Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: NCCCCSc1cccc2nccn12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCSc1cccc2nccn12)c1cccc2ccccc12
Yield: 53.3 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (300 mg, 1.36 mmoles) and triethylamine (0.29 ml, 2.08 mmoles) in methylene chloride (15 ml) was added 1-naphthalenesulfonyl chloride (307 mg, 1.35 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 296 mg of the desired product (53.0%, colorless solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Br:16]Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([Br:16])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: BrBr
Solvent: ClCCl
Product: CCCCC(Br)(C(=O)OCC)C(=O)OCC
Yield: 81.9 %

Procedure:
Diethyl-n-butylmalonate (32.2 gm) was dissolved in methylene chloride (200 ml) and treated, dropwise, with a solution of bromine (24.0 gm) dissolved in methylene chloride (25 ml). The resultant mixture was stirred (1 hour, room temperature) whereupon an orange coloration persisted. The solvent was removed under vacuum, and the residue distilled under high vacuum to give the desired product as a clear oil (boiling point temperature 105° C. to 110° C.; 36.0 gm). 1H NMR (CDCl3): δ=0.89-0.92 (t, 3H); 1.25-1.29 (t, 6H); 1.35-1.37 (m, 4H); 2.2-2.26 (m, 2H); 4.23-4.29 (q, 4H); m/z=295 and 297 (M+).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][CH:46]=[C:39]([CH3:38])[CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1cccc(CN)c1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C)c4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-methyl benzylamine, m.p. 165-166° C. MS [(+)ESI, m/z]: 556 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.72; H, 5.96; N, 7.54.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[C:19]1([NH:25][C:26]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Yield: 62.5 %

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.216 g, 0.896 mmol) and phenyl isocyanate (0.222 g, 1.86 mmol) were combined in acetonitrile (14 mL) and refluxed overnight. Phenyl isocyanate (0.106 g, 0.896 mmol) was added and the reaction was refluxed 2 hours more. Upon cooling a tan solid precipitated which was collected and recrystallized from methanol/ethyl acetate to give 0.202 g (62%) of the title product; mp 213°-214° C. Analysis calculated for C22H24N4O: C, 73.31; H, 6.71; N, 15.54. Found: C0 73.03; H, 6.55; N, 15.22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:24][CH3:25])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18 mL) is added ethyl iodide (0.36 mL) and the mixture is stirred for approximately 15 hours at room temperature. The solution is then filtered, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The separated aqueous layer is further extracted twice with ethyl acetate, and the pooled organic extracts are washed successively with 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br>C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Reaction time: 0.01 h
Yield: 60 %

Procedure:
4-Methylbenzophenone, 750 g (3.82 moles), was added to a 5 liter Morton flask equipped with an overhead stirrer and dissolved in 2850 ml of benzene. The solution was then heated to reflux, followed by the dropwise addition of 610 g (3.82 moles) of bromine in 330 ml of benzene. The addition rate was approximately 1.5 ml/min and the flask was illuminated with a 90 watt (90 joule/sec) halogen spotlight to initiate the reaction . A timer was used with the lamp to provide a 10% duty cycle (on 5 seconds, off 40 seconds), followed in one hour by a 20% duty cycle (on 10 seconds, off 40 seconds). At the end of the addition, the product was analyzed by gas chromatography and was found to contain 71% of the desired Compound VI, 8% of the dibromo product, and 20% unreacted 4-methylbenzophenone. After cooling, the reaction mixture was washed with 10 g of sodium bisulfite in 100 ml of water, followed by washing with 3×200 ml of water. The product was dried over sodium sulfate and recrystallized twice from 1:3 toluene : hexane. After drying under vacuum, 635 g of Compound VI were isolated, providing a yield of 60% and having a melting point of 112°-114° C. Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) aromatic protons 7.20-7.80 (m, 9 H) and benzylic protons 4.48 (s, 2 H). The final compound was stored for use in the preparation of a photoactivatable chain transfer agent as described in Example 7.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48]C(C)=O)[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].CO.C[O-].[Na+].C(O)(=O)C>O>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([OH:48])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32

Procedure:
15.8 mg. azadirachtin A (2.2×10-5 mole) were dissolved in 100 μl. methanol. To this solution were added three times 100 μl. amounts of a methanolic solution of sodium methylate (0.6 g. sodium in 50 ml. methanol). After each addition of 100 μl. methylate solution, there was a pause of 2 minutes and then a testing with HPLC whether azadirachtin A was still present. After the disappearance of azadirachtin A, the reaction mixture was neutralised with acetic acid, diluted with water and extracted with chloroform. The purification from by-products took place by semipreparative HPLC on a 20 cm. RP-18 column of 9 mm. internal diameter, using the elution agent methanol/ water (2:3 v/v); detection at 215 nm; yield 2.4 mg. (15.2% of theory).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[NH:8][CH2:7][C:6]=2[CH:18]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[N:8]([C:19](=[O:21])[CH3:20])[CH2:7][C:6]=2[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)NCc1cc(Br)ccc1CO2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1Cc2cc(Br)ccc2COc2ccc(Cl)cc21
Temperature: 70 °C
Yield: 96 %

Procedure:
To a stirred solution of 9-Bromo-2-chloro-11,12-dihydro-6H-5-oxa-12-aza-dibenzo[a,e]cyclooctene Example 347E (3.8 mg, 11.7 umol) and DMAP (cat. amount) in toluene (0.3 mL) was added acetic anhydride (0.10 mL, 1.05 mmol) and pyridine (0.05 mL, 46.9 umol). This reaction mixture was heated at 70° C. for 30 minutes, cooled to room temperature and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 4 g column, eluted with Hexane-CH2Cl2, detected at 220 nM to give 4.1 mg of 1-(9-Bromo-2-chloro-6,11-dihydro-5-oxa-12-aza-dibenzo[a,e]cycloocten-12-yl)-ethanone Example 347E in 96% yield. HPLC Rt=3.56 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=366.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:24]([F:27])([F:26])[F:25])([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:24]([F:27])([F:25])[F:26])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate (1 g, 2.6 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 ml). The solution was stirred for 2 hours at room temperature and then concentrated under vacuum. The crude material was diluted with water (50 ml), adjusted pH to 9 with sodium bicarbonate (saturated aqueous), and extracted with dichloromethane (3×100 ml). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford N-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine as a yellow powder (800 mg, crude); (ES, m/z): [M+H]+ 290.1; 1H NMR (300 MHz, DMSO-d6): δ 8.08 (d, J=9.0 Hz, 1H), 7.20-7.80 (br s), 7.60 (d, J=7.8 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.91 (dd, J=2.4, 9.0 Hz, 1H), 3.70 (m, 1H), 3.22 (d, J=12.6 Hz, 2H), 2.91 (dd, J=10.5, 11.4 Hz, 2H), 1.99 (d, J=11.4 Hz, 2H), 1.52 (m, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C.O[Li].O>C1COCC1.O>[CH2:36]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li]O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(NCc2ccccc2)nc1-c1c[nH]c2ncc(C(F)(F)F)cc12
Reaction time: 1 h

Procedure:
2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (50 mg, 0.096 mmol) was heated with benzylamine (21 uL, 0.19 mmol, 2.0 Eq.) and DIPEA (50 uL, 0.29 mmol, 3.0 Eq.) in THF (2 mL) under microwave conditions at 100° C. for 10 minutes. The reaction was concentrated and the residue dissolved in THF (5 mL). LiOH.H2O (20 mg, 0.48 mmol, 5.0 Eq.) in water (1 mL) was added and the reaction stirred for 1 hour. The reaction mixture was concentrated and the residue treated with MeOH. The obtained white precipitate was isolated by filtration and dried under vacuum (13 mg, 36% over 2 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
1-Bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and 3-Hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmol) were added. The reaction mixture was then heated to 100° C. for 2 h the reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. Solvent dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. (7.2 g, 79%)
Reaction SMILES: [OH:1][C@@:2]1([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C@H:6]2[CH2:8][CH2:9][C@@H:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:29][NH2:30]>CCO.C(Cl)Cl>[CH3:29][NH:30][CH2:17][CH2:16][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2C=C3c2ccccc2)cc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4.28 g of rac-toluene-4-sulfonic acid (1R*,2R*,4R*)-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl ester (see Example 1, procedures P1.1 and P1.2) were dissolved in a 8 M solution of MeNH2 in EtOH (54 mL). The mixture was stirred overnight at 40° C., diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated to give 2.73 g of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8])[CH2:4][CH3:5].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][N:6]([CH2:3][CH2:4][CH3:5])[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: BrCCCCBr
Reactant: CCCNS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCCBr)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95.5 %

Procedure:
NaH (60%, 0.70 g, 17 mmol), 65 (3.5 g, 14.5 mmol), and 1,4-dibromobutane (37.6 g, 174 mmol) in DMF (40 mL) were combined and worked up by the method of 43. Excess 1,4-dibromobutane was removed by a Kugelrohr apparatus under high vacuum. Column chromatography (7:1 hexane/EtOAc) produced 5.21 g (95%) of 67 as an oil: NMR δ 0.79 (t, 3 H, J=7), 1.46-1.54 (m, 2 H), 1.64-1.78 (m, 4 H), 2.30 (s, 3 H), 2.60 (s, 6 H), 3.11 (t, 2 H, J=7), 3.21 (t, 2 H, J=7), 3.31 (t, 2 H, J=7), 6.93 (s, 2 H). Anal. (C16H26BrNO2S) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(NC(N1CCC(CN(CC)C2CCC3C(=CC(NC(=O)C4C=CC(S(C)(=O)=O)=CC=4)=CC=3)C2)CC1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:29]([C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH2:28][CH:19]([N:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:16][CH2:17][CH3:18])[CH2:20]2)=[CH:25][CH:24]=1)([O-:31])=[O:30]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as in Example 1 (1.12 g, 2.60 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (845 mg).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[CH:4]=[N:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(I)c3n2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
A mixture of 8-iodo-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.65 g, 3.61 mmol), trimethylsilylacetylene (0.9 mL, 6.5 mmol) and triethylamine (1.51 mL, 10.8 mmol) in N,N-dimethylformamide (10 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (0.76 mg, 0.11 mmol), PPh3 (57 mg, 0.22 mmol) and CuI (7 mg, 0.04 mmol) were added. Stirring was continued at 90° C. for 3.5 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), evaporated and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to give 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-8-trimethylsilanylethynyl-imidazo[1,5-a]pyrimidine (0.82 g, 53%) as a brown solid, which was dissolved in THF (10 mL) and MeOH (10 mL), while stirring at 0° C. potassium carbonate (26 mg, 0.19 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (50 mL) and extracted with TBME (2×100 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from diethyl ether/hexane to give 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (0.54 g, 42%) as a brown solid. MS (EI) 355.1 [(M)+]; mp 163° C.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1.O>C1C=CC=CC=1>[C:2]([C:3](=[CH:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1

Procedure:
652 mg (3.00 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 0.340 ml (3.00 mmol) of 3-chlorobenzaldehyde and 0.030 ml (0.30 mmol) of piperidine were heated under reflux in 25 ml of benzene overnight while water was removed. Benzene was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1ccc(CBr)cn1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (6.1 g, 3.44 mmol) and benzoyl peroxide (218 mg, 0.09 mmol) were added successively to a solution of 2-chloro-5-methyl-pyridine (4.0 g, 3.13 mmol) in carbon tetrachloride (20 mL) and refluxed for 90 min. The reaction mixture was cooled to room temperature, water added and the organic layer separated. The organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and filtered. The resultant solution of 5-bromomethyl-2-chloro-pyridine was used as such for the next step.