Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1)=O.[Br-].[O:27]([CH2:34][CH2:35][CH2:36][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+]>O1CCCC1.CS(C)=O>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([C:2]([CH3:1])=[CH:36][CH2:35][CH2:34][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: c1ccc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenone (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phenoxypropyltriphenylphosphonium bromide (7.18 g., 0.15 M) in dimethylsulfoxide (450 ml.) is added dropwise over 1.75 hours to a suspension of 50% sodium hydride (7.89 g., 0.165 M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0°-5° C. After stirring for 4 hours at 0°-5° C. the reaction is allowed to warm to room temperature and is then carefully stirred into ice water (2000 ml.), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (5×400 ml.). The combined organic phases are washed with saturated sodium chloride solution (3×300 ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine oxide. Filtration, followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane consisting of 30% to 100% benzene. From the middle fractions 51 g. (75%) of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene is isolated as an oil; Rf =0.8 (silica gel, 2-benzene:1-hexane); m/e - 450 (m+).
Reaction SMILES: S(O[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]OS(=O)(=O)O)(O)(=O)=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([N:19]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=S(=O)(O)OCCNCCOS(=O)(=O)O
Product: C1CN(C2CC2)CCN1
Temperature: 50 °C

Procedure:
A carousel tube was charged with sulfuric acid mono-[2-(2-sulfooxy-ethylamino)-ethyl]ester (1 g) and D2O (3 mL). To the resulting stirred solution was added then added cyclopropylamin (0.7 mL). The resulting mixture was observed to form a stirrable thick slurry, which was heated at 50° C. overnight. Comparison of the 1H NMR of the title compound with the 1H NMR of the dihydrochloride salt of the title compound confirmed that the title compound was prepared and present in the resulting solution.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[CH2:18])[C:15](Cl)=[O:16].O>C(OCC)C>[CH3:13][C:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])[CH:15]=[O:16]
Reactant: C1CCNC1
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C=O)N1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2](=[CH2:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C@H:16]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:41])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)=[CH:11][CH:10]=1)[NH2:8].[F:44][CH2:45][C:46]([O:49][C:50](=[O:54])[O:51][CH2:52]Cl)([CH3:48])[CH3:47].C(=O)([O-])[O-].[Rb+].[Rb+]>CN(C)C(=O)C>[F:44][CH2:45][C:46]([O:49][C:50](=[O:54])[O:51][CH2:52][O:22][C:20]1[N:19]([C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)[N:18]=[C:17]([C@H:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH2:8])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:43])=[O:42])=[CH:10][CH:11]=2)[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:41])[N:21]=1)([CH3:48])[CH3:47]
Reactant: CC(C)(CF)OC(=O)OCCl
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCO)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [Rb+]
Solvent: CC(=O)N(C)C
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)(C)CF)n(-c3ncccn3)n2)c2cc(OC)cc(OCCO)c2F)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
Under nitrogen atmosphere, a mixture of [1-amino(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}phenyl)methylene]carbamic acid 2-methylallyl ester (Example 44, 474 mg), carbonic acid chloromethyl ester 2-fluoro-1,1,dimethylethyl ester (295 mg), rubidium carbonate (166 mg) and N,N-dimethylacetamide (15 mL) was stirred at 85° C. for 60 minutes. After cooling the mixture to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography (mixed solvent of methanol-water containing 0.1% of acetic acid), and then the obtained compound was further purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol) to obtain the captioned compound (98 mg).
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[C:26]3[C:27]([Cl:33])=[N:28][CH:29]=[C:30]([F:32])[CH:31]=3)=[N:17][C:16]=12)=[O:11])(C)(C)C.Cl>CO>[Cl:33][C:27]1[C:26]([C@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[C:18]2[CH:19]=[CH:20][N:15]3[N:14]=[CH:13][C:12]([C:10]([NH:9][O:8][CH2:7][CH2:6][OH:5])=[O:11])=[C:16]3[N:17]=2)=[CH:31][C:30]([F:32])=[CH:29][N:28]=1
Reactant: CC(C)(C)OCCONC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)—N-(2-tert-butoxyethoxy)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 224, 57 mg, 0.120 mmol) was treated with HCl (4 N dioxane, 1.49 mL, 5.98 mmol), followed by two drops of MeOH to make a clear colorless solution. After stirring 30 minutes at ambient temperature, the reaction was concentrated and dried to yield the title product as white solid, assuming quantitative yield. LCMS (apci) m/z=421.0 (M+H)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1.[CH2:13](Br)[CH:14]=[CH2:15]>>[Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:15][CH:14]=[CH2:13])[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)c1nc(O)cc(CCl)n1
Reactant: C=CCBr
Product: C=CCOc1cc(CCl)nc(C(C)C)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-isopropyl-pyrimidine is reacted with allylbromide analogously to the process described in Example 86 in order to produce 4-chloromethyl-2-isopropyl-6-(2-propenyloxy)-pyrimidine which is required as the starting material in Example 24. This product is obtained in the form of an oil, 1H-NMR (CDCl3): 1.30 (d, 2×CH3), 3.15 (m, CH), 4.55 (s, CH2), 4.93 (m, CH2), 5.37 (m, CH2), 6.12 (m, CH), 6.75 (s, CH).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](Cl)=[O:29])[C:24]([CH3:31])=[N:23]1.O>O1CCCC1>[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]([CH3:12])[CH2:3][C:2]3([CH3:13])[CH3:1])=[O:29])[C:24]([CH3:31])=[N:23]1
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Reactant: CC1CC(C)(C)c2cccc(N)c21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 1.75 g of 1,1,3-trimethyl-4-aminoindane and 2 ml of triethylamine in 50 ml of tetrahydrofuran was with stirring at room temperature added dropwise a solution of 1.73 g of 1,3,5-trimethylpyrazole-4-carboxylic acid chloride in 10 ml of tetrahydrofuran, followed by stirring at room temperature for 12 hours. Then, the reaction solution was poured into a cold water to result in separation into two layers. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was recrystallized with toluene to obtain 2.55 g of 1,3,5-trimethyl-N-(1,1,3-trimethylindane-4-yl)pyrazole-4-carboxamide (mp 176.2° C.).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:10]1([C:8](=[CH2:9])[CH2:7][OH:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(CO)c1ccccc1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
To a well stirred solution of tert-butyl-dimethyl-(2-phenyl-allyloxy)-silane (1.3 g, 5.23 mmol) in tetrahydrofuran (10 mL) is slowly added a solution of a 1 N tetrabutylammonium fluoride in tetrahydrofuran (10.5 mL, 10.5 mmol). The reaction is allowed to stir for 20 min, quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted several times with ethyl acetate The organic layers are combined, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (10% ethyl acetate in hexanes) to yield 700 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:22][C:23]1[S:24][C:25]([CH2:28]Cl)=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:28][C:25]3[S:24][C:23]([Cl:22])=[CH:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 2.2 g (7.5 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 1.1 mL (8.8 mmol) of 2-chloro-5-chloromethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 2.2 g (68% of yield) of 4-[1-(5-chloro-thiophen-2-ylmethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1>C(O)C.[Pt]>[CH:28]1([O:27][C:3]2[CH:2]=[CH:7][N:6]=[C:5]([CH:8]([N:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)(=[O:17])=[O:18])[CH2:12][CH2:11]3)[CH3:9])[N:4]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(OC4CCCC4)n3)CC2)cc1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nccc(OC4CCCC4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-Bromo-4-cyclopentyloxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine (30.0 g, 0.06 mmol) in ethanol (10 ml) was added 10 mg platinum on carbon (0.5% wt). The solution was degassing three times and the hydrogen gas was introduced through a hydrogen balloon. The reaction was heated to reflux for 18 hours at room temperature. The solution was filtrated through a celite column and the solvent was evaporated. Water (5 ml) was then added to the solution and the mixture was extracted with dichloromethane (10 ml). The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×30 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give the 4-Cyclopentyloxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine (Yield 15 mg, 60%. 1HNMR (400 MHz, CDCl3): δ 1.60-1.54 (m, 2H), 1.64 (d, J=6.82 Hz, 3H), 1.76-1.67 (m, 4H), 1.96-1.84 (m, 2H), 3.35-3.12 (m, 4H), 3.50-3.35 (m, 2H), 3.05 (s, 3H), 4.41 (q, 1H, J=13.64, 7.33 Hz), 5.38 (m, 1H), 6.60 (d, J=5.81, 1H), 6.94 (d, J=8.84, 2H), 7.56 (d, J=8.84, 2H), 8.32 (d, J=5.81, 1H). MS m/z calc. 446.2 found (ESI); 447.2 (M+1)+. Retention time 2.76 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20]S[CH2:18]1.ClC1C=C(C=CC=1)C(OO)=O.[S:33]([O-:36])([O-])=[O:34].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20][S:33](=[O:36])(=[O:34])[CH2:18]1
Reactant: CCOC(=O)c1cc(Br)cc2c(CC3CCSC3)c[nH]c12
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Reaction time: 5 h
Yield: 42.56 %

Procedure:
To a solution of ethyl 5-bromo-3-(tetrahydro-3-thienylmethyl)-1H-indole-7-carboxylate (7.61 g, 20.73 mmol) in dichloromethane (150 mL) was added portionwise 3-chlorobenzoperoxoic acid (10.69 g, 62.19 mmol) at room temperature. The resulting solution was stirred for 5 h. Sodium sulfite was added, and the mixture was washed with water, extracted with DCM (3×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column on sillal gel (petroleum: ethyl acetate=10:1 to 5:1 to 2:1), giving 3.52 g (42.56%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([BH3-])#N.[Na+].C=O>>[C:24]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][C:10]([N:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH3:30])([CH3:11])[CH3:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CCNC(C)(C)COC(c2ccccc2)c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1ccc(CCN(C)C(C)(C)COC(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared as described in Example 5, Method A, using 1-diphenylmethoxy-2-(4-methoxyphenethylamino)-2-methylpropane (see Example 2) and sodium cyanoborohydride/formaldehyde. The title compound was obtained as a colourless oil (200 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.[Cl:20][CH2:21][C:22]([CH2:24]Cl)=O.C(=O)([O-])O.[Na+].ClC(Cl)C(=O)C>O1CCOCC1>[Cl:20][CH2:21][C:22]1[N:1]=[C:2]2[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:5]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:4]=3[N:3]2[CH:24]=1
Reactant: NC1=Nc2ccc(I)cc2C(c2ccccn2)=NC1
Reactant: O=C(CCl)CCl
Agent: CC(=O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Temperature: 100 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
A, solution of 2.3 g of 2-amino-7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine and 0.87 g of 1,3-dichloroacetone in 65 ml of dioxan was treated with 0.6 g of anhydrous sodium hydrogen carbonate and the mixture was stirred at 100° C. for 24 h. A further 0.09 g of dichloroacetone and 0.06 g of anhydrous sodium hydrogen carbonate were added and the mixture was stirred at 100° C. for a further 5 h. The mixture was evaporated in a vacuum and the residue was partitioned between chloroform and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with chloroform. The chloroform extracts were dried over sodium sulphate and chromatographed over 200 g of silica gel. With dichloromethane/ethanol 197:3 there were eluted small amounts of impurities, with dichloromethane/ethanol 195:5 there were eluted 1.3 g of the desired product. After recrystallization from ethyl acetate there were obtained 1.21 g of 2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo [1,2-a][1,4]benzodiazepine of m.p. 216° C. (dec.).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:6]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)#[CH:5]
Reactant: COC(=O)COc1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A solution of methyl (4-trimethylsilylethynylphenoxy)acetate (20.00 g, 76 mmol) in dichloromethane (400 mL) was deaerated with argon. Tetrabutylammonium fluoride 24.40 g, 91 mmol) was added, and the mixture was stirred for 30 min at ambient temperature. The solution was washed with 10% aqueous citric acid (200 mL), water (5×400 mL), dried over Na2SO4 and concentrated. The residue was dissolved in diethyl ether and passed through a column filled with silica gel. Evaporation of diethyl ether yielded the title compound as a solid (12.63 g, 83%) which was chromatographically and spectroscopically identical with material synthesized previously (Takalo, H., Hemmila, I., Sutela, T. and Latva, M, 1996, Helv. Chim. Acta, 79, 789). Rf (A) 0.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([CH2:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=O)[C:5](=O)[CH3:6].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[N:29]([CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:5]=1[CH3:6])=[O:21]
Reactant: NCC1CCCCC1
Reactant: COC(=O)C(CC(=O)c1cc(OC)ccc1OC)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc(-c2cc(OC)ccc2OC)n(CC2CCCCC2)c1C
Temperature: 25 °C

Procedure:
To a solution of 2 g of -[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid methyl ester in methanol was added 0.88 ml of cyclohexanemethylamine and 40 mg of p-toluene sulfonic acid. The reaction mixture was then heated at reflux for 2 days. After such time the reaction mixture was allowed to cool to room temperature before being concentrated in vacuo and purified by column chromatography to give 2.3 g of the title compound; MS (ISP) 372.2 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[CH3:15][C:14]([CH3:18])=[CH:13][C:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:11]
Reactant: CON(C)C(=O)c1cccnc1
Reactant: CC(C)=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CC(=O)c1cccnc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of N-methoxy-N-methylnicotinamide (500 mg, 3.0 mmol) in anhydrous THF (3.5 mL) under nitrogen at −78° C. add 2-methyl propenyl magnesium bromide (12 mL, 6.0 mmol, 0.5 M in THF) dropwise. After one hour at −78° C., allow to reach room temperature. After 2 h, add saturated aqueous ammonium chloride. (10 mL) and water (2 mL). Extract with ethyl acetate three times, dry the combined organic phases with anhydrous sodium sulfate and concentrate to obtain 442 mg (91%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][O:18][CH3:19])[C:4]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26].C(O)(=O)C.C(Cl)Cl>ClCCCl>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][NH:26][CH2:6][C:5]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:4]=1[N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][O:18][CH3:19]
Reactant: CCN(CCOC)c1ccc(C(F)(F)F)cc1C=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
2-[Ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.7 g), 3,5-bis-trifluoromethyl-benzylamine (4.23 g), acetic acid (1.15 ml) are dissolved in 1,2-dichloroethane (30 ml), and thereto is added triacetoxy sodium borohydride (5.68 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.38 g). MS (m/z): 503 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[Pd].CO.[OH-].[OH-].[Pd+2]>[C:1]1([CH:7]2[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][CH2:15][NH:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccnc1-c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCCNC1c1ccccc1
Reaction time: 72 h

Procedure:
A mixture of methyl 2-phenylnicotinate (9.43 g, 44.3 mmol) and palladium on carbon (10%; 2.5 g) in methanol (150 ml) containing hydrochloric acid (5M, 25 ml) was shaken for 72 hours under an atmosphere of hydrogen at 50 psi. Palladium hydroxide on carbon (20%; 1.0 g) was then added and hydrogenation resumed for a further 24 hours. A further portion of palladium hydroxide on carbon (1.0 g) was added, and hydrogenation continued for 24 hours more, until thin layer chromatography indicated no more starting material to be present. The suspension was filtered and evaporated to dryness, leaving the desired product as the hydrochloride salt. A small portion of this was basified with sodium carbonate to liberate the free base, isolated as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 1.47-1.53 (1H, m), 1.78-1.90 (2H, m), 1.91-1.99 (1H, m), 2.81 (1H, dt, J 12.4, 2.9 Hz), 2.96-2.99 (1H, m), 3.31-3.36 (1H, m) 3.43 (3H, s), 3.95 (1H, d, J 3.4 Hz), 7.18-7.32 (5H, m).