Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].ClCCCC(NC1C=C2C(=CC=1)NC=C2CCC[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=O.C(Cl)Cl.CO>C(O)C>[CH3:37][O:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)=[N:31][CH:32]=[N:33][CH:34]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1cncnc1N1CCNCC1
Temperature: 78 °C
Yield: 36.2 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[C:7](=[C:18]([C:22](C(Cl)(Cl)Cl)=[O:23])[NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:22]([C:18]1[NH:19][C:20]([CH3:21])=[C:6]2[C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][CH2:8][C:7]=12)=[O:23]
Reactant: C[O-]
Reactant: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]c(C)c2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2

Procedure:
A mixture of 3.0 g (6.4 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-3-[(trichloromethyl)carbonyl]-2H,4H-pyrrolo[3,4-d][2]benzazepine, 0.5 ml (2 mmole) of a 4 M methanol solution of sodium methoxide and 100 ml of methanol was heated to 40° for 30 min. The methanol solution was concentrated at reduced pressure, and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried with anhydrous sodium sulfate and concentrated at reduced pressure to give (mp 228°-231°) tan needles. Recrystallization from methylene chloride gave fine colorless needles, mp 229°-231°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][CH2:13][OH:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:15]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH2:12][CH2:13][O:14][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CCO)CCc2cc(Cl)ccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(C)CCc3cc(Cl)ccc3O2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
In a nitrogen atmosphere, 11.0 g (0.0495 mol) of 6-chloro-3,4-dihydro-2-(2-hydroxyethyl)-2-methyl-2H-benzopyran was dissolved in 50 ml of pyridine, the solution was cooled to 0° C. and, with vigorous stirring, 11.3 g of p-toluenesulfonyl chloride was added gradually thereto. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 300 ml of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to give 15.3 g of 6-chloro-3,4-dihydro-2-methyl-2-[2-(p-toluenesulfonyloxy)ethyl]-2H-benzopyran.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:19])([CH3:18])[C:13](OCC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH:13]=[O:14]
Reactant: CCOC(=O)C(C)(C)NC(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C=O)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-2-methyl-propanoate (which may be prepared as described in Description 25) (4667 mg, 17.59 mmol) in toluene (100 mL) cooled to −78° C. was added diisobutyl aluminium hydride (1 M in toluene) (61.57 mL, 61.57 mmol) as a thin stream over approximately 2 minutes. The mixture was stirred at −78° C. over 30 minutes then allowed to warm to 00° C. and stirred over 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt. The quenched mixture was stirred over 1 hour, then extracted into ether (3 times). The combined ethereal extracts were dried over magnesium sulphate, filtered and evaporated to a clear oil. The oil was dissolved in DCM (60 mL) and 4 A molecular sieves (4 g) and pyridinium dichromate (16544.34 mg, 43.98 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was filtered over kieselguhr and the filtrate evaporated to a dark brown oil. Purification by silica gel column chromatography (20% EtOAc in isohexane) yielded benzyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (D26) (1840 mg, 8.3164 mmol, 47.3% yield) as a clear oil;
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:13](=[O:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:17][Mg]Br.C(OCC)C>>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:13]([OH:15])([CH3:17])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC(=O)c1c(C)c(Br)cc2c1OCC2(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Product: Cc1c(Br)cc2c(c1C(C)(C)O)OCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A stirred, cooled (ice bath) solution of 1-(5-bromo-3,3,6-trimethyl-2,3-dihydro-benzofuran-7-yl)-ethanone (Compound 48, 2.0 g, 7.09 mmol), was treated drop wise with a 3M solution of methylmagnesium bromide in diethylether (2.84 mL, 8.51 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was cooled (ice bath), quenched with saturated ammonium chloride solution and extracted with ether. The organic extract was washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to a residue which on flash column chromatography using 7% ethyl acetate in hexanes as the eluent afforded the title compound (I.51 g, 71.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.21 (s, 1H), 4.35 (s, 1H), 4.22 (s, 2H), 2.53 (s, 3H), 1.67 (s, 6H), 1.31 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:36][CH3:37])=[C:18]([CH:25]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:19]([CH3:24])=[C:20]([C:22]#[N:23])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[ClH:38].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:36][CH3:37])=[C:18]([CH:25]4[CH2:28][NH:27][CH2:26]4)[C:19]([CH3:24])=[C:20]([CH:21]=3)[C:22]#[N:23])[CH3:15])[N:9]=[C:10]([CH:11]([F:12])[F:13])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.20 g, 0.39 mmol) in methylene chloride (5 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (0.60 mL, 2.4 mmol). The resulting mixture was stirred at room temp for 3.5 h. The solvents were evaporated and the residue dried in vacuo to give 0.23 g of the product as the HCl salt. LCMS calculated for C20H22F2N7O (M+H)+: m/z=414.2; Found: 414.1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[OH-].[K+].[CH3:15]S(C)=O.IC>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: Oc1ccc2ccccc2c1Br
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 500 mL three-necked round-bottomed flask was charged with 1-bromonaphthalen-2-ol (30.0 g, 134.5 mmol), potassium hydroxide (KOH) (11.3 g, 201.7 mmol) and DMSO (300 mL), and the mixture was stirred under nitrogen atmosphere for 10 minutes, After cooling the mixture by using ice-water bath, iodomethane (28.6 g, 201.7 mmol) was slowly added dropwise thereto. Then, the resultant mixture was stirred under nitrogen atmosphere at ambient temperature for 12 hours, and then at 50° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was mixed with water (500 mL), and extracted with diethyl ether. Organic mixture was washed three times with distilled water, and dried over anhydrous magnesium sulfate (MgSO4). After removing the solvent by using a rotary evaporator, the residue was purified via silica gel column chromatography (eluent: n-hexane) to obtain 1-bromo-2-methoxynaphthalene (22.0 g, yield: 69.0%) as white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]C1C=CC([N+]([O-])=O)=CC=1)=O.Cl.[NH2:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>CN(C)C=O>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:26]
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)C(=O)N[C@@H](CO)C(=O)O

Procedure:
1.5 ml of triethylamine are added to a solution of 4.2 g of 4-nitrophenyl 2-(2,6-dichlorophenyl-amino)-phenyl-acetate and 3.6 g of the hydrochloride of the methyl ester of L-leucyl-L-serine in 30 ml of dimethylformamide and the mixture is allowed to react for one hour at room temperature. It is then acidified to pH 5 with 1 N hydrochloric acid and partitioned between chloroform and water. After washing with water, the organic phase is dried and evaporated. The residue is ground with diethyl ether. After recrystallising from a mixture of ethyl acetate and petroleum ether, the methyl ester of N-{[2-(2,6-dichlorophenyl-amino)-phenyl]-acetyl}-L-leucyl-L -serine is obtained as colourless crystals; melting point 216°-218°: [α]D 32 -30° (c=0.635 in chloroform).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)[CH3:3].Cl>>[ClH:1].[CH2:19]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)O)cc1

Procedure:
Hydrolysis of ethyl 4-(2-diethylaminoethoxy)benzoate hydrochloride with aqueous concentrated hydrochloric acid at 100° for 2 hours gives 4-(2-diethylaminoethoxy)benzoic acid hydrochloride, m.p. 166°-168°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=3)[CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.35 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.20 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.37 g of the title compound. MS (electrospray): 388 (M+1) for C17H17FN7O3.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(O)C>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:27]([OH:26])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 64 %

Procedure:
An ethanol solution of 25.2 g of sodium hydroxide was added with 160 g (0.60 mol) of 1-amidino-4-benzylpiperazine sulfate, followed by a dropwise addition of 129.4 g (0.60 mol) of diethyl ethoxymethylenemalonate over 20 minutes. After being refluxed for 5.5 hours, the reaction mixture was cooled and the precipitated crystals were collected by filtration. The thus-obtained crystals were washed with water and then dried, thereby obtaining 131.4 g of the above-identified compound (yield: 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([N+:20]([O-])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc([N+](=O)[O-])cc3c2c1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
1.02 g of 4-methyl-6-nitro-β-carbolin-3-carboxylic acid ethyl ester is dissolved or suspended in 30 ml of ethanol and 6 ml of tetrahydrofuran and, after the addition of 150 ml of palladium-carbon (10%), is hydrogenated at 24° C. and normal pressure. Within 3.5 hours, 210 ml of hydrogen is absorbed. The solution is filtered off and the catalyst and the solvent is distilled off in vacuo. The crude product is recrystallized from methanol-chloroform. 816 mg of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 225°-238° C. (decomposition) is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:14]([O-])=O.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)ccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cccc(-c2ccncc2)c1
Yield: 83 %

Procedure:
A Paar shaker bottle was charged with 0.2 g (0.85 mmol) of 4-(4-chloro-3-nitrophenyl)pyridine, 0.07 g (0.85 mmol) of sodium acetate, 0.02 g of 5% palladium-on-carbon, and 3 ml of glacial acetic acid. It was then charged with hydrogen to 40 psi, and the shaker was turned on. The reaction mixture was heated to 60°-70° C. and maintained at that temperature for two hours, after which the reaction was stopped and the catalyst removed by filtration. To the filtrate was added water and then 50% aqueous caustic to a pH greater than 7. The reaction mixture was extracted with methylene chloride. The methylene chloride fraction was washed, dried, and evaporated. Analysis of the reaction mixture showed that the process resulted in an 83% yield of 4-(3-aminophenyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:5]([N+:17]([O-])=O)[CH:4]=1>P(OCC)(OCC)OCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[NH:17][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Agent: CCOP(OCC)OCC
Product: COc1ccc2c(c1)[nH]c1cc(OC)ccc12
Temperature: 90 °C

Procedure:
The reaction was carried out in a vial. The crude biphenyl 10h (6.0 g) was dissolved in P(OEt)3 (36 mL). The vial was flushed with argon. The reaction mixture was heated to 90° C., kept at this temperature overnight, and cooled. As a result the carbazole precipitated. Et2O/CH2Cl2 mixture was added. The precipitate was filtered off and washed with CH2Cl2. The filtrate was evaporated. P(OEt)3 was added again, and the mixture was left for cyclization for 24 h. These operations were repeated until the precipitate formation ceased, and TLC indicated that the starting biphenyl disappeared. In total 2.9 g of the carbazole was obtained (65% calculated for two steps.)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:6]2/[C:7](=[O:11])[NH:8][C:9]3[C:5]/2=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)/[CH:24]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-fluorooxindole (3 g, 20 mmol) in THF (50 mL) at 0° C., was added 40 mL of 1M LHMDS in THF. The reaction mixture was stirred at 0° C. for 15 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (5) (1.91 g, 10 mmol) in 5 mL of THF was added to the above reaction mixture. The reaction was stirred at 0° C. for further 30 minutes and then at room temperature for 2.5 hrs. To the reaction, 80 mL of 2M HCl was added. The resulting mixture was stirred at 50-55° C. for one hour, cooled down to room temperature, poured to 1000 mL of water and was stirred at room temperature for one hour. The precipitates formed were collected and washed with water, dried in vacuum to give the title compound as a yellow solid product (2.4 g, yield: 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[C:11]([F:18])([F:17])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][CH:11]([F:18])[O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Br)c(OC(F)F)c1

Procedure:
This compound is obtained in the form of an oil (unpurified) by refluxing a mixture of 2-bromo-5-fluorophenol and ethyl bromodifluoroacetate in acetone overnight in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].Br[CH2:40][CH:41]([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH2:40]([N:36]1[CH2:35][CH2:34][N:33]([C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)=[CH:8][CH:9]=3)=[O:32])[CH2:38][CH2:37]1)[CH:41]([CH3:43])[CH3:42]
Reactant: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Reactant: CC(C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN1CCN(C(=O)c2cc3cc(Oc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cn4)ccc3n2C)CC1
Yield: 36.1 %

Procedure:
To a solution of N-{6-[1-methyl-2-(piperazine-1-carbonyl)-1H-indol-5-yloxy]pyridin-3-yl}-4-trifluoromethyl-benzamide (250 mg, 0.478 mmol) in acetonitrile (2 mL) were added 1-bromo-2-methylpropane (0.123 mL, 1.13 mmol), diisopropylethylamine (0.25 mL, 1.44 mmol) and sodium iodide (180 mg, 1.2 mmol). The reaction mixture was stirred under reflux for 14 hours. The solvent was removed under reduced pressure. Water was added to the residue and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) and solidified with EtOH (2 mL). The precipitate was collected by filtration and dried to give 100 mg of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:14][C:13]=2[CH3:28])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N+:7]([O-:37])=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH3:28])=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[O:21][N:20]=3)=[CH:16][C:17]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 1.08 g (2.8 mmol) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine in 30 ml of methylene chloride was added 0.71 g (1.5 eq) or m-chloroperbenzoic acid (MCPBA). The mixture was stirred under nitrogen for 18 h at room temperature, poured into saturated sodium bicarbonate solution, and the organic layer was separated and dried over sodium sulfate. The organic layer was filtered, concentrated, and the residue was recrystallized from isopropyl acetate/hexane to afford 0.93 g (83%) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide, as white needles, m.p. 119°-121° C.