Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]4[O:41][C:40](=[O:42])[NH:39][N:38]=4)[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)(C)(C)C>C(O)=O>[F:35][C:26]1[C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:21]1[CH2:22][CH2:23][C:18]([C:37]2[O:41][C:40](=[O:42])[NH:39][N:38]=2)([CH2:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:10][C:9]3[CH:8]=[CH:7][NH:6][N:5]=3)[N:16]=2)[CH2:19][CH2:20]1)=[O:36]
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Solvent: O=CO
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCC(Cc2cccc(Nc3cc[nH]n3)n2)(c2n[nH]c(=O)o2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
71 mg of 5-(4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one was dissolved in 1.5 ml of formic acid at room temperature, followed by stirring the reaction mixture at 90° C. overnight. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a preparative thin-layer chromatography (Kieselgel™ 60F254, Art5744 (Merck), chloroform/methanol=10/1) to give the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>>[C:26]1([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:1][C:2]3[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=3)[C:5]([CH:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]3)=[O:6])=[O:24])=[CH:21][CH:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(-c4ccccc4)cc3)c2)CC1
Yield: 33.8 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-biphenylcarbonyl chloride (150 mg, 0.687 mmol), 30.8 mg (34%) of the title compound were recovered.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]=[O:11])=[CH:4][C:3]=2[O:2]1.[N:12]#[C:13][NH2:14].BrN1C(=O)CCC1=O>ClCCl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10](=[N:14][C:13]#[N:12])[O-:11])=[CH:4][C:3]=2[O:2]1
Reactant: O=Nc1ccc2c(c1)OCO2
Reactant: N#CN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CN=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
3,4-Methylenedioxynitrosobenzene (1.05 g, 6.9 mmol) was dissolved in dichloromethane (20 ml). After the addition of cyanamide (0.42 g, 9.9 mmol) and N-bromosuccinimide (1.8 g, 9.9 mmol) the mixture was stirred at ambient temperature overnight. The resulting mixture was filtered and evaporated to dryness. Column chromatography on silica using 1:1 petroleum ether: ethyl acetate as eluant yielded 1.1 g 3,4-methylenedioxyphenyl-ONN-azoxycyanide as a yellow solid, m.pt. 145°-147° C. (Yield: 82.7% of theoretical).
Reaction SMILES: [SH2]=N.C(O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([NH:16][C:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH3:15].C1(O)C=CC=CC=1.[Na]>O>[CH2:12]([NH:16][C:17](=[O:18])[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(=O)O
Reactant: O=C(O)c1ccccc1
Agent: N=[SH2]
Agent: [Na]
Solvent: O
Solvent: Oc1ccccc1
Product: CCCCNC(=O)Oc1ccccc1
Reaction time: 3 h

Procedure:
5 g. N-butyl-carbamic acid benzoic acid sulfimide are suspended in the mixture of 1.67 g. phenol and 50 ml water, then while stirring (5 hours) a solution of 0.71 g. sodium hydroxyd in 50 ml water is added. After stirring another 3 hours the mixture is extracted with 2×30 ml ether. The ethereal extracts dried with sodium sulfate, then the solvent evaporated in vacuum at a temperature not above 30° C. 2.15 g. phenyl N-butyl-carbamate are obtained, which can be distilled at 146°-148° C. at 2 mmHg.
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH:11]2[CH2:12][CH2:13][CH:8]1[CH2:9][CH2:10]2)([O:3]CC)=[O:2].C(O)C.[H][H].[OH-].[K+]>[Pd].O>[CH:8]12[CH:7]([CH2:6][C:1]([OH:3])=[O:2])[CH:11]([CH2:10][CH2:9]1)[CH2:12][CH2:13]2
Reactant: [H][H]
Reactant: CCOC(=O)C=C1C2CCC1CC2
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1C2CCC1CC2

Procedure:
A mixture containing 0.05 mole of 7-carbethoxymethylene-bicyclo[2.2.1]heptane and 5 g. of 5% palladium on carbon catalyst and 250 ml. of ethanol is stirred under hydrogen until no more hydrogen is absorbed (about 1.2 liters are absorbed). The catalyst is removed by filtration and a solution containing 0.1 mole of potassium hydroxide in 20 ml. of water is added to the filtrate. The solution is then refluxed until no more starting material is observed by thin-layer chromatographic monitoring. The solvent is then removed by evaporation under vacuum and the resulting residue dissolved in 200 ml. of water and extracted three times with ethyl ether. The remaining aqueous phase is acidified with dilute aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined organic extracts are washed with water, then dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording bicyclo[2.2.1]hept-7-yl acetic acid.
Reaction SMILES: C1(O[C:8]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([CH:32]4[C:38]5=[N:39][CH:40]=[C:41]([Br:43])[CH:42]=[C:37]5[CH2:36][CH2:35][C:34]5[CH:44]=[C:45]([Cl:49])[CH:46]=[C:47]([Cl:48])[C:33]4=5)[CH2:28][CH2:27]3)=[O:25])[CH2:19]2)=[N:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.[NH4+:50].[OH-]>CC(O)C>[Br:43][C:41]1[CH:42]=[C:37]2[CH2:36][CH2:35][C:34]3[CH:44]=[C:45]([Cl:49])[CH:46]=[C:47]([Cl:48])[C:33]=3[CH:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[CH2:23][CH:20]4[CH2:21][CH2:22][N:18]([C:8](=[NH:50])[NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:19]4)[CH2:27][CH2:28]3)[C:38]2=[N:39][CH:40]=1
Reactant: O=C(N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: N=C(NC(=O)c1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 28 is dissolved in 2-propanol and concentrated NH4OH is added. he mixture is stirred at 25° C. for 24 h and then evaporated to dryness. The residue is triturated with Et2O (2×250 ml) and the ether discarded. The resulting product is chromatographed on a silica gel column to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C1([Li])C=CC=CC=1.[N+:18]([O-])([O:20]C)=[O:19]>CCOCC>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][N+:18]([O-:20])=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CO[N+](=O)[O-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: Cc1cc(Br)cc(C)c1N[N+](=O)[O-]
Temperature: -10 °C
Yield: 27.6 %

Procedure:
To a cooled (-60° C.) solution of 4-bromo-2,6-di-methylaniline (0.037 mole, 7.4 g) dissolved in anhydrous ether (100 ml) under nitrogen with stirring is added dropwise, phenyl lithium (21.5 ml, 0.040 mole). The solution is stirred for 1.5 hours at -60° C. The solution is allowed to warm to -10° C., then it is cooled to -60° C. The nitrogen flow is stopped while methyl nitrate (0.044 mole, 3.5 g) in anhydrous ether (25 ml) is added dropwise. The solution is stirred for 0.5 hour at -60° C., then it is allowed to warm to room temperature. The solution is stirred for 1.6 hours; the ether layer is evaporated. The solid is dissolved in water (250 ml), then is extracted with ether (2×100 ml). The cold water layer is acidified with 5% HCl. The precipitated product is filtered, washed with water, and dried in vacuo. Recrystallization from hot hexane yields 2.5 g of the desired product melting at 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([O:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC=C)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:20])=[C:6]1[CH3:21].N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([O:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:20])=[C:6]1[CH3:21]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cc(O[C@@H](C)C(=O)OC)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-allyl 1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.327 g, 0.72 mmol) and morpholine (0.63 mL, 7.2 mmol) in anhydrous THF (10 mL) was degassed, then Pd(PPh3)4 (0.083 g, 0.072 mmol) was added under argon protection. The reaction mixture was stirred at rt for 1 h. The solvent was removed and the resulting crude was dissolved in MeOH. The mixture was acidified with 2 N HCl to pH 3. The mixture was filtered and the solid was washed with water. The solid was dried for the next Step with no further purification. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.C([O:18]C([NH:21][N:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1C1C=CC(C=NN)=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[N:22][NH2:21])=[CH:25][CH:26]=1.[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][C:1]([CH:13]=[O:18])=[CH:2][CH:3]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NN=Cc1ccc(-c2ccccn2)cc1
Product: O=Cc1ccc(-c2ccccn2)cc1

Procedure:
The present inventors have found that 4-(pyridin-2-yl)benzaldehyde can be produced economically by reacting a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or salt thereof, all of which being novel compounds, with hexamethylenetetramine and water, and further that a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine and a salt thereof can be obtained by reacting a salt of 2-(4-tolyl)pyridine with a brominating agent. In addition, they have found that N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine can be produced more economically and easily by reacting 4-(pyridin-2-yl)benzaldehyde hydrazone with di-tert-butyl dicarbonate, and that 4-(pyridin-2-yl)benzaldehyde hydrazone can be obtained from 4-(pyridin-2-yl)benzaldehyde.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][N:5]=1>>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:2][CH3:1])=[O:9])=[CH:6][N:5]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN
Product: CNC(=O)c1ccc(Cl)nc1

Procedure:
The title compound (D42) was prepared from methylamine and 6-chloronicotinic acid according to the procedure described for Description 35.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18].S1(CCCC1)(=O)=O>O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.03 h

Procedure:
20 g of anthraquinone are introduced into 100 ml of 98 % HNO3 at 0°, the temperature rising to 10° in two minutes as a result of this addition. The reaction mixture is then nitrated at 10° for 20 minutes, with cooling by iced water. 100 ml of sulpholan are added, the temperature rising to 50° as a result. The reaction mixture is suction-filtered at 20° and the precipitate is washed with 50 ml of sulpholan and then with water, and dried. 12.7 g of 1-nitro-anthraquinone, formed by analysis to have the following composition, are obtained:
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:3]([C:5]1[C:17](=[O:18])[N:13]2[CH2:14][CH2:15][O:16][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=1[OH:19])=[O:4].ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH3:1][N:2]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:36])=[CH:24][CH:25]=1)[C:3]([C:5]1[C:17](=[O:18])[N:13]2[CH2:14][CH2:15][O:16][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=1[OH:19])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N(C)C(=O)c2c(O)c3cccc4c3n(c2=O)CCO4)cc1
Solvent: ClCCl
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccc(S(C)=O)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A mixture of 6-[N-methyl-N-(4-methylthiophenyl)carbamoyl]-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido-[1,2,3-de]-1,4-benzoxazine (1 g) and m-chloroperbenzoic acid (0.5 g) in dichloromethane (50 ml) was stirred at 5° C. for 1 hour. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from acetone to give pale brown crystals of 6-[N-methyl-N-(4-methylsulfinylphenyl)carbamoyl]-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.82 g).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:49][C:50]1[CH:51]=[C:52]([CH2:56][CH2:57][C:58](O)=[O:59])[CH:53]=[CH:54][CH:55]=1>C1COCC1>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][O:14][C:58](=[O:59])[CH2:57][CH2:56][C:52]3[CH:53]=[CH:54][CH:55]=[C:50]([OH:49])[CH:51]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2COC(=O)CCc2cccc(O)c2)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of the alcohol from Step F (79.7 mg, 0.345 mmol) and triphenylphosphine (90.0 mg, 0.345 mmol) in 0.5 mL of THF was added a solution of diethylazodicarboxylate (0.054 mL, 0.345 mmol) and 3-(3-hydroxyphenyl)propionic acid (57 mg, 0.34 mmol) in 0.5 mL of THF. After 10 minutes, HPLC analysis indicated 60% conversion. Additional triphenylphosphine (45 mg, 0.17 mmol) and diethylazodicarboxylate (0.027 mL, 0.17 mmol) were added, and the reaction was stirred for 10 more minutes. The solution was concentrated in vacuo, then purified by silica gel chromatography (3% MeOH/CH2Cl2) to provide the desired product as a white foam.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=1.[C:23](=[O:25])=[O:24]>C1COCC1.CCCCCC>[Cl:15][C:16]1[N:17]=[CH:18][CH:19]=[C:20]([Cl:22])[C:21]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Clc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1Cl
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a stirring solution of diisopropyl ethyl amine (11.1 ml, 81.08 mmol) in THF (50 ml) was added dropwise a solution of BuLi (1.46 M, 43.3 ml, 73.65 mmol) in hexane below −65° C. and the mixture was stirred for 40 minutes. To this solution was added dropwise 2,4-dichloropyridine (10 g, 67.57 mmol) in THF (15 mL) at −78° C. and stirred for 30 minutes. Carbon dioxide generated from freshly crushed dry ice was passed through CaCl2 guard tube and then charged into the reaction mixture for 10 minutes and the reaction mixture was slowly allowed to come to room temperature. The solvent was evaporated under reduced pressure and dissolved in a minimum volume of water. The aqueous layer was washed with water and acidified to pH 4 with conc. HCl. It was then extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 2,4-dichloronicotinic acid (10.6 g, 82%) as off white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[CH3:21][N:17]1[CH2:16][CH:15]([CH2:14][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[O:19][C:18]1=[O:20]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CN2CCN(c3ccccc3)CC2)OC1=O
Yield: 16.3 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.2 g (0.02 mol) of 1-phenylpiperazine, 3.0 g (0.02 mol) of 5-(chloromethyl)-3-methyl-2-oxazolidinone, 8.0 g (0.075 mol) of anhydrous sodium carbonate, and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a brown oil as residue. The oil was converted to the dioxalate and the solid was recrystallized from acetonitrile-dimethylformamide but did not give a correct combustion analysis. The salt was partitioned between methylene chloride and a 4% sodium hydroxide solution. The organic layer was dried (Na2SO4) and concentrated to yield 0.9 g (16%) of white solid, mp 110°-112° C. (2-propanol).
Reaction SMILES: [C-]#[N:2].[Na+].[OH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9](O)[C:10]([O-])=O)=[CH:7][CH:6]=1.[Na+].[Cl-].[Na+]>>[OH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][C:10]#[N:2])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CCc1ccc(O)cc1
Temperature: 135 °C

Procedure:
Sodium cyanide (25.0 g.) is added to a stirred suspension of anhydrous sodium p-hydroxymandelate (96 g. of 99% w/w material, the impurity being sodium chloride; prepared from 104 g. of monohydrate by azeotropic distillation with 500 ml. of xylene in a Dean and Stark apparatus) in N,N-dimethylformamide (100 ml.), and the mixture is heated at 135° C. for 1 hour and then cooled. Water (170 ml.) and formic acid (38 ml.) are added and the mixture is extracted twice with methyl isobutyl ketone (330 ml. and 170 ml. respectively). The combined extracts are washed twice with water (240 ml. and 180 ml. respectively) and then concentrated by evaporation. There is thus obtained a solution of p-hydroxybenzyl cyanide in methyl isobutyl ketone which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: CS([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:8][CH:7]=1)(=O)=O.[OH-].[Li+].Cl>C1COCC1.O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1cccc(CCOc2ccc(O)cc2)c1
Yield: 18.3 %

Procedure:
Methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.109 g, 0.24 mmol) was dissolved in a mixture of THF/water (7/1, 2.5 ml). Lithium hydroxide (23 mg, 0.96 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1 M) and the water phase was extracted with two portions of EtOAc. The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation and gave 16 mg of 2-({3-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoic acid (yield 18%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O-:29])=[O:28])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)C=CC=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)[O-])c1
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
Ethyl (1RS, 2RS, 3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was shaken on a Parr hydrogenator at 50 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (43 mg, 94%), which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[NH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)(C)(C)C>Cl>[CH3:17][O:16][C:14]([C:12]1[NH:13][C:9]([CH2:8][CH2:7][C:6]([OH:18])=[O:5])=[CH:10][CH:11]=1)=[O:15]
Reactant: COC(=O)c1ccc(CCC(=O)OC(C)(C)C)[nH]1
Agent: Cl
Product: COC(=O)c1ccc(CCC(=O)O)[nH]1
Yield: 111.2 %

Procedure:
Methyl 5-(3-tert-butoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (14.8 g, 58.4 mmol) was treated with 4 N HCl (100 mL) at rt for about 12 h. The solvent was removed and the white solid product was dried to give 12.8 g (94%) of 3-(5-(methoxycarbonyl)-1H-pyrrol-2-yl)propanoic acid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.73 (t, J=6.81 Hz, 2H), 2.98 (t, J=6.79 Hz, 2H), 3.83 (s, 3H), 6.01 (dd, J=3.59, 2.61 Hz, 1H), 6.83 (dd, J=3.61, 2.63 Hz, 1H), 9.70 (br s, 1H); LCMS-MS (ESI+) 198.2 (M+H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([C:15]([O:17]CC)=[O:16])[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:8]2.CCO.Cl>O.C1COCC1>[C:23]([O:22][C:20]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]1[C:15]([OH:17])=[O:16])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1c2ccc(OC)cc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
2N Aqueous lithium hydroxide solution (73.6 mL, 147.23 mmol) was added to a solution of 1-ethyl 2-tert-butyl 6-methoxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (8.23 g, 24.54 mmol) in a mixed solvent of EtOH (35 mL) and THF (35 mL) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added water, the pH of the mixture was adjusted to 3 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (7.59 g, 24.70 mmol, quant.) as a colorless oil.