.15 mmol) and 4-amino-3,5-dichloropyridine (50 mg, 0.30 mmol) in DMF (2.0 mL) was added sodium hydride (60% dispersion in mineral oil) (18 mg, 0.45 mmol) at −5° C. and stirred for 3040 minutes. Excess of DMF was removed under reduce pressure, the residue obtained was diluted with water (5 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford product (27 mg) as off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[B:11]([O:22]CCCC)([O:17]CCCC)[O:12]CCCC.[Cl-].[NH4+]>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:12][B:11]([OH:22])[OH:17]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1OB(O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromoanisole (0.25 ml) dissolved in tetrahydrofuran (5 ml) was added with magnesium (48.6 mg) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. This solution was cooled to −78° C., added with a solution of tributyl borate (0.65 ml) dissolved in tetrahydrofuran (5 ml) and gradually warmed to room temperature with stirring for 20 hours. The reaction mixture was added with saturated aqueous ammonium chloride (10 ml) with ice cooling, stirred for 10 minutes and then extracted twice with ether (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain (2-methoxyphenyl)boric acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=2)[N:13]=1
Reactant: Cc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)ccc1Cl
Yield: 37.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-106, 0.300 g, 0.859 mmol), pivaloyl chloride (0.130 g, 1.03 mmol), TEA (2.0 mL), dry THF (5 mL) to afford 0.140 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 2.37 (s, 3H), 4.29 (d, J=5.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.58 (s, 2H), 7.70 (br d, 1H), 7.91 (s, 1H), 8.20 (d, J=6.0 Hz, 1H), 12.56 (s, 1H); MS (m/z): 433.38 (M+H)+.