Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([CH2:14][CH2:15]C)[C:6]=1O.[OH:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:30](=[O:33])([O-])[O-].[K+].[K+]>>[CH2:25]([O:24][C:22](=[O:23])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([O:18][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:30]([OH:33])[C:6]=2[CH2:7][CH2:14][CH3:15])[CH:20]=1)[CH3:26]
Reactant: CCCc1c(C(C)=O)ccc(OCCBr)c1O
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCOc2cccc(C(=O)OCC)c2)ccc(C(C)=O)c1O
Yield: 62.3 %

Procedure:
A mixture of 1.5 g of 1-[4-(2-bromoethoxy)-3-hydroxy-2-propylphenyl]ethanone, 0.83 g of ethyl 3-hydroxybenzoate and 0.95 g of potassium carbonate was allowed to react according to the procedure of Example 79 to give 1.2 g, m.p. 58-60° (62% yield) of 3-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid ethyl ester, the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[S:11][CH2:10][CH2:9][C:8]2=[O:17].Cl[CH2:20][CH2:21]Cl.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[S:11][CH2:10][C:9]1([CH2:21][CH2:20]1)[C:8]2=[O:17]
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)CCS2
Reactant: ClCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)C1(CC1)CS2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
6-Methoxymethoxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen-4-one (23 mg) was dissolved in anhydrous DMF (5 mL) and treated with 1,2-dichloroethane (6.8 μL) and NaH (60% in mineral oil, 8.2 mg), and stirred for 19 h at ambient temperature. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was collected and dried over Na2SO4 followed by solvent evaporation. Column chromatography (SiO2: hexane:EtOAc, from 9:1 to 1:1 v/v) yielded a fraction containing impure desired product 6-methoxymethoxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen-4-one (<1 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:53]1[C:57](=[O:58])[CH2:56][CH2:55][C:54]1=[O:59]>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[O:59]=[C:54]1[CH2:55][CH2:56][C:57](=[O:58])[N:53]1[O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trityl acid 8 (200 mg, 0.42 mM) in dry THF (6 mL) was added dicyclohexyl carbodiimide (DDC, 206 mg, 1 mM). The reaction mixture was stirred for 30 min at r.t., N-hydroxysuccinimide (70 mg, 0.6 mM) and a catalytic amount of DMAP were added and was allowed to stir for overnight. The solvent was removed under rotaevaporator and the solid obtained was dissolved in dry ether. The precipitated DCU was filtered and the solvent ether was evaporated. The crude solid obtained was separated by silica column chromatography using CH2Cl2. Yield: about 120 mg. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.70 (m, 2H), 1.9 (t, 2H), 2.9 (s, 4H), 3.5 (m, 2H), 3.9 (t, 2H), 4.0 (t, 2H), 6.85 (m, 4H), 7.25 (m, 4H), 7.32 (m, 5H), 7.51 (m, 3H), 8.09 (d, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:2].[N+:19]([O-])(O)=O.O.N>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[NH:10][N:9]=1)[CH3:18]
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.5 g of 3-(3-diethylaminopropylamino)indazole. To the solution were added dropwise 0.41 ml of nitric acid(d=1.42) and 0.41 ml of sulfuric acid(sp. gr. 1.84) under cooling with ice, and the solution was stirred for 2 hours at 5°-10° C. To 12.1 ml of ice and water was added the solution, and the pH of the solution was adjusted to at least 11 with an aqueous ammonia solution. Then the solution was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue was dissolved in 50 ml of anhydrous benzene. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the solution was stirred for 30 minutes at 80° C. The reaction solution was added with 0.5 ml of water and stirred for 10 hours at 80° C. After cooling, the solution was filtered. The benzene layer of the filtrate was extracted three times with 20 ml of lN hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 100 g) using chloroform as the developing solvent to give 0.69 g of 3-(3-diethylaminopropylamino)-5-aminoindazole having the following analytical values in a yield of 44%.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)(Cl)Cl>ClCCl>[CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:17])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)OCc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)OCc1cccc[n+]1[O-]
Reaction time: 3 h

Procedure:
A stirred solution of 2-isopropoxymethylpyridine (18.4 g, 0.121 mol) in dichloromethane (200 mL) at room temperature was treated portionwise with meta-chloroperoxybenzoic acid (42.1 g, 0.121 mol), stirred for 3 h, poured into CHCl3 (450 mL) and washed with 2.5-M aqueous NaOH solution (2×250 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as a pale yellow oil; NMR δH (400 MHz, CDCl3), 1.19-1.21 (6H, d, J=6 Hz), 3.71-3.80 (1H, sept, J 6.5 Hz), 4.58 (2H, s), 7.37 (2H, m), 7.47-7.49 (1H, d, J 7 Hz) and 8.25-8.27 (1H, d, J 7.5 Hz)
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CC1CCCC(N)C1>C(O)(=O)C>[CH3:24][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CC1CCCC(N)C1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC1CCCC(n2cnc3c(-c4ccccc4)csc3c2=O)C1
Yield: 70.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 3-methylcyclohexanamine (0.120 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 98.4 mg (0.30 mmol, 70.5% yield) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[CH:48]=[C:49]([S:53]([N:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1.BrCCCCC>>[CH3:57][N:56]([CH3:58])[S:53]([C:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:48]=1)(=[O:54])=[O:55]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CN(C)S(=O)(=O)c1cccc(CCl)c1
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: CN(C)S(=O)(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-N,N-dimethylbenzenesulfonamide to replace 1-bromopentane, N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′-(2′H)-yl)methyl]benzenesulfonamide was obtained (40%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.72-7.62 (m, 4H), 7.29-6.99 (m, 4H), 6.50 (s, 1H), 6.07 (s, 1H), 5.06 (ABq, 2H), 4.71 (ABq, 2H), 4.19-4.05 (m, 4H), 2.50 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 154.7, 144.2, 141.9, 137.8, 134.9, 131.8, 131.5, 129.9, 128.8, 126.6, 125.9, 123.8, 123.2, 120.9, 110.9, 109.3, 98.8, 79.4, 64.2, 63.5, 57.2, 42.5, 37.4; MS (ES+) m/z 492.7 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][Si](C)(C)C)=[CH:5][N:4]=[C:3]1[C:13]([OH:16])([CH3:15])[CH3:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:13]([OH:16])([CH3:14])[CH3:15])=[N:4][CH:5]=1)#[CH:8]
Reactant: Cn1c(C#C[Si](C)(C)C)cnc1C(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cnc(C(C)(C)O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To 2-(1-Methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol (100 mg, 0.42 mmol) in 5 mL of THF was added 1M TBAF in THF (1.3 mL, 1.3 mmol). The reaction was stirred at rt overnight, and then was diluted with 50 mL of water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine and dried with MgSO4, filtered, and concentrated to provide 58 mg of 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].C(O[CH:14](N(C)C)[N:15](C)C)(C)(C)C.N[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2.C(OCC)(=O)C>C(O)CCC>[CH2:1]([O:3][C:4]([C:5]1[N:15]=[CH:14][N:7]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)[CH:6]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccc3[nH]ccc3c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.7 %

Procedure:
A mixture of ethylcyanoacetate (1.0 g, 7.75 mmol) and t-butoxy bis(dimethylamino)methane (2.7 g, 15.5 mmol) was stirred for 18 h at room temperature. After distillation under reduced pressure, 5-aminoindole (1.3 g, 7.75 mmol) was added. The mixture was dissolved in n-butanol, and refluxed for 15 h. The reaction solution was cooled, ethyl acetate was added thereto, and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.33 g, 17% Yield).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH:9]1[CH3:20])([CH3:7])[CH3:6].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>[N+](C)([O-])=O>[C:21]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[CH:9]([CH3:20])[CH:8]2[CH:5]([CH3:7])[CH3:6])=[CH:12][C:13]=1[CH3:17])(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCC(=O)c1cc2c(cc1C)C(C)(C)C(C)C2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
At 0°-5° C. a solution of 4 g AlCl3 in 50 ml nitromethane is added to a mixture of 6 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to example I or II) and 25 g propionyl chloride. Then the reaction mixture is stirred at room temperature during one hour and poured out into ice and extracted three times with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain 6-propionyl-1-isopropyl-2,3,3,5-tetramethyl indan in a yield of 80%. B.p. 145° C./1 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].IC.[H-].[Na+].O1CCC[CH2:42]1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH3:42])([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C(C)(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), iodomethane (0.076 mL), 60% sodium hydride (0.049 g) and tetrahydrofuran (15 mL) was stirred at room temperature for 20 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.32 g, 62%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]2[NH:26][CH:27]=[C:28]([NH:29][C:30](=[O:35])[C@H:31]([O:33][CH3:34])[CH3:32])[C:17]=12>CCCCO.O>[CH3:34][O:33][C@H:31]([CH3:32])[C:30]([NH:29][C:28]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:22]([F:25])([F:23])[F:24])[C:16]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:26][CH:27]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Solvent: O
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 41 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (456 mg, 2.28 mmol) and N,N-diispropylethylamine (294 mg, 0.396 mL, 2.28 mmol) were added to a suspension of (R)-N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (244 mg, 0.759 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube under a nitrogen atmosphere at 160° C. for 24 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give tert-butyl (R)-1-(3-((R)-2-methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (151 mg, 41%) as a solid. LCMS (APCI+) m/z 386.1, 486.1 (M+H)+, Retention time=3.85 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O[C:13](=O)[CH2:14][CH3:15])(=O)[CH2:9][CH3:10].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH3:10].[C:2]1([N:1]([CH2:13][CH2:14][CH3:15])[C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(=O)OC(=O)CC
Product: CCCN(C(=O)c1ccccc1)c1ccccc1
Product: CCCNc1ccccc1

Procedure:
N-Propylaniline was prepared from aniline and propionic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2.5 -dimethyl-1-piperazinyl)-3-tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamide as a light yellow solid. NMR (200 MHz, DMSO-d6): δ0.87 (t, J=7.4 Hz, 3H); 0.91 (d, J=5.9 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.51 (m, 2H); 1.69 (dd, J1 =7.2 Hz, J2 =10.9 Hz, 1H); 2.06 (dd, J1 =7.0 Hz, J2 =10.5 Hz, 1H); 2.30 (d, J=10.3 Hz, 1H); 2.39-2.54 (m, 2H); 2.65 (br d, J=10.3 Hz, 1H); 2.85 (dd, J1 =7.4 Hz, J2 =14.5 Hz, 1H); 3.16 (dd, J1 =5.1 Hz, J2 =14.2 Hz, 1H); 3.79 (t, J=7,6 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.2 Hz, 1H); 5.18 (d, J=16.0 Hz, 1H); 5.71-5.84 (m, 1H); 6.43 (d, J=7.6 Hz, 1H); 6.57 (s,1H);6.64 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.32 (s, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]=[O:16].C(C1C=CC2C3C(=CC=CC=3)C=CC=2C=1)(=[O:19])C.C(C1C=CC2C=CC3C(C=2C=1)=CC=CC=3)(=O)C>>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:1]=[C:2]([C:15]([OH:16])=[O:19])[CH:3]=1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=Cc1ccc2c(ccc3ccccc32)c1
Agent: CC(=O)c1ccc2ccc3ccccc3c2c1
Product: O=C(O)c1ccc2ccc3ccccc3c2c1
Yield: 51 %

Procedure:
Using the procedure outlined in 2A for 2-acetylphenanthrene, 3-acetylphenanthrene (Aldrich, technical grade), 25 g, 0.114 mol) gave 13 g (51%) of phenanthrene-3-carboxylic acid. 15.6 (0.07 mol) of this acid was converted to the corresponding acid chloride, then to 8.37 g (58%) of phenanthrene-3-carboxaldehyde mp 78°-80° (lit. 79.5°-80°, E. Mosettig and J. van de Kamp, J. Amer. Chem. Soc. 55 2395 (1933)), (C,H).
Reaction SMILES: CO[C:3]1[C:4]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][S:6][CH:7]=1.[C:12](=O)([O-])[O-:13].[K+].[K+].CI.Cl.[CH3:21][C:22]([CH3:24])=O>>[CH3:12][O:13][C:21]1[CH:22]=[CH:24][C:4]([CH2:8][C:9]([OH:11])=[O:10])=[CH:3][C:7]=1[S:6][CH3:5]
Reactant: CC(C)=O
Reactant: COc1cscc1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Product: COc1ccc(CC(=O)O)cc1SC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 96 %

Procedure:
To a suspension of 4-methoxy-3-thiophenylacetic acid (1.61 g, 81 mmol) in acetone was added potassium carbonate (56 g, 400 mmol, 5 equivalents), followed by methyl iodide (11.5 g, 81 mmol, 1 equivalent). After stirring at ambient temperature for 5.5 hours, 2N aqueous hydrochloric acid solution (400 mL) was slowly added. The resulting solution was then extracted with 2×200 mL of THF/diethyl ether (1:1) followed by diethyl ether (400 mL). The combined organic layers were washed with 2×250 mL of 10% aqueous sodium thiosulfate and 250 mL of saturated aqueous sodium chloride solution (brine), dried over anhydrous magnesium sulfate, filtered and concentrated to give 56 g (96% yield) of the title compound as a pale yellow solid; DCI MS M/Z: 230 (M+NH4)+ ; 1H NMR (CD3OD) δ 3.36 (s, 3H), 3.53 (s, 2H), 3.82 (s, 3H), 6.83 (d, 1H, J=8.7 Hz), 7.02 (dd, 1H, J=8.7, 2.7 Hz), 7.06 (d, 1H, J=2.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:25][CH2:26][CH3:27])([CH2:22][CH2:23][CH3:24])[C:9]([CH:11](C(OCC)=O)[C:12]([O:14]CC)=O)=[O:10])=[CH:4][CH:3]=1.ClCCl.Cl>CS(O)(=O)=O.O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]([CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH3:27])[C:9](=[O:10])[CH:11]=[C:12]2[OH:14]
Reactant: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC1(CCC)C(=O)C=C(O)c2cc(F)ccc21
Temperature: 50 °C
Yield: 69.9 %

Procedure:
The compound of Example 14F (6.0 g, 15.75 mmol) was dissolved in methanesulfonic acid (35 mL) and warmed at 50° C. for 5 h. The mixture was cooled and added to a mixture of ice and dichloromethane, followed by stirring until all ice had melted. The layers were separated and the aqueous phase was extracted again with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford an amber oil, which was dissolved in tetrahydrofuran (60 mL) and warmed at reflux with 1 N HCl solution (50 mL) for 18 h. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organic layer was extracted with water and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid, which was triturated with ether-hexane and collected by filtration. These procedures afforded the title compound (2.89 g, 70%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.51 (m, 2 H) 0.64 (m, 6 H) 0.84 (m, 2 H) 1.84 (m, 2 H) 1.99 (m, 2 H) 5.80 (s, 1 H) 7.43 (m, 1 H) 7.57 (dd, J=9.56, 2.57 Hz, 1 H) 7.67 (d, J=5.52 Hz, 1 H) 11.75 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[O:26]>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[NH:24][C:25]([NH:15][C:13]1[CH:14]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:10]=[CH:11][N:12]=1)=[O:26]
Reactant: Nc1cc(Nc2ccc(F)cc2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: O=C(Nc1cc(Nc2ccc(F)cc2)ncn1)Nc1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A suspension of N-(4-fluoro-phenyl)-pyrimidine-4,6-diamine (408.4 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 14 h at 80° C. After cooling to 5° C. the suspension is filtered, the residue washed with half-saturated K2CO3 solution, H2O and acetone and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:15]([N:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a stirred solution of 4-bromoaniline (500 mg, 2.92 mmol, 1.0 eq) and K2CO3 (1.21 g, 8.76 mmol, 3.0 eq) in CH3CN (10 mL) was added benzyl bromide (1.24 g, 7.30 mmol, 2.5 eq) and the mixture stirred for 16 h at 80° C. and cooled to RT. K2CO3 was filtered out, the filtrate concentrated, the resulting crude product was purified by CC using EtOAc/PE (1:19) to get N,N-dibenzyl-4-bromoaniline (900 mg, 87%; TLC system: EtOAc/PE (3:7), Rf: 0.7).