Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[C:18]1([C:24]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:32]3[CH:28]([CH2:29][NH:30][CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[C:34]1([C:24]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]3[CH:28]([CH2:29][N:30]([C:14](=[O:16])[CH2:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)Cc1ccccc1N1CCOCC1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCOCC3)CC12
Reaction time: 1.25 h
Yield: 25.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.35 g) is added to a solution of 2-[2-(4-morpholinyl)phenyl]acetic acid (0.48 g) in dry dichloromethane (25 cc), cooled to +5° C. The mixture is stirred for 75 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.71 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 8 hours at 20° C. It is washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 2.2 cm, height 12 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) under a nitrogen pressure of 0.7 bar and collecting 50 cc fractions. Fractions 4 and 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from ethylene oxide (2 cc). The crystals are drained, washed with isopropyl ether (1 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-[2-(4-morpholinyl)phenyl]acetyl]-4-perhydroisoindolone (0.27 g) melting at 167° C. is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:40]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][C:32]([CH:35]([F:37])[F:36])=[CH:31][C:30]=5[O:38][CH3:39])=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:37][CH:35]([F:36])[C:32]1[CH:33]=[CH:34][C:29]([C:25]2[C:24]3[N:23]([N:22]=[C:21]([NH:20][C:17]4[CH:16]=[CH:15][C:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:19][CH:18]=4)[N:40]=3)[CH:28]=[CH:27][CH:26]=2)=[C:30]([O:38][CH3:39])[CH:31]=1
Reactant: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12

Procedure:
[8-(4-Difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.191 g, 0.348 mmol) and trifluoroacetic acid (0.500 mL) in a manner analogous to Example 312 to give product (0.170 g, 99%). MP=208-212° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.57 (s, 1H), 8.78 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.32 (s, 1H), 7.25 (m, 1H), 7.15 (m, 3H), 7.10 (br m, 1H), 3.78 (s, 3H), 3.28 (br m, 3H), 2.92 (m, 2H), 2.65 (m, 1H), 1.83 (m, 2H), 1.65 (m, 2H): MS=450 (MH)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([CH3:18])=[C:7]([N+:15]([O-:17])=[O:16])[C:8](O)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)(=[O:4])=[O:3].O.P(Cl)(Cl)([Cl:22])=O>CN(C)C1C=CC=CC=1>[Cl:22][C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:18])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 4-(methylsulfonyl)-2,6-dinitro-m-cresol (4.9 g.) in phosphorus oxychloride (21 ml.), N,N-dimethylaniline is added at such a rate that the temperature does not exceed 34° C. When the addition is complete and the initial exotherm has subsided, the mixture is heated to 60°-65° C. and held there for 10 minutes. The reaction mixture is carefully decomposed by pouring into a ice and water mixture. The desired product as a precipitated solid (4.49 g.) is collected and recrystallized from benzene-pet ether to give a solid with m.p. of 174°-175° C. Analysis: Calcd. for C8H7ClN2O6S: C, 32.59; H, 2.37; N, 9.50; S, 10.86; Cl, 12.05. Found: C, 32.62; H, 2.37; N, 9.39; S, 10.65; Cl, 12.25.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](OC)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CCCCCCC.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)CCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
A solution of 6.0 g (35 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 11.4 g (78 mmol) dimethyl succinate in 60 mL of heptane is brought to reflux. 0.05 mL of tetraisopropyl orthotitanate is added and the reaction mixture is refluxed for 16 hours while the evolved methanol is trapped in a Dean-Stark trap. The reaction mixture is then concentrated and the title compound is isolated as a red oil after column chromatography and melts at 76° C.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(OCC)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Solvent: CCOCC
Product: COc1cccc(Nc2ncc(C(=O)N3CCCCC3)c3c(C)c[nH]c23)c1

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-methoxyaniline (54 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether to give 1-[7-(3-methoxy-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-piperidin-1-yl-methanone (65 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CN1CCN(c2ccc(I)cn2)CC1
Product: CN1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)CC1

Procedure:
Prepared according to general working method I from 1-(5-iodo-pyridin-2-yl)-4-methyl-piperazine (235 mg, 0.78 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (167 mg, 0.78 mmol).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=C(B(O)O)C=CC=1>>[Cl:21][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3cccc(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-chlorophenylboronic acid (130 mg, 0.83 mmol) were coupled to yield 2-(3-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 151 mg (67%), as a shiny pale-yellow solid. mp 147-149° C.; 1H NMR (300 MHz, d6-DMSO) δ3.06 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.46 (m, 1H), 7.58 (m, 4H), 7.70 (m, 2H), 7.64 (m, 1H), 8.11 (br t, 1H), 11.68 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.9 H2O) C, H, N.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=1)#[N:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([N:8]1[CH2:7][CH2:6][N:5]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=2)[C:4]1=[N:3][C:1]#[N:2])(=[O:25])[CH3:24]
Reactant: CC1(C)C=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(2-cyanoiminoimidazolidin-1-yl)-2,2 -dimethyl-2H-1-benzopyran-6-carbonitrile (0.59 g) and acetic anhydride (0.94 ml) in pyridine (5.9 ml) was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with 5% hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 4-(3-acetyl-2-cyanoiminoimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.41 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[CH:3]([C:8]([F:9])([F:10])[F:11])[CH:4]([NH:7][S:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cccs1
Temperature: 25 °C

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (prepared according to the method of Example 28, Part A, 105 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added pyridine (100 μL) and 2-thiophenesulfonyl chloride (90.5 mg, 0.5 mmol) in CH2Cl2 (1 mL). The solution was stirred for about 8 to about 16 h at 25° C. and then concentrated. EtOAc (1 mL) was added and the solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by the Biotage Flash™ 12 chromatography system, eluting with EtOAc/hexanes (2:3), to give thiophene-2-sulfonic acid (3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-amide (26.5 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CCOCC>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:9]=1[NH:10][C:11](=[O:20])[CH2:12][CH:13]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)CCCSc1ccccc1NC(=O)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCSc1cccc2c1NC(=O)CC2c1ccccc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
2'-(3-Dimethylaminopropylthio)cinnamanilide, hydrochloride (30.0g) is mixed with polyphosphoric acid (700g) with stirring and heating. The temperature is allowed to reach 130°-145° C where the mixture is maintained for 15 minutes. After cooling to 60° C, the mixture is poured onto 2 liters of crushed ice and gradually treated with 1 kg. of potassium carbonate (foaming is partially controlled by addition of ethanol and ether). The basic solution is extracted with 200 ml of ether-100 ml of chloroform (3 times). The organic phases are combined, washed with 100 ml of water, dried over magnesium sulfate, filtered and the filtrate evaporated to give 24.2 g of a syrupy residue. Distillation of this material gives 17.7 g of distillate; boiling point 120°-220° C(0.1 mm of Hg). Subsequent fractionation gives 3.2 g of forerun, 2-(3-dimethylaminopropylthio)aniline, boiling point 120°-140° C(0.1 mm of Hg) and 14.0 g of pale yellow distillate; boiling point 170°-190° C(0.1 mm of Hg). This material partly solidifies and is crystallized from 5 ml of isopropanol to give 10.7 g of colorless solid, melting point 57°-80° C. After crystallization from 10 ml of acetonitrile, the material weighs 9.5 g, melting point 57°-90° C. The melting point indicates that this material is a mixture and an attempt is made to separate the mixture as a salt. A solution of 9.4 g of the base in 100 ml of chloroform is treated with 4.0 ml of 6.9 N ethanolic hydrogen chloride. The resulting yellow solution is diluted to 400 ml with ether to give a yellow amorphous product weighing 9.2 g, melting point 145°-147° C (sintering 130° C). Since this material is only partly soluble in water, a separation of this mixture is attempted by suspending 8.3 g of material in 150 ml of water. After 30 minutes, the solid is filtered, air-dried (wt. 2.3 g, melting point 104°-106° C), and the filtrate is made basic by the addition of a solution of 10 g of potassium carbonate in 20 ml of water. The liberated base is extracted with 100 ml of chloroform-200ml of ether (twice), the organic phases combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give 5.0 g of the title compound, melting point 64°-66° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:8][C:9]1[CH:13]=[CH:12][NH:11][N:10]=1>ClCCl>[C:1]([NH:5][C:6]([N:11]1[CH:12]=[CH:13][C:9]([CH3:8])=[N:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc[nH]n1
Solvent: ClCCl
Product: Cc1ccn(C(=O)NC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To tert-butyl isocyanate (1.57 mL, 1.34 g, 13.70 mmol) in dichloromethane (30 mL) was added 3-methyl-1H-pyrazole (0.98 mL, 1 g, 12.18 mmol). The mixture was stirred overnight at room temperature and then concentrated under vacuum. The crude material was purified by silica chromatography (eluting with dichloromethane) to give the title compound (2.1 g).
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][OH:25])[CH2:19]3)[C:6]=2[CH:5]=1.Cl[CH:27](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:27][N:21]1[CH2:22][CH2:23][N:18]([C:7]2[C:6]3[CH:5]=[C:4]([CH3:3])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:19][C@@H:20]1[CH2:24][OH:25]
Reactant: CC(Cl)Cl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CO)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CO)C1
Reaction time: 0.03 h

Procedure:
Add aqueous 37% formaldehyde (1.1 eqiv) to a solution of [(R)-4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-methanol (1 mmol) in dichloroethane (60 mL per 1 mmol non-alkylated starting material). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 mmol per 1 mmol non-alkylated starting material). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) affords the title compound as a yellow powder: mp 118-124° C.; 1H NMR (CDCl3) δ 2.31 (s, 3H), 2.43 (s, 3H), 2.45 (m, 1H), 2.59 (m, 1H), 2.82 (m, 1H), 3.31 (m, 1H), 3.58 (dd, 1H) 3.67-3.79 (m, 3H), 3.86 (dd, 1H), 4.96 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.96 (t, 1H), 7.01 (d, 1H); MS (APCI) m/z (rel intensity) 343 (100).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:4]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Br:1])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 187.7 %

Procedure:
Under an atmosphere of argon, to a solution of 2-bromo-5-nitrobenzoic acid (5.14 g) in DMF, benzyl bromide (2.73 mL) and potassium carbonate (4.33 g) were added. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was washed with hexane/ethyl acetate to give the title compound (6.59 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:15])=[C:6]([CH3:16])[N:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[CH3:16][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:15])=[C:2]([CH3:1])[N+:3]([O-:22])=[CH:4][N:5]=1
Reactant: Cc1cc(O)ccc1-c1c(C)ncnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(O)ccc1-c1c(C)nc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol (1.0 g, 4.7 mmol) in dichloromethane (25 mL) was added 3-chloroperoxybenzoic acid (887 mg, 5.14 mmol) at 0° C. The reaction was stirred at 0° C. for 2 hours, then at room temperature for 14 hours. After removal of solvent in vacuo, purification by chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in petroleum ether) provided the product. Yield: 742 mg, 3.22 mmol, 69%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 6.82-6.91 (m, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[N:10]1
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)nn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
6-(Methoxycarbonyl)-3-methyl-1H-indazole (0.40 g, 2.1 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was ice-cooled. Sodium hydride (85 mg, 60% suspension in oil, 2.1 mmol as NaH) was added and the mixture was stirred at 0° C. for 30 min. 2,4-Dichlorobenzyl chloride (0.45 g, 2.31 mmol) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was extracted with ethyl acetate/water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystalline residue was separated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to give the objective compound (0.54 g, 74%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])=[O:5].[P:17]([O-:22])([O:20][CH3:21])[O:18][CH3:19]>>[P:17]([O:5][CH:4]([P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])[C:3]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=1[CH3:1])([O:20][CH3:21])([O:18][CH3:19])=[O:22]
Reactant: COP([O-])OC
Reactant: COP(=O)(OC)C(=O)c1cc(C)ccc1C
Product: COP(=O)(OC)OC(c1cc(C)ccc1C)P(=O)(OC)OC

Procedure:
A mixture of 5.0 g (20.7 mmol) dimethyl 2,5-dimethylbenzoylphosphonate and 2.73 g (24.8 mmol) dimethyl phosphite was heated at 110° for 5 h. The excess of dimethyl phosphite and the unreacted benzoylphosphonate were removed under vacuum. The yellow viscous residue was then purified by column chromatography with chloroform as the eluent. Dimethyl α-(dimethoxyphosphinyl)2,5-dimethylbenzyl phosphate was obtained as a white oil (2.06 g, 29%); GLC and TLC analysis showed the compound to be pure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(CN2CC[C@H](N3CCNCC3)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of 1-benzyl-3-phenyl-piperidin-4-one (10.0 g, 37.7 mmol) and piperazine (13.0 g, 151 mmol) was added tetraisopropyl-orthotitanate (42.8 mL, 151 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (300 mL) and sodium cyanoborohydride (10.5 g, 151 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (10 mL). The inorganic precipitate was filtered off and washed with ethanol. The solvent was evaporated and the residue was taken up in ethylenglycol (130 mL) and sodium hydroxide (13.6 g, 37.7 mmol) was added. The reaction mixture was stirred at 130° C. for 15 min. After cooling water (200 mL) was added and the mixture was extracted twice with 200 mL diethylether. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with methylene chloride/triethyl amine 99:1 gave rac-cis-1-(1-benzyl-3-phenyl-piperidin-4-yl)-piperazine (4.63 g, 36%), as a yellow oil, MS: m/e=336.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]1([C:29](=[N:31]O)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:7]([C:8]1[O:10][N:31]=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=NO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Cc2nc(-c3ccccc3)no2)cc1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of phenylacetic acid (2.04 g) in 50 mL of DMF was added carbonyldiimidazole (2.7 g). The mixture was stirred for 20 min and then benzene amidoxime (2.04 g) was added. The resulting mixture was stirred for 20 min at r.t. and 18 h at 75 ° C. After cooling, the reaction mixture was poured in to 50 mL of water and extracted with 2×50 mL of 1:1 hexane/EtOAc. The extract was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 1:5 EtOAc/hexane to give 2 g of the title compound as a yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:16][OH:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:16][O:17][CH3:23])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(C)nc2CO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(C)ccc1OCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
1.55 g (6.00 mmol) of [3-(4-Methoxy-benzyloxy)-6-methyl-pyridin-2-yl]-methanol in cold 10 ml THF (0° C.) was treated 30 min with 0.41 g (10.30 mmol) of NaH (55% in oil), then 0.43 ml (6.90 mmol) of iodomethane was added and the yellow suspension stirred 1 h. An extraction (water/CH2Cl2) and a chromatography (silica gel, AcOEt/n-n-heptane) delivered 1.41 g (86%) of the title compound as a yellow oil. MS: 274.3 (MH+).