Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 99 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 4-methylbenzaldehyde (0.74 g, 1 equiv.) and TFA (1 mL, 2 equiv.) to give the title compound (1.6 g, 100%) as a white powder. MP: 207-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: FC(F)(F)CCI
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CCC(F)(F)F)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at −78° C. lithium diisopropylamide solution (31 ml 1M in THF, 31 mmol). After stirring the mixture for 20 min 1-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (1.75 g, 47%); MS (EI): 264.9 (M+.).
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6](=[NH:9])[NH:7][OH:8])[CH3:5])[CH2:3][CH2:2]1.[CH2:26](N(CC)CC)[CH3:27].C(OC(=O)C)(=O)C>CN(C=O)C>[CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6]2[N:9]=[C:26]([CH3:27])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(N-hydroxycarbamimidoyl)-ethyl]-amide (Example 78f, 800 mg, 1.88 mmol) in dry DMF (10 ml) was added triethylamine (190 mg, 262 μl, 1.88 mmol) followed by addition of acetic anhydride (192 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 1 hours and was then stirred at 125° C. for 30 min under microwave radiation. DMF was removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (492 mg, 47%) as a light yellow oil. MS (ESI, m/z): 449.3 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:10]=1[NH:11][C:12](=[O:21])[C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>[Zn].C(O)(=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:19]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:25]=1
Reactant: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O

Procedure:
A solution of 2 g. of ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime in 40 ml. of methylene chloride is treated with 2 g. of zinc dust. 4 ml. of glacial acetic acid are added dropwise within 5 minutes with stirring. After the addition, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered and the filtrate evaporated. The residue is boiled under reflux for 2 hours in 20 ml. of benzene and 2 ml. of glacial acetic acid. The reaction mixture is washed out with 10% soda solution, dried over sodium sulphate and evaporated. Crystallization of the residue from alcohol yields ethyl 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylate, m.p. 232°-234°. Further material crystallizes from the mother liquor.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([O:10]CC)=[O:9])#[N:2].O.O[Li].O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)cnc1C(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(C(F)F)c(C(=O)O)c1
Reaction time: 0.83 h
Yield: 66.7 %

Procedure:
To a solution of ethyl 5-cyano-2-(difluoromethyl)nicotinate (1.2 g, 5.3 mmol) in THF: water (20 mL: 5 mL) was added LiOH.H2O (0.267 g, 6.3 mmol) at 0° C. and the reaction mass was stirred for 40-60 minutes. The reaction mass was acidified with dil. HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.37-7.72 (t, J=53.7 Hz, 1H), 8.24 (s, 1H), 9.30 (s, 1H), 14.25 (br s, 1H); MS (m/z): 199.34 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11](F)[N:12](F)F)=[O:10])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:22]CC(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([Cl:22])[C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(Cl)n1)N(F)N(F)F
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: NNC(=O)C(Cl)c1cccc(Cl)n1
Reaction time: 1 h

Procedure:
A mixture of 3.0 g. of 2-chloro-6-hydrazinopyridine (prepared in Example 1), 1.7 g. of pyridine and 35 ml. of methylene chloride is treated with 2.5 g. of chloroacetyl chloride according to the procedure of Example 2. The reaction mixture is stirred for one hour, then is filtered and washed with methylene chloride to collect 2.3 g. of colorless solid. The solid is recrystallized from tetrahydrofuran-hexane to give the product of the Example m.p. 176°-177° C.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)#[N:2].[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>C(O)(=O)C>[N+:9]([C:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]([CH3:8])[CH:5]=1)([O-:11])=[O:10]
Reactant: Cn1cccc1C#N
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1cc([N+](=O)[O-])cc1C#N
Temperature: 0 °C
Yield: 73.7 %

Procedure:
Compound 22-4 (1 g) was dissolved in anhydrous acetic acid (100 ml), and cooled to 0° C. To the solution was slowly added dropwise nitric acid (380 μl) with stirring, followed by stirring at the same temperature for 1 hour and subsequently at room temperature for 18 hours. After confining the completion of the reaction, to the mixture was added an ice-water (200 ml), followed by slowly adding solid sodium hydroxide (20 g) thereto and stirring for 1 hour. The obtained mixture was extracted with ether (50 ml×3). The obtained organic layer was washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 22-5 (1.05 g, 73.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][C:24]([SH:25])=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnc(S)o2)cc2[nH]cnc2c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in 3 mL absolute EtOH and cooled to 0° C. under N2. CS2 is added (26 mg, 0.346 mmol) followed by powdered KOH (8 mg, 0.150 mmol). After stirring at 0° C. for 30 minutes, the reaction mixture is heated to reflux. After 3.5 hours, the reaction mixture is quenched by the addition of water, followed by the addition of ethyl acetate and 1N HCl. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give the desired product as a yellow solid: LC/MS ESI (+) m/z 376, 378 (M+ Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.29 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH2:4].[CH:5]([CH:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6]>>[CH:5]([CH:7]([N:4]([CH:7]([CH:5]=[CH2:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6]
Reactant: CN
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=CC(c1ccccc1)N(C)C(C=C)c1ccccc1
Reaction time: 1 h

Procedure:
20 grams (0.5 mole) of 98.2% sodium hydroxide pellets are dissolved, with stirring and cooling to a temperature maintained at 10° C., in a saturated solution of monomethylamine (large excess greater than one mole), which is prepared by bubbling gaseous monomethylamine into 200 ml. of distilled water at 10° C. until saturated. Then, 77.8 grams (0.5 mole) of 98% vinylbenzyl chloride are added at a uniform rate over a period of 30 minutes while maintaining the batch temperature below 20° C. Upon removing external cooling, the batch temperature rises to 32° C. in one hour as a result of an exotherm. The batch is then agitated at ambient temperature (26° C.) overnight. On stopping agitation, the phases cleanly separate within a period of one hour. The lower aqueous layer of 250 grams is withdrawn and discarded. The upper product layer of 50 grams is washed with three successive 100 ml. portions of water adjusted to a pH of 8.9, followed by one 100 ml. portion of distilled water (neutral pH). (Without the pH adjustment of the initial three wash portions, some foaming and emulsification occurs.) The washed product layer is then dried over calcium chloride and anhydrous sodium sulfate. Upon removing the drying agent, 38 grams of product is obtained. Analyses showed this material to have the following properties:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]([C:11]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: CCCCCBr
Product: CCCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-bromopentane (109.8 g, 0.727 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 15 minutes. After stirring for an additional 2 hours at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (101.4 g, crude pentylcyclopentadiene). To the crude pentylcyclopentadiene (50 g) dissolved in THF (200 mL) was added n-BuLi (35 mL of 10 M in hexanes, 0.35 mol) at 0° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (60.7 g, 0.334 mol) dissolved in THF (280 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 50° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (74.3 g) as a dark red viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 57.5 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (60 mg) was prepared by following General Procedure F starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (65 uL). LC/MS: m/z 418.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.48 (t, 1H), 8.05 (s, 1H), 7.95 (dd, 1H), 7.77 (d 1H), 7.58 (dd, 1H), 7.47 (d, 1H), 3.61 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Yield: 102.6 %

Procedure:
A solution of 4-chloro-3-nitro-pyridine (2.0 mmol, 0.32 g), triethylamine (3.0 mmol, 0.42 mL) and piperazine-1-carboxylic acid tert-butyl ester (2.5 mmol, 0.47 g) in dioxane (2 mL) was irradiated using microwave for 8 minutes at a temperature of 150° C. The reaction mixture was concentrated in vacuo, and the resulting residue was purified using flash column chromatography on silica gel (eluent: ethyl acetate) to provide 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (633 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 6.87 (d, J=6.0 Hz, 1H), 3.68-3.56 (m, 4H), 3.32-3.18 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
To a solution of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.5 g) in acetone (75 ml) was added 6N hydrochloric acid (7.5 ml) and the mixture was stirred at room temperature for 6 hours. The precipitates which were separated out during the reaction course were collected by filtration to give yellowish crystals of dimethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.26 g), and the filtrate was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and the acetone was distilled off under reduced pressure to give additional crops of orange-yellow crystals (3.84 g) of the same product, (total yield, 6.1 g). A small portion of the first crop was recrystallized from methanol to give pure crystals, m.p. 157°-157.5° C.
Reaction SMILES: Cl.NO.C([N:7](C(C)C)CC)(C)C.C(O)C.[Cl:16][C:17]1[N:22]=[C:21]([NH:23][C:24]([NH:26]C(OCC)=O)=S)[C:20]([O:32][CH3:33])=[CH:19][CH:18]=1>O>[NH2:7][C:24]1[N:23]=[C:21]2[C:20]([O:32][CH3:33])=[CH:19][CH:18]=[C:17]([Cl:16])[N:22]2[N:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(Cl)ccc1OC
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)n2nc(N)nc12
Yield: 58.6 %

Procedure:
Hydroxylamine hydrochloride (9.6 g, 138 mmol) and diisopropylethylamine (14.4 mL, 10.7 g, 83 mmol) were mixed with ethanol (300 mL) for a few minutes and then N-(6-chloro-3-methoxy-2-pyridinyl)-N'-carboethoxythiourea (7.6 g, 27.5 mmol) was added with stirring. The resulting mixture was stirred at room temperature for 20 min and then heated to reflux for 3 hours. The volatile components were removed by evaporation and the residue obtained was mixed with water. The resulting slurry was filtered and the solids collected were washed with ether, a small amount of methanol, and finally hexane and were then dried. The title compound (3.2 g) was obtained as a tan powder melting at 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. Afer dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[C:1]1([S:7]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][CH3:11])=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Yield: 67 %

Procedure:
The title compound was prepared from benzene sulfonyl chloride and 5-methoxy-1H-indole, according to Method A, described above. Yield 67%; mp 73-75° C.; 1H NMR (CDCl3) δ 7.55-7.82 (m, 3H), 7.41-7.48 (m, 2H), 7.31-7.37 (m, 2H), 6.83-6.90 (m, 2), 6.51-6.52 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 156.9, 138.6, 134.2, 132.2, 129.9, 129.6, 127.5, 127.1, 114.8, 114.2, 109.8, 104.1, 56.0; MS (ES+) m/z 287.99 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH3:48][N:47]([CH3:49])[C:46]([NH:45][C:42]1[CH:41]=[CH:40][C:39]([C:33]2[C:32]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)(=[O:24])=[O:23])[C:9]([C:11]5[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)=[CH:10][C:3]=34)=[CH:36][N:35]([CH2:37][CH3:38])[N:34]=2)=[CH:44][CH:43]=1)=[O:50]
Reactant: CS(=O)(=O)Nc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(NS(C)(=O)=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with N-{3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanesulfonamide. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 684.4
Reaction SMILES: [C:1](OCC)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.C(O[CH:25]=[CH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])C.Cl>C(#N)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:8])[O:32][C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(F)(F)F)oc1=O
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Diethyl malonate (33.7 g, 0.2 mol) was dissolved in acetonitrile (200 mL), and magnesium chloride (21.4 g, 0.22 mol) was slowly added thereto at 0 to 5° C. After 10 minutes, triethylamine (44.5 g, 0.44 mol) was added dropwise thereto at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. To the reaction mixture, 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (37.0 g, 0.22 mol) was added dropwise at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. The reaction mixture was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. Thus obtained oily product was dissolved in toluene (100 mL), p-toluenesulfonic acid (5 g) was added thereto, and the mixture was allowed to react for 3 hours under heating. After cooling, the solvent was distilled off, and thus obtained crystal was recrystallized from ethyl acetate, to obtain 31.8 g of a desired product (yield: 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>CS(C)=O.N.[Cu].[Pd](Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Brc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]
Agent: N
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1-c1ccccn1
Reaction time: 0.5 h
Yield: 11.8 %

Procedure:
A solution of 2-nitrobromobenzene (2.02 g), 2-bromopyridine (0.80 g), copper powder (1.29 g), and palladium dichloride (0.049 g) in 15 mL of DMSO was heated at 120° C. under N2 for 2 hours. Once cooled, the mixture was diluted with 100 mL of 10% aqueous ammonia and stirred for 30 min. This mixture was filtered, and the filtrate was extracted several times with CHCl3. The combined extracts were dried (Na2SO4) and evaporated. The crude product was purified by chromatography on silica gel with 20% EtOAc/hexanes to yield 0.12 g (22%) of 2-(2-Nitrophenyl)pyridine. [This compound was reported by Molina, Pedro; Lorenzo, Angeles; Aller, Enrique; Tetrahedron; 1992, 48, (22), 4601-4616.]