Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[C:36]([Cl:35])=[CH:41][CH:40]=[CH:39][C:38]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5c(Cl)cccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,6-dichloro-phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[H+].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.N1C2C=CC=CC=2NC=1>CCOCC>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[NH+:9]1[CH:13]=[CH:12][NH:11][CH:10]=1
Reactant: c1c[nH]cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Agent: c1ccc2[nH]cnc2c1
Solvent: CCOCC
Product: c1c[nH+]c[nH]1
Temperature: 0 °C

Procedure:
Hexafluorophosphoric acid (65% in water) is purchased from Fluka and evaporated with pyridine three times to concentrate. A solution of imidazole or benzimidazole (20 mmol) in ether (100 mL) is treated with 20 mmol of evaporated hexafluorophosphoric acid under stirring and at 0° C. After mixing the solution is evaporated and the slurry is treated with anhydrous ether. The salt is isolated by filtration, followed by washing with ether and drying in vacuo.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>C1(C)C=CC=CC=1>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: C=O
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.05 g of dried particles of size 3.5 μm with quaternary base groups from Example 3 was dispersed in 50 g toluene in presence of a steric stabilizer (H-190-332 from ICI). Then 0.4 g resorcinol and 0.6 g of 37% formaldehyde solution were added. After stirring for 5 hours, at 25° C., particles of size 6.4 μm were formed.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CCC2(C)C
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5 M solution in hexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0 mg (6.28 mmol) of ZnCl2 in 5.0 mL THF was added and the resulting solution stirred for 30 minutes. This solution was added to a second flask containing 570.0 mg (1.57 mmol) of methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4) and 76.0 mg (0.063 mmol) of tetrakis(triphenyphosphine)palladium(0) in 4.0 mL THF, and the resulting solution was heated to 50° C. for 3 h. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. The dry solution was concentrated under reduced pressure and the title compound was isolated from the residue as a yellow oil by column chromatography (5-10% EtOAc/hexanes).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12][C:11]1=2.N1C2C(=CC=CC=2)CCC1C.[Cl-].[NH4+]>C(OCC)C.Cl>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12][C:11]1=2
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc2c(n1)CCCC2=O
Agent: CC1CCc2ccccc2N1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc2c(n1)CCCC2(O)c1ccccc1

Procedure:
To a stirred solution of 0.155 moles of phenylmagnesium bromide in 250 ml of diethyl ether was added dropwise a solution of 2.0 g (0.124 mole) of 5-keto-5,6,7,8-tetrahydroquinaldine in 100 ml of diethyl ether. After all of the tetrahydroquinaldine had been added the mixture was then treated with an excess of a saturated aqueous ammonium chloride solution. The ether layer was separated, dried and evaporated to provide a residue. This residue was dissolved in dilute hydrochloric acid and the aqueous acid layer was then extracted sequentially with diethyl ether and hexane. The acid layer was then basified with aqueous sodium hydroxide. Filtration provided yellow solid 5-hydroxy-5-phenyl-5,6,7,8-tetrahydroquinaldine, which had a m.p. of 130°-134° C. after recrystallization from a dichloromethane-hexane mixture. Analysis: Calculated for C16H17NO: %C, 80.3; %H, 7.2; %N, 5.9; Found: %C, 80.2; %H, 7.2; %N, 5.5. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[C:42]6[CH:41]=[CH:40][C:39]([CH:43]=[O:44])=[CH:38][C:37]=6[C:36]6[C:31]5=[CH:32][CH:33]=[CH:34][CH:35]=6)=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].O.Cl>C1COCC1>[OH:44][CH2:43][C:39]1[CH:40]=[CH:41][C:42]2[N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:21]4[CH:20]=[CH:19][C:18]([N:9]5[C:8]6[CH:7]=[CH:6][C:5]([CH2:3][OH:4])=[CH:17][C:16]=6[C:15]6[C:10]5=[CH:11][CH:12]=[CH:13][CH:14]=6)=[CH:23][CH:22]=4)=[CH:25][CH:26]=3)[C:31]3[C:36]([C:37]=2[CH:38]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4cc(C=O)ccc43)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4cc(CO)ccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
Sodium borohydride (2.40 g, 63.4 mmol)) was added to the 4,4′-bis(3-formyl-carbazol-9-yl)biphenyl (2) (3.42 g, 6.33 mmol) in THF (1.2 L) and the resulting suspension was stirred at room temperature for 24 h. Once the reaction was complete, the mixture was slowly poured into water (400 ml) and the mixture was left to stir at room temperature for a further 30 min. The reaction mixture was acidified to pH 6 with hydrochloric acid (5M) and the product was extracted with dichloromethane (3×300 ml). The combined organic phase was washed with water (400 ml) and brine (400 ml), dried (MgSO4), filtered and the filtrate evaporated to dryness. The crude product was purified by chromatography on silica using 50% THF/toluene as the eluent The product, 4,4′-bis(3-(hydroxymethyl)carbazol-9-yl)(3) was obtained as a pale yellow solid (3.22 g, 94%) with m.p. 268° C. (dec). 1H n.m.r.: (300 MHz, CDCl3): δ 8.23 (2H, d, J 7.61 Hz, aromatic H); 8.18 (2H, s, aromatic H); 8.06 (4H, d, J 8.19 Hz, aromatic H); 7.75 (4H, J 8.19 Hz, aromatic H); 7.50-7.38 (8H, m, aromatic H), 7.29 (2H, m, aromatic H); 5.25 (2H, t, J 5.58 Hz, OH); 4.68 (4H, d, J 5.56 Hz, CH2). λmax(CH2Cl2): 216 nm (ε/Lmol−1 cm−1 177 455), 240 (57 873), 271 (56 595), 294 (55 330) 329 (37 758). FTIR (solid): 3343, 1604, 1500, 1485, 1455, 1362, 1330, 1230, 803, 745 cm−1. m/z (TOF) 544 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2ccc(N)nc2)CC1
Yield: 57.8 %

Procedure:
The suspension of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (5 g, 22.5 mmol), NH4Cl (12 g, 225 mmol), and Fe (5 g, 5 mmol) was stirred in EtOH/H2O (1:1) (100 mL) at 80° C. for 3 h. TLC showed starting material 1-methyl-4-(6-nitropyridin-3-yl)piperazine disappeared. After filtration on a pad of Celite, the solvent was removed under vacuum. EA and brine were added into the mixture and the organic layer was separated, dried over Na2SO4 and concentrated at reduced pressure to give 2.5 g of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (yield 60%). LCMS: (M+H)+ 193
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:20][N:21]([CH3:23])[NH2:22].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH:34]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[F:51])[C:35]2[N:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl.CO>[CH3:20][N:21]([CH3:23])[NH:22][C:41](=[O:42])[C:38]1[CH:37]=[CH:36][C:35]([CH:34]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])[C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[F:51])=[N:40][CH:39]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C)NC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 minol) were added to the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with dichloromethane:methanol =50:1 was concentrated under reduced pressure, whereby the title compound (60 mg, 0.13 mmol, 68%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:26]([O:28]C)=[O:27])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
N-(1-Octyl-5-methoxycarbonyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide (580 mg) was dissolved in methanol (10 ml) and a solution of NaOH (290 mg) in water (5 ml) was added, which was followed by stirring at 60° C. for 4 hr. Methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 6-7 with 2N sulfuric acid and extracted with chloroform (100 ml). The chloroform layer was washed with water and dried over anhydrous sodium sulfate. Chloroform was evaporated under reduced pressure to give 380 mg of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[C:19]([CH3:25])[C:9]=1[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11]>O1CCCC1>[OH:11][CH:10]([C:9]1[C:19]([CH3:25])=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:8]=1[OH:7])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)CCCCC(=O)O)c(O)c1C
Temperature: 0 °C

Procedure:
To a well stirred suspension of lithium aluminum hydride (2 parts) in dry tetrahydrofuran (50 volume parts) was added a solution of 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the free form) in dry tetrahydrofuran (10 volume parts) at room temperature. After being stirred under reflux for 2 hours, the mixture was cooled to 0° C., acidified with cold dilute hydrochlororic acid, and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel and eluted with carbon tetrachloride-acetone (5:1). From the 1st fraction, 6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-3 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.45 part) was obtained as colorless needles melting at 165°-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[K+].[Cl-].[NH4+]>C(O)C.O>[N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][C:9]=1[NH2:15])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c([N+](=O)[O-])ccc(N)c1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
2,4-dinitro-3-methylaniline was prepared by a modification of the procedure described by Meisenheimer, et al., Chem. Ber. (1906) 39:2533. A mixture of 2,6-dinitrotoluene (55.0 g) and hydroxylamine hydrochloride (55.0 g) was stirred in 1.4 L of ethanol until solution took place. 2N Potassium hydroxide solution (550 mL) was added all at once and the resulting mixture allowed to stir for 24 hr. A solution of ammonium chloride (71 g) in water (350 mL) was added and the mixture stirred for an additional hour. The reaction mixture was evaporated under reduced pressure. The residue was partioned between ethyl acetate (750 mL) and 50% saturated sodium chloride solution (500 mL). The ethyl acetate extract was separated and dried over magnesium sulfate. Evaporation under reduced pressure afforded a crude product (52.6 g) which was flash chromatographed on silica and eluted, first with ethyl acetate:hexane (1:3), then with ethyl acetate:hexane (1:2) to afford 36.0 g of product, mp 126.7-131.4° C.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7].CO.C1COCC1>O>[CH:10]1[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1
Reactant: COC(=O)c1ccc2[nH]c3ccccc3c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A mixture of dicylcohexylphosphino-2′,3′-dimethoxy biphenyl (17 mg, 0.04 mmol), palladium(II) acetate (5 mg, 0.02 mmol) in toluene (20 mL) was degassed with argon gas for 15 min. To the resulting mixture was added aniline (136 mg, 1.4 mmol), K3PO4 (636 mg, 3.0 mmol), and 4-bromobenzoic acid methyl ester (300 mg, 1.4 mmol) and stirring was continued at reflux temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 15% ethyl acetate in hexane as eluent) to afford 200 mg (63.4% Yield) of 4-phenylamino-benzoic acid methyl ester. A stirred solution of 4-phenylamino-benzoic acid methyl ester (98 mg, 0.43 mmol), Palladium acetate (193 mg, 0.86 mmol) in acetic acid (2 mL) was heated at 110° C. for 15 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 10% ethyl acetate in hexane as eluent) to afford 120 mg (60.3% Yield) of 9H-carbazole-3-carboxylic acid methyl ester. LiOH.H2O (680 mg, 16.2 mmol) was added to a stirred solution of 9H-carbazole-3-carboxylic acid methyl ester (120 mg, 0.53 mmol) in the mixture of methanol (1 mL), THF (3 mL) and H2O (1 mL). The reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with aqueous 10% aqueous HCl solution, filtered the solid to afford 104 mg (92.85% Yields) of 9H-carbazole-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[O:13][CH2:12]1.O>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][CH:11]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:20]2=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cccnc1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxypyridine (8.56 g, 90.0 mmol) in 300 ml anhydrous DMF was added portionwise 3.6 g of 60% NaH in oil (90 mmol. 1.0 eq.). Stirring 0.5 hour was followed by the addition of 30.0 g (90.0 mmol, 1.0 eq.) of 3-bromo-6-benzyloxy-4-chromanone in one portion. After 1 hour, the reaction was poured into 1 liter H2O and extracted 3×250 ml ethyl acetate. The organic layers were combined, washed 1×100 ml H2O, 1×100 ml 10% LiCl and 1×100 ml brine, then dried over Na2SO4. Filtration and solvent removal afforded 40 g crude product. Silica gel chromatography with 1:4 ethyl acetate:CH2Cl2 as eluant afforded 1.13 g (3.6%) of purified title product; m.p. 133-134° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I:10]Cl>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:10])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: ClI
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Product: Nc1c(F)cc(I)cc1F

Procedure:
2,6-difluoroaniline (5) is reacted with iodine chloride in acetic acid to yield 2,6-difluoro-4-iodaniline (6).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Referring to FIG. 37, to a solution of ethyl 2-(3,5-dimethylphenoxy)acetate (19 g, obtained from the previous step) in methanol (150 mL) was added NaOH solution (6 N, 50 mL). The reaction mixture was stirred at room temperature for 4 h and then adjusted to pH=1˜2 with 2 N HCl solution. The resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps); 1H NMR (CDCl3, 300 MHz): δ 6.69 (s, 1H), 6.58 (s, 2H), 4.68 (s, 2H). 2.31 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+:11]>O>[Na+:11].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8]
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCCCCC(=O)[O-]
Reaction time: 2 h

Procedure:
1 equivalent of 6-aminohexanoic acid (ACA), 1 equivalent of sodium hydroxide (NaOH), and suitable amount of water serving as solvent were added into a reaction bottle. After reacting for 2 hours, the reaction bottle was heated to remove the water, and then a solid mixture was obtained. Next, the solid mixture was dried at 90° C. for 12 hours in oven, and then solid 6-aminohexanoic acid sodium salt (ACA-Na) was obtained. Next, 0.97 g (0.005 mole) of dimethyl terephthalate (DMT), 2.32 g (0.015 mole) of dried 6-aminohexanoic acid sodium salt, and 20 ml of ethylene glycol (EG) were put into a reaction bottle. The reaction bottle was heated at 85-90° C. for 14 hours in the presence of nitrogen gas, and then cooled to room temperature and 20 ml of distilled water was added into it. After the solid reactant was dissolved, sulfuric acid aqueous solution (0.1M) was added dropwise slowly into the reaction bottle until the pH value of the solution was 6. Next, after the reaction bottle was set aside at room temperature for 20 hours, a solid precipitate was observed and collected to a glass bottle. Then, the solid precipitate was washed with 3 times weight of distilled water and filtered, and repeated 5 times these washing and filtration steps. Next, the washed solid was dried in an oven at 80° C., N,N′-bis(carboxypentyl)terephthalamide (BCTM) was obtained after drying. The above-mentioned reaction is represented as:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[CH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
This intermediate (157 g.) was prepared using the procedure described in Example 12a except using 110.0 g. (0.738 mole) of 4-chlorobenzyl cyanide, 81.0 g. (0.74 mole) of 3-pyridinecarboxaldehyde, and 40 ml. of 10% aqueous sodium hydroxide.
Reaction SMILES: C(OC(CC)C=O)(=O)C.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=[O:18])(=[O:12])[CH3:11]>CO>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCC=O
Agent: CCC(C=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCCCCO
Yield: 99 %

Procedure:
The procedure in Example 1 was followed but instead of the acetoxybutyraldehyde isomer mixture, 4-acetoxybutyraldehyde was employed and the hydrogenation was carried out in the presence of 5% by weight of methanol. After a hydrogenation time of 35 minutes, and after filtering off the catalyst and freeing the filtrate from methanol, 4-acetoxybutan-1-ol was obtained in 99% yield.