Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].Cl>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([C:17]([OH:18])([CH3:19])[C:16]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(=O)C(=O)[O-]
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 71 %

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (5 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added dropwise, with stirring, to magnesium turnings (0.49 g.) in dry tetrahydrofuran (13 ml.). When the addition was complete, the mixture was stirred and boiled under reflux for one hour. A suspension of sodium pyruvate (2.2 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added rapidly to the refluxing solution. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring for a further hour. The mixture was then cooled in an ice-bath and dilute hydrochloric acid (5 N; 50 ml.) was added. The mixture was stirred and extracted with ether. The extract was then extracted with aqueous potassium carbonate (1 N) and this extract acidified with dilute hydrochloric acid. The precipitate which separated, was collected and dried to give 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, m.p. 166°-9° C. in 71% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([CH3:15])[NH:12][C:11]3=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].CNC1CCCCC1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([CH3:15])[N:12]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:11]3=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CN(c2ccc3ncsc3c2)C(=O)N1
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1C(=O)N(c2ccc3ncsc3c2)CC1C
Yield: 16.3 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-4-methyl-imidazolidin-2-one (I-167b: 150 mg, 0.643 mmol) was refluxed with 3-iodo-4-methyl-pyridine (155 mg, 0.708 mmol), copper iodide (12.21 mg, 0.0643 mmol), N,N′-dimethyl-cyclohexane-1,2-diamine (27.39 mg, 0.192 mmol), potassium phosphate (341.5 mg, 1.607 mmol) and 1,4-dioxane (5 mL) at 120° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (10% MeOH in chloroform). Purification by column chromatography on silica gel (3% methanol in chloroform) followed by preparative HPLC afforded 34 mg of the product (16.66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14]([CH3:17])(Cl)[CH3:15])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:8])=[CH:4][C:5]2[C:14]([CH3:17])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: Oc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromophenol (10 g, 57.8 mmol) and 2,5-dichloro-dimethyl hexane (13.04 g, 69.36 mmol) in 160 mL anhydrous CH2Cl2 at 5° C. was added, portionwise, AlCl3 (2.31 g, 17.34 mmol). Upon addition of AlCl3, HCl gas evolution was observed. The solution changed from yellow to reddish orange. The reaction solution was kept at 5-20° C. for two hours and then allowed to stir at room temperature overnight. The reaction mixture was poured into 160 g of ice and extracted with 160 mL CHCl3). The organic phase was washed with water, aqueous, saturated NaHCO3, saturated NaCl and dried (Na2SO4). The organic solution was then concentrated in vacuo and chromatographed (5 to 10% EtOAc/hexane) to provide 12.83 g of 2-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white solid in 80% yield. 1H NMR (400 MHz, CDCl3) δ 7.34(s, 1H, aromatic), 6.93(s, 1H, aromatic), 5.24(s, 1H, phenolic OH), 1.64(s; 4H, 2CH2), 1.23(s, 6H, 2CH3), 1.22(s, 6H, 2CH3).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4].[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:19](=[O:21])[CH3:20])[C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Sodium hydride (0.8 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 2,3-dimethylindole-5-carboxylic acid ethyl ester (3.50 g) in dry N,N-dimethylformamide (25 ml) and the mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of acetyl chloride (1.27 g) in dry N,N-dimethylformamide (2.5 ml) was added dropwise with stirring over 2 minutes. The resulting mixture was stirred at room temperature for 3 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by product. Evaporation of the product-containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 1-acetyl-2,3-dimethylindole-5-carboxylic acid ethyl ester (1.22 g), m.p. 98°-101°.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][NH2:18]>CN(C)C=O>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[NH:18][CH3:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN
Reactant: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100 %

Procedure:
Methyl 4-chloro-3-methoxy-5-nitrobenzoate (available from, for example, Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (140 mL) and cooled to ˜0° C. in an ice/water bath. Methanamine (2M in THF) (114 mL, 228 mmol) was added dropwise with vigorous stirring using a dropping funnel and the mixture was flushed with nitrogen and heated at 80° C. for 3 hr. The mixture was allowed to cool to room temperature over the weekend. The reaction mixture was diluted with water (500 mL), and filtered under vacuum to give the title compound as an orange solid (13.69 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)(=[O:53])=[O:52])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.8 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (0.25 g, 0.520 mmol) in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 90 minutes, then evaporated, azeotroping twice with toluene to give a brown oil. This material was re-dissolved in dichloromethane (8 mL), and diisopropylethylamine (0.454 mL, 2.60 mmol) was added, followed by 4-fluorobenzene-1-sulfonyl chloride (0.121 g, 0.624 mmol), and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was then evaporated in vacuo and the residue purified by column chromatography on silica gel (gradient: 0 to 40% ethyl acetate in isohexane) to give a white solid (204 mg). 80 mg of this sample was purified by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 25-80% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-(4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a pale yellow solid (45 mg). LCMS (Method F, ES-API): RT 2.58 min, m+H=538.9; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.1 Hz), 7.75-7.70 (m, 2H), 7.68 (d, 1H, J=3.1 Hz), 7.45-7.40 (m, 2H), 7.29 (s, 1H), 7.20-7.11 (m, 4H), 6.53 (d, 1H, J=2.2 Hz), 5.49 (dd, 1H, J=12.3, 2.0 Hz), 4.20 (d, 1H, J=16.8 Hz), 3.93-3.86 (m, 1H), 2.94-2.83 (m, 2H), 2.74 (d, 1H, J=12.4 Hz), 2.57-2.47 (m, 2H).
Reaction SMILES: CN(C)C(C1C=[CH:9][C:8](Br)=[CH:7][N:6]=1)=O.[Br:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.Cl.N1CCC1>>[N:6]1([C:20]([C:17]2[N:18]=[CH:19][C:14]([Br:13])=[CH:15][N:16]=2)=[O:22])[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: C1CNC1
Agent: Cl
Product: O=C(c1ncc(Br)cn1)N1CCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-caboxylic acid (1.60 g, 7.877 mmol) and azetidine hydrochloride (1.11 g, 11.8 mmol) to give a yellow solid (331 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 2 H) 4.64 (t, J=7.71 Hz, 2 H) 4.29 (t, J=7.83 Hz, 2 H) 2.29-2.41 (m, 2 H); LCMS for C8H8BrN3O m/z 241.00 and 243.00 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH2:22](O)[CH3:23]>>[CH2:22]([O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21])[CH3:23]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 18 h
Yield: 97 %

Procedure:
1 ml of conc. sulfuric acid was added to an ethanol solution of 0.1 mole (21.4 g) of 4'-hydroxybiphenyl-4-carboxylic acid, and stirred for 18 hours. The reaction solution was concentrated, and then purified by column chromatography, to obtain 22.8 g of 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester [m.p. 144.4°-145.6° C⟧ (yield: 97%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][C:13]1[N:12]=[N:11][C:10]([NH2:14])=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Nc1nncc(-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Yield: 51.8 %

Procedure:
6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1.95 g, 49%) was prepared from 5-(4-fluorophenyl)-1,2,4-triazin-3-amine (2.8 g, 14.00 mmol) and N-bromosuccinimide (7.87 g, 44.00 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:27]1([C@H:33]([NH2:35])[CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([C@H:33]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[C:9]([O:12][C:13]3[C:18]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=4)=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][C:3]=2[F:2])[CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(F)c(C(=O)Cl)c2)n1
Reactant: C[C@@H](N)C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(F)c(C(=O)N[C@H](C)C3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-5-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride hydrochloride (86 mg, 0.22 mmol) in THF (2.0 mL) was added (R)-1-cyclohexyl-ethylamine (0.029 mL, 0.20 mmol). The mixture was stirred overnight at RT, quenched with excess NEt3, concentrated and purified by preparative TLC (100% EtOAc) to yield N-((1R)-1-cyclohexylethyl)-2-fluoro-5-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)benzamide. MS m/z=450 [M+1]+. Calc'd for C25H28FN5O2: 449.53.
Reaction SMILES: [Cu][C:2]#[N:3].[C-]#N.[Na+].[NH2:7][C:8]1[C:13](Br)=[N:12][C:11]([Br:15])=[CH:10][N:9]=1>CN(C=O)C>[NH2:7][C:8]1[C:13]([C:2]#[N:3])=[N:12][C:11]([Br:15])=[CH:10][N:9]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(Br)cnc1N
Temperature: 125 °C
Yield: 67.2 %

Procedure:
A solution of copper(i) cyanide (1.20 g, 13.42 mmol) and sodium cyanide (0.658 g, 13.42 mmol) in DMF (10 mL) was heated to 125° C. 2-amino-3,5-dibromo pyrazine (2.61 g, 10.32 mmol) was added in portions. The reaction was stirred at 125° C., and after 5 h quenched in ice cold NaHCO3 solution. The black precipitate was filtrated off and the filtrate was extracted (3×) with EtOAc. The organic layer was washed with brine, dried and evaporated. Purification by chromatography (CH2Cl2) gave pure 3-amino-6-bromopyrazine-2-carbonitrile 14 (1.38 g, 67.2%). 1H-NMR (400 MHz, CDCl3) 5.29 (br s, 2H), 8.30 (s, 1H). (m/z)=199 and 201 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=O)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC(=O)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butan-1-one (3.2 g, 9.0 mmol), prepared according to procedure described in Example 151 Step 5, in CH2Cl2 (40 mL), cooled to 0° C., was added tBuNH2 (3.0 mL, 27.0 mmol). To this mixture was added a solution of TiCl4 (5.4 mL, 1M, 5.4 mmol) in CH2Cl2 dropwise via an addition funnel. Upon completion of addition, the reaction was stirred at room temperature for 24 hrs before it was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude product that was used immediately without further purification. LC-MS 413.5 [M+H]+, RT 0.98 min.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:19][CH2:20][CH2:21][CH2:22][OH:23].O1CCCC1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:23][CH2:22][CH2:21][CH2:20][F:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Reaction time: 90 h
Yield: 85.4 %

Procedure:
Triethylamine (11 mL, 79.4 mmol), 4-dimethylaminopyridine (390 mg, 3.19 mmol), and p-toluenesulfonyl chloride (13.4 g, 70.4 mmol) were added to a mixture of commercially available 3-fluoropropan-1-ol (5.0 g, 64 mmol) and tetrahydrofuran (120 mL) under nitrogen atmosphere at 0° C., and the mixture was stirred at mom temperature for 90 hours. Water and ethyl acetate were added to the reaction mixture for partition. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, the resultant residue was dissolved in dichloromethane and n-heptane, and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=10:1-2:1) to obtain the title compound (12.7 g, 85%).
Reaction SMILES: [CH2:1]([OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[Si:33]([O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: C#CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
9.6 g (0.0214 mol) of hentriacont-30-yn-1-ol of Example 10 were stirred vigorously in a mixture of 100 ml of chloroform and 4.4 ml of triethylamine for 1 h at room temperature. 3.5 g (0.0235 mol) of t-butyldimethylsilyl chloride were added, followed by a catalytic amount (spatula tipful) of 4-dimethylaminopyridine. The mixture was left to stand overnight at room temperature and half the solvent was stripped off. The remaining solution was chromatographed on a silica gel column (chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH2:18][CH2:19][N:9]23)=[CH:4][CH:3]=1.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[NH:17][CH2:18][CH2:19][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCN21
Agent: Cl
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccccc1C1=NCCN1

Procedure:
Ten grams of 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ol, as described in Example X, are suspended in 75 ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered, evaporated to dryness and the residue recrystallized from ethanol-ethyl acetate to afford 4'-chloro-2-(2-imidazolin-2-yl)benzophenone hydrochloride, m.p. 170°-2°C., dec., as a white crystalline solid which is soluble in water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[CH:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 4.6 mmol) and tert-butyl (2-oxoethyl)carbamate (1.4 g, 8.8 mmol) in methanol (10 mL), acetic acid (0.027 g, 4.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.352 g, 4.68 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired product (0.62 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>O1CCCC1.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951;1565–1570) in 100 mL of tetrahydrofuran (THF) is cooled to −78° C. and a solution of 4.66 g (60 mmol) of 40% aqueous methylamine in 20 mL of 2-propanol is added dropwise over 5 minutes. After a further 10 minutes at −78° C., the mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is then extracted into ethyl acetate (EtOAc), washed with water, and dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with hexane/EtOAc (92:8), gives 4.87 g (86%) of the title compound: mp (hexane) 86–87° C. (lit. mp: 90–91° C.; G. B. Barlin, J. Chem. Soc. (B), 1967:954–958).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]([O:35]C(=O)C)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]([OH:35])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(OCC(Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(OCC(O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.293 g (0.562 mmol) tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate is dissolved in 20 ml absolute methanol, mixed with 2.24 ml (1.12 mmol) of a 0.5M sodium methanolate solution and stirred at room temperature for 15 min. Following concentration to half the volume on the rotary evaporator, the batch is diluted with diethyl ether. Washing of the organic phase with semi-saturated and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
To a solution of 48.67 g (0.35 mol) of 1-fluoro-4-nitrobenzene and 67.15 g (0.38 mol) of 1-benzylpiperazine in 600 mL of acetonitrile, add 52.65 g (0.381 mol) of anhydrous potassium carbonate. Heat the reaction mixture to reflux for 20h under nitrogen. After this time, add 300 mL of water and concentrate mixture to 500 mL volume. Extract the mixture with 3×500 mL of methylene chloride. Remove the solvent of the combined organic layers in vacuo. Triturate the resulting crystalline residue with 1000 mL of diethyl ether and filter to obtain title compound.