Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)=[CH:7][N:8]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>ClCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[N:8][CH:7]=[C:6]([N:9]3[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]3)[N:5]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)n(-c2cnc(CN)c(Nc3ccc(Cl)cc3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ncc(-n2nc(C)cc2C)nc1Nc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
[3-Aminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl ]-(4-chloro-phenyl)-amine (40 mg, 0.12 mmol), triethylamine (19 μL, 0.13 mmol) and dichloromethane (2 mL) was cooled on an ice bath. Acetic anhydride (12 μM, 0.12 mmol) was added and the mixture was stirred for 45 min. Aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give N-[3-(4-chloro-phenylamino)-5-(3,5-dimethyl -pyrazol-1-yl)-pyrazin-2-ylmethyl]-acetamide (29 mg, 64%) as a white solid. Mp. 228-230° C. LC-ESI-HRMS of [M+H]+ shows 371.1404 Da. Calc. 371.138712 Da, dev. 4.5 ppm
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N(CC)CCCN=C=NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCNC(=O)c2cccs2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol), 2-thiophenecarboxylic acid (0.847 g, 6.61 mmol), 1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.330 g, 6.94 mmol) in anhydrous CH2Cl2 (20 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 18 hr. The reaction mixture was washed with 1M NaOH (10 ml) followed by 1M HCl (10 ml), dried over MgSO4, and concentrated in vacuo to give 1.859 g of yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.637 g (95% yield) of yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[C:3]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:4]([CH3:13])[C:5]=2[O:9]1
Reactant: Cc1ccc(-c2c(Br)cc3c(c2C)OC(C)(C)C3)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Cc1ccc(-c2c(N3CCN(c4ccc(F)cc4)CC3)cc3c(c2C)OC(C)(C)C3)cc1
Yield: 154.8 %

Procedure:
By using 5-bromo-2,2,7-trimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (150 mg, 1.49 mmol) synthesized in Reference Example 157 and 1-(4-fluorophenyl)piperazine (82.0 mg, 0.450 mmol), the reaction was carried out in the same manner as Example 129 to obtain 300 mg of the title compound as a colorless solid (yield 15%).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:20][CH3:21])[C:9]([O:18][CH3:19])=[CH:10][C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:23]1([N:29]2[C:33]([SH:34])=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:35](#N)C>>[C:23]1([N:29]2[C:33]([S:34][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:20][CH3:21])[C:9]([O:18][CH3:19])([CH3:35])[CH2:10][C:11]=4[CH:15]([CH3:17])[CH3:16])[S:4]3(=[O:6])=[O:5])=[N:32][N:31]=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1OC)S(=O)(=O)N(CCl)C2=O
Reactant: CC#N
Agent: [Na]
Product: COC1=C2C(=C(C(C)C)CC1(C)OC)C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 70 %

Procedure:
By a method similar to that of Example 44 condensation of 2-chloromethyl-4-isopropyl-6,7-dimethoxysaccharin (0.095 g) and 1-phenyltetrazol-5-thiol sodium salt (0.120 g) in acetonitrile (2 mL) and purification of the product by crystallization from ethanol afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6,7-dimethoxy-6-methylsaccharin, 0.099 g, 70% yield, mp 169°-171° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15]C(C#N)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.Cl.O.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:16]=[CH:15][C:21]([C:20]([OH:23])=[O:22])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: CN(C)C1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: O
Product: CN(C)C1CCN(c2ccc(C(=O)O)cc2)CC1
Yield: 85 %

Procedure:
280 mg (1.22 mmol) of 4-(4-dimethylamino-piperidin-1-yl)-benzonitrile (reference example 114a) was dissolved in 2 ml of acetic acid, 4 ml of 6 N HCl was added and the mixture stirred with reflux for 16 h. After cooling 20 ml of water was added and extracted with DCM (3×). The pH of the aqueous phase was adjusted to 5 with KOH pellets, white solid precipitated which was filtered off, washed and dried to give 257 mg of the title compound (85% yield). 1H NMR (CDCl3): δ 7.88 (dd, 2H), 6.98 (dd, 2H), 4.09 (d, 2H), 3.42 (m, 1H), 3.29 (t, 2H), 2.90 (s, 6H), 2.89-2.96 (m, 2H), 2.18 (m, 2H), 1.80 (dq, 2H). MS (ion spray) m/z 249 (M+H)+. 90% pure by analytical HPLC.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:10]1[C:13]([CH3:15])([CH3:14])[C:12]([CH3:17])([CH3:16])[C:11]1=[O:18].[C-:19]#[N:20].[Na+]>O>[CH3:17][C:12]1([CH3:16])[C:13]([CH3:14])([CH3:15])[CH:10]1[C:11]([O:8][CH:1]([C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Reactant: CC1(C)C(=O)C(Cl)C1(C)C
Agent: [Na+]
Solvent: O
Product: CC1(C)C(C(=O)OC(C#N)c2ccccc2)C1(C)C
Temperature: 23 °C

Procedure:
A 50ml round-buttomed flask provided with a magnetic stirrer was charged with 10 mmol of benzaldehyde, 10 mmol of 2-chloro-3,3,4,4-tetramethylcyclobutanone, 12 mmol of sodium cyanide, 20 ml of a solvent and 1 ml of water. The reaction mixture was stirred vigorously at a temperature of 23° C. Two experiments ware carried out in this manner. Table II states the solvents used and presents the yields of the alpha-cyanobenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH:25]([NH2:30])[CH2:24][C:23]1([CH3:32])[CH3:31]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:25]2[CH2:24][C:23]([CH3:31])([CH3:32])[N:22]([CH3:21])[C:27]([CH3:29])([CH3:28])[CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1C(C)(C)CC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1(C)C

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1,2,2,6,6-pentamethylpiperidin-4-amine (20.4 mg, 0.12 mmol). The title compound was obtained as a solid (16.9 mg, 34% yield). MS m/z: 503.09, 505.08 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([CH2:15][N:16]2[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[C:18]([Cl:33])[C:17]2=[O:34])=[CH:13][N:12]=[C:11]([CH3:35])[N:10]=1.C(N(CC)CC)C.C([O:46][CH2:47][C:48](Cl)=[O:49])(=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:33][C:18]1[C:17](=[O:34])[N:16]([CH2:15][C:14]2[C:9]([NH:8][C:47](=[O:46])[CH2:48][OH:49])=[N:10][C:11]([CH3:35])=[N:12][CH:13]=2)[C:21]([CH3:22])=[CH:20][C:19]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ncc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(N)n1
Reactant: CC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(NC(=O)CO)n1
Temperature: -20 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
To a chilled solution of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one trifluoroacetate (0.200 g, 0.38 mmol) in DMF (20 mL) and a catalytic amount of DMAP was added triethylamine (0.064 mL, 0.38 mmol). The reaction stirred at −20° C. and acetoxyacetyl chloride (0.082 mL, 0.76 mmol) was added. The reaction stirred cold for 15 minutes and then allowed to warm up to room temperature for 3 hours. The reaction was monitored by LR-ES MS m/z=466. The reaction was incomlete after 3 hours. Added acetoxyacetyl chloride (0.05 mL, 0.466 mmol), and triethylamine (0.2 mL, 1.43 mmol) to the reaction mixture and continued to stir overnight at room temperature. The next morning the reaction heated at 65° C. for 3 hours. The solvent was removed in vacuo and 1N LiOH (2.5 mL) was added to the residue. The reaction was heated at 60° C. for 5 hours. The reaction was diluted with acetonitrile and water (1:1) and purified by reverse phase HPLC in 10-90% CH3CN/water (30 minute gradient) at a flow rate of 50 mL/min. The appropriate fractions were freeze dried to afford the desired product (0.020 g, 9%). 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.6 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.26 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 465.1161 (M+H calculated for C21H20N4O4F2Cl requires 465.1136).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.[BH4-].[Na+].CCN(C(C)C)C(C)C.[CH3:35][C:36]([O:39][C:40]([O:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])([CH3:38])[CH3:37]>CO.C(Cl)Cl>[C:36]([O:39][C:40](=[O:41])[N:12]([CH2:11][C:10]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:8]([C:7]([CH3:18])([CH3:17])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[CH2:22][CH:19]1[CH2:20][CH2:21]1)([CH3:38])([CH3:37])[CH3:35].[CH3:38][C:36]([O:39][C:40]([O:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])([CH3:35])[CH3:37]
Reactant: O=CC1CC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol) and cyclopropancarboxaldehyde (0.784 mL, 10.5 mmol) in MeOH (70 mL) was heated to reflux for 4 h. The mixture allowed to cool to rt. NaBH4 (397 mg, 10.5 mmol) was added in portion, and the mixture was stirred for 1 h at rt. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-cyclopropylmethyl-amine. This crude product was dissolved in CH2Cl2 (70 mL). DIPEA (3.60 mL, 21.0 mmol) and Boc2O (2.30 g, 10.5 mmol) were added. The mixture was stirred at rt for 2 h, and the mixture was diluted with CH2Cl2 (30 mL). The resulting mixture was washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane→EtOAc/heptane 10:90) yielded the title compound contaminated with Boc2O (3.60 g, quantitative yield). LC-MS: tR=1.25 min; ES+: 440.80.
Reaction SMILES: OC[CH:3]([S:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19]OC(=O)C1C=CC(CCl)=CC=1>C1(C)C=CC=CC=1>[C:9]1([CH:4]2[CH2:3][S:10][C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[O:18]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:19]=1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: OCC(Sc1cc(O)ccc1O)c1ccccc1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)SCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol (0.83 g) in dry toluene (60 ml) was stirred with Amberlyst 15 (0.5 g) at 60° C. until disappearance of the starting material. After the mixture was filtered and solvent evaporated the crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7, 3.0 Hz), 5.10 (dd, 1H, J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0, 9.6 Hz), 3.06 (dd, 1H, J 13.0, 1.9 Hz).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:8](C=O)[C:7]([OH:12])=[CH:6][CH:5]=1.[CH2:13](Br)[CH:14]=[CH2:15].ClC1C=C(C=CC=1)C(OO)=[O:22]>CN(C=O)C.CCCCCC>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:11][C:8]=1[OH:22])[CH:14]=[CH2:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 14 g (0.35 mole) of 60% sodium hydride/mineral oil dispersion in a two liter flask was added 500 ml of hexane. The mixture was swirled briefly, the solid allowed to settle and the supernatant liquid decanted. DMF (800 ml) was added, followed by a solution of 47 g (0.30 mole) of 5-chlorosalicylaldehyde in 50 ml of DMF. The mixture was stirred at room temperature under nitrogen for 30 minutes, then 54.5 g (0.45 mole) of allyl bromide was added. The mixture was heated at 65° C. under nitrogen for 18 hours. The solvent was then removed in vacuum and replaced with one liter of methylene chloride. This solution was washed with water and with saturated brine and dried over sodium sulfate. It was then filtered and 150 g (0.50-0.75 mole) of 57-86% m-chloroperoxybenzoic acid added and the mixture stirred at room temperature overnight. The reaction was filtered and the filtrate washed with three 400 ml portions of saturated aqueous sodium bicarbonate and with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was dissolved in 750 ml of methanol and stirred with 150 g of basic alumina for 15 hr. The mixture was then filtered and evaporated in vacuum and the crude product partitioned between 500 ml each of 1N NaOH (aq) and methylene chloride. The organic phase was extracted with an additional 500 ml of base, and the combined basic extracts back-washed with 500 ml of methylene chloride. Finally, the basic extracts were carefully acidified with concentrated HCl and extracted with two 400 ml portions of methylene chloride. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to give 37.3 g of the title compound as a yellow oil. 1H (CDCl3) singlet, 6.90δ(1 H); quartet, 6.70δ(2 H); singlet, 6.20δ(1 H, OH);.multiplet, 5.97δ(1 H); quartet, 5.25δ(2 H); doublet, 4.50δ(2 H).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([NH:20][C:21]([C:23]1[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[CH:26]=[CH:25][CH:24]=1)=[O:22])[CH2:13]2.CN(C)C=O.Cl>O1CCCC1>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@H:14]([N:20]1[CH:1]=[C:31]3[CH2:30][CH2:29][CH2:28][C:27]4[C:32]3=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]1=[O:22])[CH2:13]2
Reactant: [Li]CCCC
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2c1CCCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=c1c2cccc3c2c(cn1[C@@H]1CN2CCC1CC2)CCC3
Temperature: -10 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of n-butyllithium in hexane (60 mmol) was added dropwise at -70° C. to a solution of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro1-naphthalenecarboxamide (7.70 g, 21 mmol), prepared as in Example 3, in dry tetrahydrofuran (400 mL). The reaction mixture was stirred at -10° C. for one hour, cooled to -70° C., and dimethylformamide (100 mmol) added in one portion. The reaction mixture was allowed to warm to room temperature over 1.5 hours, then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was washed with ethyl acetate, then made basic with 10N aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and evaporated to give 7.58 g (95% yield) of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro1H-benz[de]isoquinolin-1-one as white crystals; m.p. 117°-118° C.; [α]D25 +43.2° (c=0.98, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]1)[CH3:27].C(C1C=CC(C2C=NN(C3C=CC(C(O)=O)=CN=3)C=2O)=C(C)C=1)#N>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCN[C@H](C)C1
Agent: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-3-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.33 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.33 (d, J=2.53 Hz, 3 H) 2.95-3.26 (m, 4 H) 3.34-3.55 (m, 2 H) 3.73-4.28 (m, 3 H) 7.64 (br. s., 1 H) 7.71-7.78 (m, 1 H) 7.93-8.68 (m, 4 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6]O)[C@@H:3]([OH:4])[CH2:2]1.[N-:18]=[N+:19]=[N-:20].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>>[N:18]([CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
Thymidine (2.42 g, 10.0 mmol) was dried under reduced pressure for 1 hour. Thereto was added 2.20 g (4.5 eq) of lithium azide, and the mixture was further dried for 1 hour. Distilled DMF (50 ml) was added to the reaction vessel, and the pressure was reduced for about 10 minutes with stirring. Further, 3.41 g (1.3 eq) of triphenylphosphine was added and, after confirmation of the dissolution of triphenylphosphine, 4.97 g (1.5 eq) of carbon tetrabromide was added to initiate the reaction. On that occasion, the solution turned yellow. After 40 minutes, the completion of the reaction was confirmed by TLC, and the reaction was quenched with methanol. The solution was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase MeOH:CHCl3=1:9) to give 5′-azido-5′-deoxythymidine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: NC(=O)c1cccc(Cl)c1Cl
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1cccc(Cl)c1Cl

Procedure:
starting from 2,3-dichlorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 2,3-dichlorobenzimidate as an oil; mass spectrum: 216 (16), 189 (20), 182 (9), 173 (100), 172 (56);
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:28]N1C(=O)CCC1=O>O1CCCC1>[I:28][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I

Procedure:
5-Amino-2-nitrobenzotrifluoride (16.25 g, 78.8 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (100 mL) and to this solution was added p-toluenesulfonic acid (0.18 g, 0.95 mmol) and N-iodosuccinimide (17.8 g, 78.8 mmol). The solution was stirred all day. N-iodosuccinimide (0.78 g, 3.47 mmol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) were then added and the solution stirred overnight at room temperature under nitrogen. The solution was concentrated under vacuum to a small volume. Water (200 mL) was added to the reaction mixture and a brown solid precipitated out. The solid was filtered and washed with water, then dissolved in ethyl acetate (100 mL) and diethyl ether (60 mL). The organic solution was washed with 10% sodium thiosulfate solution (50 mL). This created an emulsion which was alleviated by adding diethyl ether and water and filtering undissolved material. The layers were separated and the organic layer was washed with 10% sodium thiosulfate solution (50 mL), water was then added to the aqueous layer and the layers separated. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound as a brown solid that was dried under vacuum.