Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH2:9].[OH-].[Na+].[CH:12](O)=O>>[Br:8][C:4]1[C:3]2[N:9]=[CH:12][NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=CO
Reactant: Nc1cccc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Product: Brc1cccc2[nH]cnc12

Procedure:
A solution of 1,2-diamino-3-bromobenzene (2.00 g, 10.7 mmol) in formic acid (10 mL) was stirred at 100° C. for 1 hour. The pH of the mixture was adjusted to 14 by the addition of 4 M sodium hydroxide solution, precipitating the product as a solid. This was separated by filtration, washed with water and air-dried affording the product as an off-white solid. A further crop of equally pure material precipitated from the filtrate upon standing at room temperature for a few days. Total yield=1.98 g, 94%. 1H NMR (500 MHz, d6-DMSO): δ 12.83 (1H, s), 8.30 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.41 (1H, d, J=7.1 Hz), 7.14 (1H, t, J=7.8 Hz); m/z (ES+) 197, 199 [MH+].
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1>CO>[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=3)[CH2:4][N+:1]([O-:3])=[O:2])=[CH:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Solvent: CO
Product: O=[N+]([O-])CC(c1ccc(Cl)cc1)c1c[nH]c2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
1-((1E)-2-Nitrovinyl)-4-chlorobenzene (0.206 g, 1.12 mmol) was added to a solution of 6-bromoindole (0.200 g, 1.02 mmol) in methanol (5 mL), followed by the addition of sufamic acid (39.6 mg, 0.40 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was concentrated then diluted with EtOAc (15 mL) and washed with H2O (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane (0-50%) to give 6-bromo-3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indole (0.175 g, 45.2%). 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.51 (s, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.25-7.20 (m, 3H), 7.17 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 5.12 (t, 1H), 5.01 (q, 1H), 4.88 (q, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 94.3 %

Procedure:
Dissolve 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.49 mmol) in methanol (20 mL). Add 20% palladium hydroxide on carbon (0.33 g) and stir 1 h under one atmosphere of hydrogen gas. Filter through filter agent and concentrate to give the title compound as a white foam (0.45 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](I)[CH3:32].O>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([O:26][CH2:31][CH3:32])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
4'-Benzyloxy-6-carboxyflavone (1 eq.) was dissolved in HMPA (hexamethylphosphoramide), followed by the addition of sodium hydride (1.1 eq.). Thirty minutes later, ethyl iodide (2 eq.) was added, and the resulting mixture was stirred further for 2 hours at room temperature. The mixture was charged into water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound represented by the following formula was obtained (yield: 25%). ##STR18##
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C@:7]1([CH3:22])[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>ClCCl>[Cl:3][C@:7]1([CH3:22])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCN2CCC[C@@]2(C)CO)cc1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC[C@@](C)(Cl)C2)cc1
Yield: 34.7 %

Procedure:
Thionyl chloride (238 mg) was added slowly to a solution of (S)-2-hydroxymethyl-1-(4-methoxyphenethyl)-2-methylpyrrolidine (see Preparation 10) (349 mg) in dichloromethane (15 ml) and the mixture was heated under reflux for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a brown gum, (130 mg), which was characterised by NMR and used directly in Example 4 without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: CN1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2CC1CN2c1ccc(N)cc1
Yield: 64.6 %

Procedure:
A mixture of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane (0.19 g, 0.815 mmol) and a catalytic amount of Pd/C in ethanol (0.2 mL) is hydrogenated at 1 atmosphere at room temperature overnight. It is filtered through Celite, and the organic solution is evaporated, and then treated with 10 mL of methanol. It is then treated with hydrochloric acid in methanol, followed by ethyl ether, and filtered to give 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamine as bluish solid (0.107 g, 65%). MS (ESI) m/z 204.2 (M−H)+1.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:21][CH2:22][C:23]#[N:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:17][CH2:18][C:19]#[N:20])[CH2:13][CH2:14][C:15]#[N:16])#[N:2].[H][H]>O1CCOCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCCCCCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCCCCN(CCCN)CCCN
Yield: 88.5 %

Procedure:
16.42 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,6-hexanediamine, 1.64 g of Raney Co and 90 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2.5 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 15.24 g of the title compound.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:10]=1/[N:11]=[CH:12]/[CH:13]([CH3:15])[CH3:14])[CH3:8].C([N-]C(C)C)(C)C.[Li+:29]>CCCCC>[CH2:7]([C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:10]=1[N-:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:8].[Li+:29]
Reactant: CCc1cccc(CC)c1/N=C/C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: CCCCC
Product: CCc1cccc(CC)c1[N-]C=C(C)C
Temperature: 50 °C
Yield: 80.6 %

Procedure:
Benzene (70 mL) and compound A (6.63 g, 32.6 mmol) were combined. Solid lithium diisopropylamide (4.01 g, 37.4 mmol) was then added. The mixture was heated to 50° C. to form a cloudy red-orange solution. After a few hours the solution was filtered through diatomaceous earth to afford a clear yellow solution. The volatiles were evaporated to give a yellow solid. Pentane (15 mL) was added and the mixture was stirred briefly and then cooled to −10° C. overnight. The product was then collected on a glass frit and washed with pentane (2×20 mL) to yield 5.50 g of compound B (80.6%) as a white solid that was dried under reduced pressure and used without further characterization.
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:15][C:16](=[O:36])[C:17]([C:22](=O)[CH2:23][O:24][C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[CH:18]N(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:38]1([CH3:46])[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][NH2:45]>CC#N>[CH2:8]([O:15][C:16]([C:17]1[C:22]([CH2:23][O:24][C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)=[N:45][N:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:46])[CH:18]=1)=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=C(C(=O)COC12CC3CC(CC(C3)C1)C2)C(=O)OCc1ccccc1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1-n1cc(C(=O)OCc2ccccc2)c(COC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
NEt3 (0.2 mL, 1.43 mmol) was added to a mixture of 2-[2-(adamantan-1-yloxy)-acetyl]-3-dimethylamino-acrylic acid benzyl ester (0.539 g, 1.4 mmol), and o-tolylhydrazine hydrochloride (0.222 g, 1.4 mmol) in MeCN (8 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 17 h. The precipitated solid was filtered off, washed with MeCN and dried to afford the product, (0.359 g, 56%).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:14]([O:15][CH2:16][CH2:17][OH:18])=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)([O-])=O.O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:14]([O:15][CH2:16][CH2:17][OH:18])=[N:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(OCCO)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc2[nH]nc(OCCO)c2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
Iron powder (0.075 g 1.34 mmol) and ammonium chloride (0.14 g, 2.68 mmol) were added to 2-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (60 mg, 0.27 mmol) in ethanol:water (5 mL, 2:1). The mixture was heated at 85° C. in a sealed vial. After 5 hours, the reaction mixture was filtered and evaporated to afford crude product as a solid. The crude was absorbed on silica gel and chromatographed on a silica gel plug with 10:1 ethyl acetate:methanol. Fractions 2-5 contained 2-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (21.8 mg, 0.112 mmol, 42% yield) as a solid.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:7]=[CH:6][C:5]=12.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:45]=3)=CC=2OC1>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:45])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.16) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[2,1,3]thiadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:24])[CH:16]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][C:15]2[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:24])[CH:16]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C=Cc2cc(=O)cc(C(=O)O)o2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(=O)cc(C=Cc2ccc(O)cc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boron tribromide (2.5 ml) was added to a stirred suspension of 6-[2-(4-methoxyphenyl)ethenyl]-4-oxo-4H-pyran-2-carboxylic acid (1.4 g) in methylene chloride (140 ml) and the mixture was stirred for 3 hours at room temperature and 1 hour under reflux. Water (30 ml) was added to the stirred mixture and the solid product was crystallised from ethanol-water to give the title product (mp 256° C. with decomposition).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:8][C:7]2=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:13])=[CH:11][CH:12]=[C:6]2[O:5]1)[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:13][C:10]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:7]3[CH2:8][CH:4]([O:3][CH2:1][CH3:2])[O:5][C:6]3=[CH:12][CH:11]=2)[N:21]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOC1Cc2c(ccc(O)c2C(=O)OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OC)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture comprising 1.0 g of methyl 2-ethoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate, 1.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.78 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 100° C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.5 g (yield: 95%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>O1CCCC1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:11][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc([N+](=O)[O-])c1N)(C(C)C)C(C)C
Yield: 105.4 %

Procedure:
A solution of 2-amino-3-nitro-phenol (42.9 g, 278 mmol) and imidazole (28.4 g, 417 mmol) in tetrahydrofuran (750 ml) was treated with chloro-triisopropyl-silane (62.3 g, 323 mmol). After 18 hours the mixture was filtered, diluted with ethyl acetate, washed with water, dried and evaporated to give an oil (91 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.C([Li])CCC.CCCCCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[CH2:7]([C:5]1[S:6][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][N:4]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1ncc(Br)s1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
To a solution of 5-bromo-2-isobutylthiazole (2.10 g, 9.54 mmol) in THF (20 mL) was added 1.6 M n-butyllithium in hexane solution (7.15 mL, 11.44 mmol) dropwise over 45 minutes at −78° C. The resulting solution was stirred at −78° C. for 10 minutes. Then the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.13 g, 11.44 mmol) was added to the above solution and stirred at −78° C. for 1.5 hours. The reaction was quenched with 1:1 saturated ammonium chloride and water and warmed up to close to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water, brine and concentrated. The residue was subjected to flash column chromatography using 30% ethyl acetate/hexane to give a yellow oil (454 mg, 18% yield). 1H NMR, 400 MHz, CDCl3: δ 8.13 (s, 1 H), 2.95 (d, J=7.1 Hz, 2 H), 2.10-2.19 (m, 1 H), 1.36 (s, 12 H), 1.00 (d, J=6.6 Hz, 6 H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:60])[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]>CN(C=O)C>[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH:60][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc(CC(N)C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1N
Reaction time: 0.5 h

Procedure:
To 4-nitrobenzoic acid (50.1 mg), HATU (114 mg) and DIEA (105 μL) was added 1 mL DMF and the mixture was stirred for 30 minutes. Then the resulting solution was added to 3-(4-acetyl-3-aminophenyl)-2-aminopropanoic acid (66.7 mg, 1.0 equiv) in 1.0 mL DMF, and the reaction was stirred at room temperature, monitored by LC-MS. The title product was then isolated by preparative HPLC. 1H NMR (400 MHz, MeOD): δ 8.28 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 6.61 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 3.28 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 3.02 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 2.51 (s, 3H); ESI-MS (m/z) 372.34 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][N:23](C)[CH2:22][CH2:21]3)[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)C)=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(Br)c2)cc1N1CCN(C)CC1
Agent: CC(Cl)OC(=O)Cl
Product: COc1ccc(S(=O)(=O)Nc2cccc(Br)c2)cc1N1CCNCC1

Procedure:
The title compound was prepared using a similar procedure to that of example E29 using N-(3-bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide (E3) and 1-chloroethyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](Br)[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.C([Li])CCC.[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Brc1cc(Br)c2c(c1)CCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Brc1ccc2c(c1)CCO2
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5,7-Dibromo-2,3-dihydrobenzo[b]furan (see WO 02/070020) (3.0 g) in diethyl ether was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 5.09 ml). The mixture was stirred at the same temperature for 30 minutes, and poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2,3-dihydrobenzo[b]furan (2.0 g) as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2,3-dihydrobenzo[b]furan and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give the desired 2-(2,3-dihydro-5-benzo[b]furanyl)thiophene as pale yellow crystals. APCI-Mass m/Z 203 (M+H).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[C:5]1=[O:26])(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:6]2[NH:7][C:8](=[O:10])[C:9](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:4][C:5]2=[O:26])=[N:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(OCc3ccccc3)cn2)C1=O
Reactant: O=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 60 °C
Yield: 83 %

Procedure:
Compound A (3.51 g) was added to a 40 mL of dimethylformamide solution containing equal molar of benzaldehyde and 4 equivalents of triethylamine. The solution was refluxed at 60° C. for 16 hr and cooled at ice bath to produce a yellow precipitate. The precipitate was then collected and washed with ethyl acetate to give 3.3 g (83%) of the desired product 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-phenylmethylidenepiperazine-2,5-dione (Compound 1) as a mixture of isomers. The mixture was predominately the ZZ and EZ isomers.
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=O>>[Cl:34][C:35]1[CH:36]=[C:37]([C:38]2[O:4][N:3]=[C:2]([N:5]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[CH2:6][CH2:7][C:8]3[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:19])([CH3:20])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)[N:1]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(-c3cccc(Cl)c3)n2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-chlorobenzoyl chloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[OH-].[Li+].Cl>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([OH:4])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc2ccc(C)cn2c(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc(C(=O)O)c(OCc3ccccc3)c(=O)n2c1
Reaction time: 3 h

Procedure:
To a stirred solution of the product from Example 8.1 (400 mg, 1.23 mmol) in methanol (20 mL) was added 1N aqueous lithium hydroxide solution (2.46 mL) at room temperature. After 3 h, 1N aqueous hydrochloric acid (20 mL) was added. The mixture was extracted with ethyl acetate and the organic phase were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was used directly in Example 8.3.