Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[C:12]([O:15][CH2:16]Br)(=[O:14])[CH3:13]>CN(C=O)C>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:13][C:12]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: CCNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC(=O)OC)c1ccccc1
Reaction time: 0.75 h
Yield: 95.9 %

Procedure:
N-Ethylaniline 5 (2 g, 16.52 mmol) was added to a stirred suspension of sodium hydride (436 mg, 18.17 mmol) in DMF (20 ml) at ambient temperature under argon. After 45 minutes, bromomethyl acetate (3.02 g, 18.17 mmol) was added and the reaction mixture was stirred for 22 hr. DMF was removed under reduced pressure and the residue was treated with ethyl acetate (60 ml) and water (50 ml). The organic extract was washed with saturated brine (50 ml), dried (Na2SO4), filtered and evaporated to give crude Methyl 2-(ethylphenylamino) acetate 7 as liquid (3.06 g, 96%).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:19]=[C:18]([NH:20][C:21]2[S:22][C:23]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]=3[N:25]=2)[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[C:18]([NH:20][C:21]2[S:22][C:23]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]=3[N:25]=2)[CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:1]([CH3:2])=[N:15][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(=O)NN
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1nnc(C)o1
Reaction time: 40 h
Yield: 65 %

Procedure:
At room temperature, acetic anhydride (108 μL) was added to a suspension of 2-methoxy-4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzoic acid hydrazide (130 mg, 0.33 mmol) in dimethylformamide (5 mL). The mixture was stirred for 40 hours and evaporated to dryness. The residue was taken up in 10% w/w (3 mL) phosphorous pentoxide in methanesulfonic acid (prepared by mixing 5 g phosphorous pentoxide and 30 mL methanesulfonic acid and stirring for 2 h at 90° C.) and stirred for 18 hours. The mixture was poured into 75 ml water, neutralized to pH 5-6 with 32% aqueous sodium hydroxide and the precipitate filtered off. The solid was dissolved in ethyl acetate (30 mL), washed four times with water and once with brine, dried with magnesium sulfate and concentrated in vacuo, affording the title compound (69 mg, 65%) as an off-white solid. NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (d, 1H), 7.61 (d, 1H), 7.31-7.15 (m, 5H), 6.82 (dd, 1H), 4.03 (m, 1H), 3.34 (m, 3H), 2.73 (m, 2H), 2.50 (m, 3H), 2.14 (m, 1H), 1.79 (m, 3H). MS ISP (m/e): 419.1 (100) (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19]C)=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:21]>O1CCOCC1>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH2:21])=[O:19])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Temperature: 100 °C

Procedure:
Methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (3.0 g) [see Preparation 25) was dissolved in 1,4-dioxane (30 ml) and 0.88 aqueous ammonia solution (25 ml) was added. Ammonia gas was bubbled through the mixture for 20 mins. and the reaction mixture was heated to 100° C. in a sealed vessel for 56 hours. After this time the mixture was cooled and the solvent removed under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxamide (1.77 g) as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[I:16])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[I:16])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Solvent: CC(=O)O
Product: CCn1c(I)c(C#N)c2cc([N+](=O)[O-])c(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
1-Ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1Ga, Step A, is suspended in acetic acid (620 μL) at 0° C. Nitric acid (4.25M in AcOH) is added. This is stirred at room temperature for 2 hours. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is washed with aqueous NaHCO3, and then is dried and concentrated. Purification by silica gel chromatography (6/4, CH2Cl2/hexanes), followed by ether trituration, yields 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (16 mg, 29%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15]C(=O)C)=[C:4]([NH:19][C:20]2[C:29]3[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:3]=1.O.[OH-].[Na+]>Cl>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:19][C:20]1[C:29]2[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3NC(C)=O)ccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3N)ccnc2n1
Temperature: 25 °C

Procedure:
The product from Example 185d was dissolved in 50% HCl:H2O and heated to 100° C. for 1 hr. Reaction mixture was then cooled to room temperature, made basic with 2N NaOH, and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. Purified by HPLC with TFA providing the product as a trifluoroacetic acid (87 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H), 1.79-1.92 (m, J=7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 2.32 (s, 3H), 3.00 (t, J=7.54 Hz, 2H), 6.34 (d, J=6.99 Hz, 1H), 6.49 (t, J=7.54 Hz, 1H), 6.68 (d, J=6.99 Hz, 1H), 6.92 (d, J=8.09 Hz, 1H), 7.05-7.13 (m, 1H), 7.15-7.20 (m, 1H), 7.24 (d, J=8.46 Hz, 1H), 7.28 (s, 1H), 7.84 (d, J=8.82 Hz, 1H), 8.42 (d, J=6.99 Hz, 1H), 9.06 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 401 (M+H−TFA)+; (ESI−) m/z 399 (M−H−TFA)−.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17]O)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OO)cc2)C1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 1d), the alkylation of the (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 4-fluorobenzylbromide in presence of potassium carbonate yields the (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light yellow powder; MS: m/e=344 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[OH:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[O:9])[CH:7]=1
Reactant: OC(c1cncnc1)c1cc(Br)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1cncnc1)c1cc(Br)ccc1F

Procedure:
To a stirring solution of (5-bromo-2-fluorophenyl)(pyrimidin-5-yl)methanol (2.42 g, 8.55 mmol) in DCM (40 mL) was added Dess-Martin periodinane (4 g, 9.4 mmol) portion-wise over several minutes. The reaction was then quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (80 mL) and stirred until gas evolution ceased. The aqueous layer was extracted with DCM, dried over MgSO4, and purified by column chromatography (gradient 0 to 30% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 9.09 (d, J=1.6 Hz, 2H), 7.81 (dd, J=6.0, 2.6 Hz, 1H), 7.74 (ddd, J=8.8, 4.5, 2.6 Hz, 1H), 7.13 (t, J=9.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[S-:14][C:15]#[N:16].[NH4+].O.N>C1(C)C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH2:16])=[S:14])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#C[S-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(N)=S)cc1
Temperature: 75 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
10.7 g of 4-toluidine was added dropwise to 27% aqueous sulfuric acid solution which contains 5.4 g of sulfuric acid. After the reaction mixture was heated to 75° C., 8.4 g of ammonium thiocyanate in a solid state was slowly added thereto. Upon complete addition, the reaction mixture was stirred for 20 hours at 80° C. to 90° C. After adding toluene, the whole mixture was refluxed for one hour, cooled to room temperature and then adjusted to pH 7.5 to 8 by slowly adding ammonia water. The resulting white solid was filtered, washed once with each of water and toluene and then dried under reduced pressure to obtain the title compound as a white solid (Yield: 78.5%).
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C1N2CCN(CC2)C1>ClCCl>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])(=[O:14])=[O:15])=[O:18])[N:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(1-methylethyl)sulfonyl]benzenesulfonyl isocyanate (2.3 g, 0.008 mol) in dichloromethane (12 ml) was added to 2-amino-4,6-dimethylpyrimidine (0.74 g, 0.006 mol) and DABCO (catalytic amount) and the suspension was stirred overnight at room temperature. The solvent was removed in vacuo and acetonitrile was added to the residue. The precipitated solid was filtered and dried to give N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-[(1-methylethyl)sulfonyl]benzenesulfonamide as a white powder, m.p. 188°-193° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OC1C=CC(C(OC)=O)=CC=1)CCCCCCCCCCCCCCCCC>>[CH2:33]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
This compound was prepared from methyl 4-hydroxybenzoate and docosylbromide (C22H45Br) in an analogous manner to that described above for methyl 4-octadecyloxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[CH:16]=[N:15][N:14]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1nncc(-c2ccc(Cl)cc2)n1
Product: Clc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A mixture of 4.4 g. of 5-(p-chlorophenyl)-3-hydrazino-1,2,4-triazine and 20 ml. of ethyl orthoformate is refluxed for 4 hours cooled and filtered giving the desired product as light yellow plates, m.p. >300° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:29])[C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([OH:27])[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:28])[CH:16]=1>>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:29])[C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:28])[CH:16]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: COC(=O)CBr
Product: COC(=O)COc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from methyl 2-bromoacetate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.83 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.73 (s, 2H), 4.66 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H); MS (ESI): 424.8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O)=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=CCCCCc1ccncc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNCCCCCc2ccncc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a solution of 2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethylamine (162 mg) and 5-(4-pyridyl)-pentanal (100 mg in 2 mL dry chloroform) was added anhydrous magnesium sulfate (735 mg) and the mixture stirred at 0° C. for 15 minutes. At this time sodium borohydride (92.7 mg) was added followed by 3 mL dry methanol and the mixture stirred at 0° C. After 1 hour, the reaction was quenched by pouring into water (25 mL), stirred for 30 minutes then extracted with methylene chloride (4×25 mL). The combined organics were dried over potassium carbonate, concentrated in vacuo and the residue purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (172 mg). m/e=412 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:21][CH2:22][CH2:23][CH2:24]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCCC1
Yield: 82.9 %

Procedure:
A solution of N-(t-butoxycarbonyl)-α-(1-hydroxycyclopentyl)glycine, benzyl ester (1.81 g, 4.98 mmoles) in 30 ml of absolute ethanol at 25° C. was treated with 0.4 g of 10% palladium on charcoal and hydrogen at one atmosphere for 2.5 hours. The catalyst was filtered and the solvent evaporated. Benzene was added and evaporated. Crystallization from isopropyl ether (first crop) and hexane (second crop) gave a total of 1.07 g of product, melting point 132°-134° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][O:3][C:4]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)(O)c1ccccc1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (1.05 g., 50% w/w dispersion in mineral oil), was added to a stirred solution of ethyl 2-hydroxy-2-phenylpropionate (3.48 g.) at 4° C. in dimethylformamide (100 ml.). After 1 hour, 4-(4-chlorophenyl)benzyl chloride (4.74 g.) was added and stirring was continued at 4° C. for 1 hour and then at room temperature for 20 hours. The mixture was neutralised by cautious addition of N-hydrochloric acid and then extracted with ether. The extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylpropionate as an oil (7.9 g.).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Yield: 86.2 %

Procedure:
A mixture of 2.77 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine and 1.20 g of ethyl acrylate in 14 ml of ethanol was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give 3.25 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 133°-134° C.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][OH:16])=[O:12])=[C:9]([I:21])[C:8]([NH:22][C:23](=[O:27])[CH2:24][O:25][CH3:26])=[C:7]([I:28])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:30]>>[I:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH2:15][OH:16])([CH2:19][OH:20])[CH2:17][OH:18])=[O:12])=[C:9]([I:21])[C:8]([NH:22][C:23](=[O:27])[CH2:24][O:25][CH3:26])=[C:7]([I:28])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:30]
Reactant: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Product: COCC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(C(=O)NC(CO)(CO)CO)c1I

Procedure:
2,4,6-Triiodo-5-methoxyacetamido-N-[tris(hydroxymethyl)methyl]isophthalamic acid (2.03 g.) was dissolved in a stoichiometric quantity of 0.1032 N NaOH. The solution was evaporated under reduced pressure at 60° C. and the residual sodium salt was dried at 45° C. overnight. The solubility of this sodium salt in water at 25° C. is approximately 67.4% (w/v).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]([NH2:25])=[O:24])=[CH:20][C:19]=2[CH:26]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([C:23]([NH2:25])=[O:24])=[CH:20][C:19]=3[CH:26]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC(=O)c1cc2cc(Br)ccc2o1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1C
Product: NC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Temperature: 125 °C
Reaction time: 0.25 h

Procedure:
0.30 g of P(t-Bu)3, 4.5 g of 5-bromobenzofuran-2-carboxamide, 4.9 g of benzylpiperazine and 5.0 g of Na t-OBu are added to a suspension of 0.085 g of Pd(II) acetate in 150 ml of xylene after the latter has been stirred for 15 minutes, and the mixture is warmed at 125° C. for 12-18 hours under the protective gas nitrogen. After cooling, the mixture is added to 500 ml of 2N hydrochloric acid, and the aqueous phase is extracted 3 times with 200 ml of ethyl acetate. The aqueous phase is adjusted to pH 10 using aqueous NaOH (20%) with pH and temperature monitoring (20-25° C.), and the 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide produced as a solid is filtered off and crystallized, for example, from ethanol/water (product weight: 4.0 g/64%/m.p. 277-279°).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][C:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].C(O)C>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][CH:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate (4.87 g, 9.41 mmol), 1 N aqueous sodium hydroxide (10.4 mL, 10.40 mmol), ethanol (10 mL), and acetone (10 mL) was stirred at 50° C. overnight. The mixture was concentrated and the residue was dissolved in dimethoxyethane (20 mL), and stirred at 80° C. overnight. The mixture was concentrated, and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (2×5 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The material obtained was purified by flash chromatography (10:90 ethyl acetate/hexane) to give ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light yellow oil (3.53 g, 99% yield). LC-MS ret. time 4.18 min, m/z 446.0 (MH+); 1H NMR (CDCl3) δ: 1.33 (t, 3H), 1.83–2.17 (m, 2H), 2.58 (s, 3H), 2.67–2.78 (m, 2H), 3.00 (dd, 1H), 3.14 (m, 1H), 3.49 (dd, 1H), 4.09 (q, 2H), 7.14–7.36 (m, 5H), 7.47–7.55 (m, 2H), 7.72–7.83 (m, 3H), 8.33 (d, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH:41]([OH:43])C.O[C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH2:41][O:43][C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncccc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) and DEAD (13.65 mL of a 40% solution in toluene) in THF (200 mL) at 0° C. was added a solution of 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6.21 g, 0.021 mol, 98%) as a pink solid. 1H NMR (CDCl3, 300 MHz) δ1.8-1.85 (d, 3H), 6.0-6.15 (q, 1H), 7.0-7.1 (t, 1H), 7.2-7.21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05 (d, 1H).