Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10](I)[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[C-:26]#[N:27].[Na+]>C(#N)C.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.[Cu]I>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:26]#[N:27])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1cc(I)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C#N)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A mixture of 5-methoxy-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.060 g, 0.13 mmol), Pd(PPh3)4 (0.015 g, 0.013 mmol), sodium cyanide (0.013 g, 0.26 mmol), and CuI (0.003 g, 0.013 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-methoxy-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.032 g, 68%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.89 (s, 3H), 4.36 (s, 2H), 4.77 (s, 2H), 7.10 (s, 1H), 7.17 (d, 2H), 7.25 (s, 1H), 7.36 (d, 2H). GC-MS: m/z 362 (M+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])[CH:3]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: O=C1NCCN1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCNC2=O)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 224 mg of 2-imidazolidinone, 26 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 185 mg of tripotassium phosphate and 23 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}imidazolidin-2-one as white powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 56 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O.[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]1[O:6][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2nc3ccccc3o2)c(Cl)c1
Temperature: 140 °C

Procedure:
A 2.0 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a condenser containing a nitrogen inlet valve, and a thermometer was charged with 250 g of 2,4-dichlorobenzoic acid, 157.1 g of 2-aminophenol, and 250 mL of polyphosphoric acid. The mixture was heated under nitrogen for 16 h. The solution was cooled to 140° C. and was poured over a chilled 1M aqueous sodium hydroxide solution. The solid brown precipitate was collected by filtration. The material was then vacuum distilled with a head temperature of 160°-180° C. The solid was recrystallized from toluene and dried in a vacuum oven at 80° C. for 12 h. Yield 257 g (74%); mp=130.6-131.3.
Reaction SMILES: [C:1]1([S:11]([NH:14][NH2:15])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH:16](=[N:15][NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:12])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNS(=O)(=O)c1cccc2ccccc12
Reactant: O=Cc1ccccc1
Solvent: CO
Product: O=S(=O)(NN=Cc1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 111 g (0.5 mol) of 1-naphthalenesulfonohydrazide and 700 ml of methanol, and 63.6 g (0.6 mol) of benzaldehyde was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](N)=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=1)[CH3:2].N([O-])=O.[Na+].[I-:18].[K+]>O.Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:18])=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(N)c(CC(=O)O)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc(I)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of water (405 ml) and concentrated HCl (48 ml) is stirred and cooled to 0°. 5-Ethyl-2-aminophenylacetic acid (53.7 g, 300 mmol) is slowly added while maintaining the temperature at 0-2°. After this addition a solution of sodium nitrite (22.2 g, 322 mmol) in 60 ml water is added dropwise over 30 minutes keeping the temperature at 0-2°. After a further 20 minutes a solution of potassium iodide (48 g, 290 mmol) in 18 ml conc HCl and 130 ml water is added dropwise while keeping the temperature below 10° C. The reaction mixture is allowed to warm to room temperature and then heated to reflux for 2 hours. The mixture is extracted with ethyl acetate and ether (1:1 mixture, 4×300 ml), the organic layer is then washed first with a 30% aqueous solution of sodium thiosulfite and then with a sodium hydroxide solution (0.1M) before being acidified to pH 6 and extracted with ethyl acetate. This solution is washed with saturated brine, dried (magnesium sulfate), filtered, and the solvent removed under reduced pressure. The residue is treated with hexane to yield 5-ethyl-2-iodophenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (46.4 mg, 41%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCCC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with pyrrolidine in ethanol to provide yellow crystals of 2-nitro-3-phenyl-5-(1-pyrrolidylmethyl)benzofuran, m.p. 111°-112.5° C., having the structure ##STR9##
Reaction SMILES: I.[CH3:2][S:3][C:4]([N:6]([CH3:15])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[NH:5].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[CH3:2][S:3][C:4]([N:6]([CH3:15])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:5][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(=NC(C)=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate-hydroiodide* (4 g) and triethylamine (2.5 g) were dissolved in dichloromethane (50 ml). To this solution acetyl chloride (1.05 g) was added slowly maintaining temperature below 20° C. The mixture was stirred at room temperature in a dry nitrogen atmosphere for 1.5 h. The organic residues were washed with water (5×20 ml), dried over anhydrous sodium sulphate and the solvent removed in vacuo giving a yellow solid which upon trituration with ether gave the title compound (2.30 g) as an off-white solid of m.pt. 102°-104° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:30])[N:16]=[C:17]([CH3:29])[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[OH-].[Li+].S(=O)(=O)(O)O>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:30])[N:16]=[C:17]([CH3:29])[C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(C)nn(C)c1=O
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a 10 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-1-methyl-2-oxoacetyl]-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39) (809 mg), toluene (2.3 ml), and methanol (0.5 ml) were added. To the mixture, lithium hydroxide monohydrate (77 mg) was added at 0° C., stirred for 4 hours, and left to stand at 5° C. for 16 hours. The pH of the mixture was adjusted to 1 with 20 w/w % of sulfuric acid. The organic layer was removed, and then the aqueous layer was extracted with toluene 2 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=3:1) to give 711 mg of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-(4-methylphenylsulfonyl)-2,3-dihydro-3-pyridazinone ((2-36)-(1)-39).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][CH2:13][CH:12]=[CH2:11]
Reactant: C=CC[Mg]Br
Reactant: Fc1ccc(Br)c(CBr)c1
Solvent: C1CCOC1
Product: C=CCCc1cc(F)ccc1Br
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 2-bromo-5-fluorobenzyl bromide (1 g, 3.73 mmol) in THF (15 mL) was added allylmagnesium bromide (5.60 mL, 5.60 mmol) at 0° C. It was warmed to rt and then refluxed for 5 h. The reaction mixture was quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOac/hexane to isolate 1-bromo-2-(but-3-en-1-yl)-4-fluorobenzene (0.7 g, 3.06 mmol, 82% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.53-7.45 (m, 1H), 6.99-6.94 (m, 1H), 6.82 (td, J=8.3, 2.9 Hz, 1H), 5.89 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.14-4.98 (m, 2H), 2.89-2.76 (m, 2H), 2.45-2.33 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2]>C1COCC1.CCO.[Pd]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1C(=O)O)C2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cc1ccccc1C(=O)O)C2
Reaction time: 5 h
Yield: 99.3 %

Procedure:
A mixture of the product of Step 1 (25 g, 85 mmol) and 10% Pd/C (2.5 g) in THF/EtOH (100 ml each) was hydrogenated at 40 psi for 5 hrs. The mixture was filtered through celite and concentrated to give 25 g of the title compound, which was used as such for the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3[Cl:19])=[CH:11][CH:10]=2)[C:4]1=[O:20].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[CH:37]2)=[CH:32][CH:31]=1>CC#N>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:40]([C:36]4[CH:35]=[CH:34][C:33]5[C:38](=[CH:39][C:30]([O:29][CH3:28])=[CH:31][CH:32]=5)[CH:37]=4)(=[O:42])=[O:41])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (1.74 g, 5.6 mmol) is suspended in CH3CN (120 mL). To this solution is added triethylamine (2.35 mL, 16.9 mmol) followed by 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.93 mmol). The mixture is stirred overnight, then concentrated to dryness. The crude product is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the title compound (2.7 g, 5.4 mmol) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 22 %

Procedure:
Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone and sodium carbonate in butanol, the title compound was prepared in 22% yield, m.p. 131°-135° C., after recrystallization from isopropyl alcohol.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:41][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38]CC)=[O:37])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)[CH2:41][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)Cc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylmethyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted with 5N hydrochloric acid to pH 7 and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:3]=1[C:4]([NH:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]>CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: C[C@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)c1c(N)cccc1F)C(=O)O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a suspension of iron powder (437 mg, 7.81 mmol) in AcOH (5 mL) was added (S)-2-(2-fluoro-6-nitrobenzamido)propanoic acid (200 mg, 0.78 mmol) at rt and stirred at 60-70° C. for 30 min. Work-up of the reaction mixture as described in example 6 gave the product as an off-white color solid (132 mg, 75%), mp 194-198° C. 1H NMR (400 MHz, DMSO-d6): δ 7.97 (1H, br s), 7.05 (1H, dd, J=15.2, 8.0 Hz), 6.49 (1H, d, J=8.4 Hz), 6.37 (2H, br s), 6.28 (1H, dd, J=11.2, 8.4 Hz), 4.14 (1H, br s), 1.30 (3H, d, J=7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 176.6, 163.7, 160.7 (d, J=241 Hz), 150.2 (d, J=6 Hz), 131.0 (d, J=12 Hz), 111.5, 106.6 (d, J=19 Hz), 101.2 (d, J=23 Hz), 49.4, 18.1; LC-MS (positive ion mode): m/z 227 (M+H)+.
Reaction SMILES: [CH3:1]NCCN(C)C.C([Li])CCC.C1CCCCC1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.IC>C1COCC1>[CH3:1][C:29]1[CH:28]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:35])=[CH:26][CH:25]=2)[S:31][C:30]=1[CH:32]=[O:33]
Reactant: CNCCN(C)C
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Temperature: -18 °C
Reaction time: 0.25 h

Procedure:
To a solution of trimethylethylenediamine (0.296 mL, 2.28 mmole) in THF at −78° C., is injected 2.0M n-butyllithium in cyclohexane (1.14 mL, 2.28 mmole) dropwise. The mixture is stirred for 15 minutes, then added a solution of 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.530 g, 2.07 mmole) in THF (5 mL) and stirred for another 15 minutes. To the resulting mixture is injected 2.0M n-butyllithium in cyclohexane (1.55 ml, 3.10 mmole) at −78° C. and warmed up to −18° C. for an hour. The reaction is cooled down to −78° C. again, quenched with excess amount of iodomethane (0.644 mL, 10.35 mmole) and allowed to warm up to room temperature, then poured into well stirred ice-water (30 mL). The aqueous solution is then extracted with ethyl acetate (2×30 mL). The combined organic solution is washed with brine (3×30 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, gradient eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as yellow crystalline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN=C2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CCNC2c1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A suspension of 38 parts of 6-benzyloxy-7-methoxy-1-phenyl-3,4-dihydroisoquinoline in 435 parts of ethanol is heated to approximately 55°C. 32 Parts of sodium borohydride is added portionwise over a 45 minute period, while maintaining the reaction temperature at 50°-60°C. The mixture is stirred for an additional 3 hours at approximately 50°C. and a precipitate forms. The reaction mixture is then poured into water and the precipitate is separated by filtration, giving 6-benzyloxy-7-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, melting at about 118°-119°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:24][CH2:25][OH:26]>CC(C)=O.O.C(OCC)(=O)C.CCCCCC>[OH:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: OCCBr
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCCO)c1
Yield: 14.3 %

Procedure:
To methyl 3-hydroxy-4-nitrobenzoate (Dictionary of Organic Compounds, Heilbron, I.; Brunburg, H. M., Eds.; Vol. 3; 1953, Oxford University Press: New York, N.Y.; p 700) (5.0 g, 0.0254 mol) dissolved in acetone (50 mL) was added potassium carbonate (4.3 g, 0.0300 mol), sodium iodide (0.375 g, 0.0025 mol), and 2-bromoethanol (3.44 g, 0.0275 mol). After refluxing for 60 h, thin-layer chromatographic analysis (SiO2, 3:2 hexane:ethyl acetate) showed partial disappearance (50%) of the starting material along with the formation (50%) of a new, lower-running spot (Rf =0.2). To the reaction mixture, additional potassium carbonate (4.3 g, 0.0300 mol), sodium iodide (0.375 g, 0.0025 mol), and 2-bromoethanol (3.44 g, 0.0275 mol) were added. After refluxing for 24 h more, thin-layer chromatographic analysis (SiO2, 3:2 hexane:ethyl acetate) showed increased disappearance of the starting material along with the formation (70%) of a lower-running spot (Rf =0.2). One-half of the reaction was poured into water (200 mL) and then extracted three times with 100-mL portions of ethyl acetate. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexane. The material was collected by filtration and dried in vacuo at acetone reflux to give 0.878 g (14%) of methyl 3-(2-hydroxyethoxy)-4-nitrobenzoate as an orange solid, mp 97°-98° C.