Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25]([NH:55][CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: NCc1ccncc1
Reactant: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)O)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)NCc3ccncc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Using the procedure of method 1A, triethylamine (4.0 ml, 28.0 mmol) was added to a mixture of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 5.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC.HCl, 1.6 g, 8.4 mmol), and 1-hydroxybenzotriazole (1.1 g, 8.4 mmol) in anhydrous THF (50 ml). The resulting solution was stirred at rt for 10 min. To the resulting reaction solution was then added 4-aminomethylpyridine (0.72 g, 6.7 mmol) and this solution was stirred at rt for 24 h. The resulting reaction solution was concentrated via evaporation under reduced pressure, and the residual solid was resuspended in EtOAc (250 mL). This EtOAc suspension was washed with H2O (200 ml), NaOH (0.1 N, 2×200 ml), potassium phosphate buffer (50 mM, pH 7, 2×200 ml) and H2O (200 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated via evaporation under reduced pressure until a solid began to precipitate. This mixture was allowed to stand at rt, and the precipitated solid was collected and washed thoroughly with Et2O and once with 50% Et2O-EtOAc to afford a white solid (2.2 g, 90%): mp: 209-210.5 C; LRMS (m/z) 450; 13C NMR (CDCl3): δ 171.8, 156.4, 153.7, 153.1, 151.7, 150.8, 150.5, 135.7, 132.0, 130.5, 128.3, 124.5, 124.3, 114.2, 105.6, 104.4, 57.4, 49.8, 43.7, 43.6, 15.9. Anal. Calc'd for C23H23C1N6O2: C, 61.26; H, 5.14; N, 18.64; Cl, 7.86. Found: C, 61.03; H, 5.22; N, 18.66; Cl, 8.02.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([C:16](=[O:19])[CH2:17][CH3:18])=[C:6]1[CH2:20][CH3:21].C[Sn]([N:30]=[N+:31]=[N-:32])(C)C.Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[NH:32][N:31]=[N:30][N:15]=3)[CH:12]=2)[C:7]([C:16](=[O:19])[CH2:17][CH3:18])=[C:6]1[CH2:20][CH3:21]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C#N)ccc12
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(-c3nnn[nH]3)ccc12
Temperature: 120 °C
Reaction time: 14 h
Yield: 64.1 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carbonitrile (107 mg) in xylene (5 ml) was added trimethyltin azide (190 mg), and the mixture was stirred at 120° C. for 14 hours. The resulting mixture was poured into 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% methanol in chloroform to give 1-(2-chlorobenzyl)-2-ethyl-3-propionyl-6-(1H-tetrazol-5-yl)indole (77 mg) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1.I[CH2:32][CH3:33]>C(#N)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:32]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:33]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O[C@@H]3CCCNC3)ccnc21
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN1CCC[C@@H](Oc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
To a solution of (R)-4-(piperidin-3-oxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (84 mg, 0.20 mmol) in acetonitrile (1.0 mL) was added iodoethane (24 uL, 0.30 mmol), and the mixture was heated at 50° C. for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow oil, which was used in the next step without any further purification (46 mg, 51%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[P:3]1(=[O:25])[O:18]C1C=CC=CC=1.C(#N)C.[OH2:29]>>[CH3:8][N:5]([CH:4]([P:3](=[O:25])([OH:18])[OH:29])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:6]([NH:2][CH3:1])=[O:7]
Reactant: COc1cc(C2N(C)C(=O)N(C)P2(=O)Oc2ccccc2)ccc1O
Reactant: O
Solvent: CC#N
Product: CNC(=O)N(C)C(c1ccc(O)c(OC)c1)P(=O)(O)O

Procedure:
A solution of 10.0g of 1,4-dimethyl-3-(4-hydroxy-3-methoxyphenyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide in 90g of acetonitrile and 10g of water was warmed at reflux for 0.5 hr, and then most of the solvent was allowed to evaporate. The residue was recrystallized twice from ethanol to give 4.6g of white solid: mp 183°-184° (dec); 31P nmr (CD3SOCD3) -18.6 ppm (d, J= 24Hz), 1H nmr 10.0 (broad, 3, OH), 5.7 (d, 1, J = 24Hz, CH), 3.8 (s, 3, OCH3), 2.9 (s, 3, NCH3), 2.7 (s, 3, NCH3); 6.7-7.3 (m, 4, aryl and HN).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>CCCCCC>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccc2oc3ccccc3c2c1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1

Procedure:
The Rf values of the objective substance, 2-iododibenzofuran, and aniline were respectively 0.28, 0.59, and 0.07, which were found by silica gel thin layer chromatography (TLC) (with a developing solvent of ethyl acetate and hexane in a ratio of 1:10).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](O)=[O:22]>>[CH3:29][O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16]2)[CH2:12]1)=[O:22]
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: COc1cccc(OC)c1C(=O)O
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nc(C)cc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing in a manner analogous to Example 15, utilizing Intermediate 23 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. C21H26N4O3, 382.47; m/z found 383.1 [M+H]+. 1H NMR (CD3OD): 7.38 (t, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.81-6.70 (m, 2H), 4.04-3.89 (m, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76-3.55 (m, 4H), 3.27-3.13 (m, 3H), 2.53 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15])[C:7]([O:9][CH2:11][C:12]1[CH:13]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8]
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Yield: 198.6 %

Procedure:
6-Hydroxy-2(S)-phthalimidohexanoic acid (5.0 g) was dissolved in a mixture of 90 ml of methanol and 9 ml of water. To this solution, an aqueous 0.5M cesium carbonate solution (18 ml) was added and the mixture stirred for a few minutes. Most of the methanol was removed in vacuo and the resulting aqueous residue was freeze-dried. The lyophilized material was dissolved in DMF (70 ml) and treated with 3.08 g of benzyl bromide. After stirring under nitrogen for 6 hours, the reaction mixture was diluted with 450 ml of water and repeatedly extracted with ethyl acetate. Organic layers were then back-washed with water, dried (Na2SO4), and concentrated to give 6.58 g of benzyl 6-hydroxy-2(S)-phthalimidohexanoate. Recrystallization from ether gave a white solid, m.p. 106.5°-108°; [α]D25° =-27.6° (MeOH, c=1.77).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][Br:17])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCC(=O)Nc1ccc(C)cc1C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Yield: 106.6 %

Procedure:
The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2-propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1,3-dibromo-5,5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHCl3 (500 mL) and CCl4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room temperature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18:2 ->17:3 ->16:4) as eluent afforded the pure title compound (6.40 g, 53%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:17]([C:10]1([CH2:15][CH3:16])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:18]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-diethyl-4-hydroxypiperidine (3.9 g, 15.85 mmole) and 20% palladium hydroxide (1.0 g) in methanol (100 ml) was stirred at 40° C. in hydrogen atmosphere (3.5 atm.) for 6 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-diethyl-4-hydroxypiperidine as oil. Yield 1.8 g (73%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][CH:12]([F:27])[C:13]1[CH:17]=[CH:16][NH:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C1(P(C2C=CC=CC=2)(=O)[NH2:35])C=CC=CC=1.O>CN(C=O)C>[NH2:35][N:15]1[CH:16]=[CH:17][C:13]([CH:12]([F:11])[F:27])=[C:14]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccccc1)c1[nH]ccc1C(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1ccc(C(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
1.1 ml (1.1 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide was added to a solution of 3-(difluoromethyl)-N-phenyl-1H-pyrrole-2-carboxamide (100 mg, 0.42 mmol) and DPPONH2 (P,P-diphenylphosphinic amide, available from Sigma Aldrich®, cat. no. 5994-87-6) (250 mg, 1,1 mmol) in DMF (4 mL) at room temperature. A thick suspension formed and additional 4 mL of DMF were added. The mixture was stirred at room temperature for 1 hour and then it was poured into 50 mL of water and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (2×). The combined organic layer was washed with water and brine and was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (0% to 33% AcOEt/Hexanes) to yield 40 mg (38% yield) of the title compound.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([S:17][CH2:18][C:19]([NH:21][CH2:22][C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:24]2)=[O:20])[S:15][CH:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[Cl:36])[CH2:29][N:25]1[CH2:26][CH2:27][O:28][C@@H:23]([CH2:22][NH:21][C:19](=[O:20])[CH2:18][S:17][C:14]2[S:15][CH:16]=[C:12]([C:10]([NH:9][NH2:8])=[O:11])[N:13]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NNC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reaction time: 8 h

Procedure:
The resultant product (4.01 g) of (42-1) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, a 1 mol/L aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and methanol to give the title compound (453 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1COCC1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>B>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1)NCC2
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
6-Chloroindole (1.0 g, 6.6 mmol) was dissolved in a solution of borane in THF (1 M, 9.83 mmol) at 0° C. and stirred for 30 min. TFA (9.83 mL) was added dropwise and the solution stirred at 0° C. for 30 min. 6 M aqueous NaOH was added until the solution was basic (pH 11). The aqueous solution was extracted with DCM (3×25 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (864 mg, 86%) as a yellow oil. 1H NMR (Me-d3-OD): 6.99 (1H, d), 6.64-6.55 (2H, m), 3.50 (2H, t), 2.95 (2H, t).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:16]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([NH:30][NH2:31])=[O:28])[C:11]=1[NH:10][C:9]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1)=[O:8]
Reactant: NN
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cccc12
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.27 g of 8-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-4H-3,1-benzoxazine-4-one, 0.025 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of chloroform and methyl t-butyl ether to obtain 0.21 g of N-[2-chloro-6-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[O:23][C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1.75 h
Yield: 88 %

Procedure:
1.24 g (3.08 mmol) of N-(2-t-butyl-5-hydroxymethyl-phenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 14) were added to 12 ml of a methylene chloride suspension containing 1.06 g (4.92 mmol) of pyridinium chlorochromate. The mixture was then stirred for 1.75 hours. At the end of this time, the reaction suspension was diluted with diethyl ether, filtered through a column using 50 ml of Florisil (trade mark) absorbent, and eluted with a 1:1 by volume mixture of methylene chloride and diethyl ether. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 50 g of silica gel. Elution with a 1:9 by volume mixture of diethyl ether and methylene chloride afforded the title compound containing a small amount of impurities. Recrystallization of this from a mixture of ethyl acetate and hexane afforded 442 mg of the title compound as crystals, melting at 172.5°-174° C. (after recrystallization from a mixture of ethyl acetate and hexane). The mother liquors were condensed and subjected to column chromatography through 100 g of silica gel. Elution with a 4:6 by volume mixture of ethyl acetate and hexane afforded a further 643 mg of the title compound. The total yield was 88%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23](OCC)=[O:24])[C:13]1=[O:28].[NH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[C:13]1=[O:28]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Temperature: 100 °C
Yield: 43 %

Procedure:
To a stirring suspension of ethyl 1-(benzo[d]thiazol-2-ylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (930 mg, 2.346 mmol), tert-butyl 2-aminoacetate (369 mg, 2.82 mmol) in dioxane (5 mL) was added DIPEA (410 μl, 2.346 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 43% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[CH2:14][OH:15])=[CH:9][CH:8]=1.N1C=CN=C1.[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:15][CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=1)[OH:16])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethane-1,2-diol (18.8 g), imidazole (8.17 g), and a catalytic amount of DMAP were dissolved in 60 mL of anhydrous DMF. tert-Butyldiphenylchlorosilane (18.7 mL) was added drop-wise and the mixture stirred at rt for 16 h. The reaction mixture was poured into 1 L of a mixture of water-ethyl acetate-hexanes (2:2:1) and the layers were separated. After an additional extraction with 0.5 L 3:1 EtOAc/hexanes, the organic extracts were dried over sodium sulfate and concentrated. The yellow oil was purified by silica gel flash chromatography (ethyl acetate/hexanes) to give 14.0 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:36]([Sn:40](Cl)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:20]1[C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][N:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ncnc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2ncnn12
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (370 mg, 0.78 mmol) in THF (12 mL), are added 2M isopropylmagnesium chloride in THF (0.78 mL, 1.56 mmol), and after 5 minutes stirring, tributyltin chloride (0.42, 1.56 mmol) is added. The reaction mixture is stirred at −78° C. for 15 minutes and at room temperature for an additional 15 minutes. After removing the solvent, the residue is purified by silica gel column chromatography eluting with 5:1 petroleum ether:ethyl acetate followed by 1:1 petroleum ether:ethyl acetate. The title compound is isolated (105 mg, 20%).