Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(#N)C.C(N(CC)C(C)C)(C)C.[CH3:25][O:26][CH2:27]Cl>C(OCC)(=O)C.CCCCCCC>[CH3:25][O:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: COCCl
Reactant: O=c1ccc2cc(O)ccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCOc1ccc2oc(=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution. Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetate/heptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:9]([NH2:12])(=[O:11])=[O:10])[S:7][CH:8]=1)([O-:3])=[O:2].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:13]([NH:17][C:18]([NH:12][S:9]([C:6]1[S:7][CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:10])=[O:11])=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Temperature: 0 °C

Procedure:
A stirred suspension of 10 g of 4-nitrothiophene-2-sulfonamide, 6 g of n-butyl isocyanate and 7 g of anhydrous potassium carbonate in 100 ml of acetone was heated to reflux for 3 hours. The resultant viscous mixture was poured into ice-water and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. The resulting tarry precipitate thus obtained was extracted into methylene chloride, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated in-vacuo. The residue which showed absorption peaks by NMR at 0.7 to 1.7 (multiplet), consistent for butyl and at 8.3 and 8.5, consistent for the thiophene ring was used without further purification in the following example.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH2:24][OH:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:26])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[C:28]1[CH:29]=[CH:30][C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>>[OH:25][CH2:24][CH2:23][C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:26])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][C:31](=[O:35])[N:32]([CH3:34])[CH:33]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Product: CC[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 18 using 5-bromo-1-methylpyridin-2(1H)-one in Step 2. LC-MS Method 2 tR=1.627 min, m/z=447.1; 1H NMR (CDCl3) 1.06 (m, 3H), 1.87-2.06 (m, 2H), 2.11-2.28 (m, 2H), 2.33 (m, 3H), 2.96 (m, 1H), 3.53 (m, 1H), 3.62 (s, 3H), 3.78 (m, 1H), 5.48 (m, 1H), 6.69 (m, 1H), 7.03 (m, 2H), 7.14 (m, 2H), 7.21-7.38 (m, 4H), 7.41 (s, 1H), 7.56 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:17][C:18]([C:20]1[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=1)=[O:19])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
The mixture of 5-methoxy-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (80) (458 mg, 1.2 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (81) as a pale brown solid (448 mg, 100%).
Reaction SMILES: BrCC1C(CBr)=CC=CC=1.[C:11]1(=O)[NH:15][C:14](=O)[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].Cl.C[N:25](C)C=O>>[NH2:15][CH2:11][C:12]1[C:13]([CH2:14][NH2:25])=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: BrCc1ccccc1CBr
Agent: Cl
Agent: [K]
Product: NCc1ccccc1CN

Procedure:
12.3 g of α,α'-dibromoxylene and 17.3 g of potassium phthalimide are stirred in 390 ml of N,N-dimethylformamide at a bath temperature of 150° C. for 2.4 hours. After cooling the resulting intermediate is filtered off under suction, washed with ethyl acetate, dried and then reacted in 200 ml of ethanol with 4.6 ml of hydrazine hydrate under reflux. After cooling the resulting suspension is treated with 50 ml of 25% hydrochloric acid, filtered and concentrated to 1/3 of its volume. After repeated filtration the mixture is adjusted to pH 14 by the addition of concentrated sodium hydroxide solution and evaporated. The product is dissolved out from the residue with 300 ml of methylene chloride. After evaporation of the solvent the residue as is taken up in 25 ml of isopropanol and the dihydrochloride of the product is crystallized with 20 ml of 3.26N isopropanolic hydrochloric acid. There are obtained 2.64 g, colourless crystals; m.p.:>250° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
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: Cc1ccccc1
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture solution of dibenzo[b,d]thiophen-4-boronic acid (1.84 g, 8.04 mmol), bis(3-bromophenyl)diphenylsilane (9.97 g, 20.17 mmol), Pd(PPh3)4 (0.19 g, 0.16 mmol) and potassium carbonate (6.69 g, 48.4 mmol,) in toluene (60 mL) and water (20 mL) was heated at 100° C. under nitrogen overnight. After cooling to room temperature, the reaction mixture was quenched with water, extracted with DCM, washed with brine and water, and dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5 to 9:1, v/v) as eluent. The crude product was dissolved in DCM, precipitated with methanol, and filtered to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-4-yl)phenyl)diphenylsilane (3.0 g, 62%) as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.C1CCCCC1.[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1>CCOCC>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][CH:2]=[O:3])=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: O=CCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a suspension of (methoxymethyl) triphenylphosphonium chloride (5.29 g, 14.9 mol) in Et2O (50 mL) was added 1.8 M phenyl lithium in 30% Et2O in cyclohexane (8.58 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 10 min. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (4 g, 14.9 mmol) in Et2O (18 mL). The mixture was stirred at ambient temperature for 4 hr, filtrated, and concentrated. To the above residue was added 10% H2SO4 in AcOH (40 mL). The mixture was stirred at ambient temperature for 90 min. The solution was poured into H2O, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with saturated aqueous NaHCO3, washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 9% EtOAc in hexane) to give (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (1.25 g, 30%) as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[NH2:14]
Reactant: COC(OC)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(OC)c1cc(N)cc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
To 1-(dimethoxymethyl)-3-nitro-5-(trifluoromethyl)benzene (1.9 gm, 7.6 mmol) in ethanol (20 ml), 10% Pd/C (200 m) was added, stirred under balloon pressure for 5 h. Then the reaction mixture was filtered and volatile were removed under vacuum to provide 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(N)CC=Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C(CC=Cc1ccccc1)N=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-5-phenyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-5-phenyl-4-pentenoate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:33]([O:35][CH3:36])=[O:34])[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:23])([CH3:22])[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]1)=[O:9].C(O)C.Cl.C(OC(C)C)(C)C>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:33]([O:35][CH3:36])=[O:34])[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:22])([CH3:23])[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C=O)CC2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Yield: 80.5 %

Procedure:
460 mg of 3-(4-formyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in 1.5 ml of methanol and 0.3 ml of an ethanol solution of 9.9H hydrogen chloride was added. After stirring the mixed solution for one night, isopropyl ether was added. The solid which separated was collected by filtration, dissolved in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After washing with saturated solution of sodium chloride, the extract was dried with anhydrous sodium sulfate; then, the solvent was evaporated under reduced pressure to give 350 mg of the subject compound (yield: 81%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)[NH2:3].CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21]>Cl.O.CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([N:2]2[CH:18]=[CH:19][C:20]([CH3:21])=[N:3]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NN)cc1OC
Reactant: COC(CC(C)=O)OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1OC
Temperature: 90 °C
Yield: 53.7 %

Procedure:
To a stirred solution of 4-hydrazino-2-methoxybenzoic acid, methyl ester hydrochloride (0.88 g) from Example 104 and one drop of concentrated hydrochloric acid in a 1:1 water/methanol (10 ml) mixture was added acetylacetaldehyde dimethylacetal (0.53 g). The reaction was heated to 90° C. for 5 minutes. The reaction was concentrated in vacuo and partitioned between 1 N sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed and washed with brine, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo afforded a brown oil which was combined with a previous lot (0.54 g) and recrystallized three times from diisopropyl ether to give 2-methoxy-4-(3-methyl-pyrazol-1-yl)-benzoic acid, methyl ester (0.5 g). m.p. 167-169° C., MS, m/z: 246 (M)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:15])[CH3:14]>>[Cl:1][CH2:2][C:3]([O:16][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([CH3:14])[CH3:15])=[C:7]([CH3:6])[CH:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(O)ccc1C(C)C
Product: Cc1cc(OC(=O)CCl)ccc1C(C)C

Procedure:
By the same method of Synthesis Example 6, chloroacetyl chloride was allowed to react with 3-methyl-4-isopropylphenol, the reaction mixture was washed with water and then the solvent was evaporated under a reduced pressure to obtain the title compound as a transparent oil. The title compound was used in the subsequent reaction without distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 2-nitro-4-tertbutylanisole with an acid mixture of nitric acid and sulfuric acid to produce 2,6-dinitro-4-tertbutylanisole; and
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][C:20]([CH3:29])([CH2:24][C:25](=O)[CH2:26][CH3:27])[C:21]([OH:23])=[O:22]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:20]([CH3:29])([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCC(=O)CC(C)(C)C(=O)O
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl)hydrazine hydrochloride 1.9 g and 2,2-dimethyl-4-oxohexanoic acid (950 mg) as starting materials, in t-butanol as solvent, after 16 hrs. at reflux, the solvent was removed in vacuo, and the title compound was isolated by crystallization and filtration, followed by crystallization from hot ethyl acetate:hexane 9:1.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](OCC)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CCOCC>[CH2:28]([O:27][C:25](=[O:26])[C:24](=[O:30])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7])[CH3:29]
Reactant: CCOC(=O)CCCc1cc(OC)ccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=O)C(CCc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Potassium t-butoxide (26.94 g) was suspended in 130 ml of anhydrous ether and cooled to 0° C. A solution of 60.24 g ethyl 4-(2-bromo-5-methoxy phenyl)butyrate and 43.84 g diethyl oxalate in 60 ml ether was added dropwise over 20 min. After 2 h at 25° C., the reaction was poured into 400 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 71.26 g of the desired product as a colorless oil (89%). NMR (CDCl3) δ 1.25 (t, 3H), 1.4 (t, 3H), 2.25 (m, 2H), 2.75 (m, 2H), 3.78 (s, 3H), 4.0-4.5 (m, 5H), 6.64 (dd, 1H), 6.79 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[CH:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22][C:21]2=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCn1cc(N2CCN(C(=O)OC)CC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 1-[1-ethyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one (0.200 g, 0.569 mmol) in DCM (10 mL) is added triethylamine (0.095 mL, 0.683 mmol), followed by methyl chloroformate (0.052 mL, 0.683 mmol). The reaction is then stirred overnight. The reaction is diluted with MeOH, and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is then concentrated in vacuo to give the title compound as an orange oil (0.1643 g, 0.401 mmol). MS (m/z): 410 (M+1). 1H-NMR (300.13 MHz, CDCl3): δ 1.37 (t, 3H). 3.79 (s, 3H), 3.74-3.82 (br, 2H), 3.83-3.90 (br, 2H), 4.15 (q, 2H), 4.27-4.39 (br, 2H), 5.58 (s, 2H), 6.71 (d, 1H), 7.04 (s, 1H), 7.19 (t, 1H), 7.45-7.50 (m, 1H), 7.64-7.70 (m, 2H), 8.60 (d, 1H).
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5].[C:56](OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:5][CH:4]([C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:56]
Reactant: CCOC(C)=O
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
4.0 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise at -10° C. to a solution of 1.2 g of ethyl 4-formyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 5 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature between -10° C. and 0° C. for 3 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and with an aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 20 minutes. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:4 and 1:2 by volume mixtures of ethyl acetate and methylene chloride as the eluent, to give 1.23 g of the title compound as a viscous oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]>O1CCCC1.C(OCC)(=O)C>[N+:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[NH:4][CH2:3][CH2:1][OH:2])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A mixture of ethanol amine (5.96 mL, 49.4 mmol) and 2-chloro-1,3-dinitrobenzene (5.00 g, 24.7 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid (5.54 g, 24.4 mmol, 99%).