Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH2:13])[CH3:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:36]3[N:37]=[C:38]4[C:44]([C:45](O)=[O:46])=[CH:43][N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:39]4=[N:40][CH:41]=3)=[N:31][N:32]2[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:15][C:4]([F:14])([F:3])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH:13][C:45]([C:44]2[C:38]3[C:39](=[N:40][CH:41]=[C:36]([C:30]4[C:29]5[C:33](=[CH:34][C:26]([F:25])=[CH:27][CH:28]=5)[N:32]([CH3:35])[N:31]=4)[N:37]=3)[N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=2)=[O:46])[CH3:12])[CH:6]=1
Reactant: C[C@@H](N)c1cc(C(F)(F)F)ccn1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of (R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethylamine dihydrochloride (89 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 122 mg (88%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide as a white solid.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(Cl)[Cl:24]>>[ClH:24].[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:22]
Reactant: NC1CCCCCC1
Reactant: ClCCl
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1CCCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
In a 2 liter erlenmeyer flask was placed 49.8 g (0.44 mole) of cycloheptylamine, 66.6 g (0.66 mole) of triethylamine and 1 liter of methylene chloride. The resulting solution was stirred, while 73.4 g (0.44 mole) of ethyl bromoacetate was added dropwise. The mixture was stirred for 16 hours at room temperature and then filtered. The filtrate was washed with water (3×200 mL), dried over magnesium sulfate, filtered and solvent was removed by rotary evaporation. The resulting oil was run through a short column with the eluent being first methylene chloride and then methylene chloride containing 0.25% ammonium hydroxide and 2.5% methanol. A small amount of a fast moving impurity was separated from the bulk of the product. Solvent was again removed from the product by rotary evaporation and the resulting oil was dissolved in ether, dried over magnesium sulfate and filtered. Hydrogen chloride saturated ether was then added to the filtrate and the resulting precipitate was filtered off and dried in vacuum to give 47.8 g (47%) of N-cycloheptylglycine ethyl ester hydrochloride.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.[C:12]1(C)[C:13](S(O)(=O)=O)=[CH:14][CH:15]=[CH:16][CH:17]=1.C=CCCCC>>[C:1]([O:8][CH2:14][CH2:13][CH2:12][CH2:17][CH2:16][CH3:15])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CC(=O)CCC(=O)O
Solvent: O=CO
Solvent: C=CCCCC
Product: CCCCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 2 mmoles of levulinic acid and 0.2 mmoles of formic acid. 3 wt. % toluene sulfonic acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-hexene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-hexene. After cooling, the organic phase is separated. A mixture of hexyl formate and hexyl levulinate is formed as product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]CC(C1C=C(Cl)C=CC=1Cl)=O>>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[O:10]
Reactant: CC(=O)c1ccccc1Br
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Product: O=C(CBr)c1ccccc1Br
Yield: 57 %

Procedure:
This compound was prepared from 1-(2-bromo-phenyl)-ethanone (2.5 g, 12.6 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.98 g (57%) of 2-bromo-1-(2-bromo-phenyl)-ethanone as a clear oil. 1H-NMR (CD2Cl2) δ 8.13 (t, J=2 Hz, 1H), 7.92 (dm, J=8 Hz, 1H), 7.78 (dm, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 4.49 (s, 2H); TLC Rf=0.38, 15%, ethyl acetate-hexanes.
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][N:12]=1.N>C1COCC1>[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: COCOc1ccc(Br)nc1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]
Agent: N
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(C)C)nc1
Reaction time: 0.67 h

Procedure:
6.69 g (74.7 mmol) copper(I)cyanide in 15 ml dry THF was cooled to −75° C., where 149 ml (149 mmol) of a 1M tert-butylmagnesium chloride solution was added drop-wise. Stirring was continued for 40 min. After that, 4.07 g (18.67 mmol) 2-bromo-5-methoxymethoxy-pyridine (Zhong, W. et al. WO2008147547) dissolved in 30 ml dry THF were added drop-wise. The reaction mixture was stirred at −75° C. for 1 h and then allowed to reach room temperature, where stirring was continued for another 6 h. Then 30 ml of 25% aqueous ammonia was added to the reaction mixture. The mixture was filtered and extracted twice with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield 2.64 g of the pure title compound as an oil. LCMS: tR=0.55 min, M+H=196 (method K).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:24])[CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(C)=O

Procedure:
To a solution of Example 179B (0.15 g, 0.5 mmol) in benzene (5 mL) was added celite (0.15 g), pyridinium dichromate (0.75 g, 2.0 mmol), and a solution of 70% t-butyl peroxide in water (0.25 mL, 2.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (5% to 15% ethyl acetate/hexane gradient) affored the product as colorless oil (0.12 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1 H), 0.76 (m, 7 H), 1.35 (m, 1 H), 1.73 (s, 3 H), 1.80 (m, 1 H), 2.09 (m, 1 H), 3.84 (s, 3 H), 4.51 (m, 2 H), 5.97 (s, 1 H), 7.43 (m, 2 H), 7.59 (m, 1 H), 8.20 (d, J=7.72 Hz, 1 H); MS m/z 317.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6]C(NC)[CH2:4][CH2:3]1.[CH2:10]([O:17][C:18]([NH:20][C:21]1[CH:52]=[CH:51][C:24]([O:25][C:26]2[N:31]=[CH:30][N:29]=[C:28]([N:32](C(OC3C=CC=CC=3)=O)C(=O)OC3C=CC=CC=3)[CH:27]=2)=[CH:23][C:22]=1[F:53])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:54][N:55]([CH3:58])[CH:56]=[O:57]>>[F:53][C:22]1[CH:23]=[C:24]([O:25][C:26]2[CH:27]=[C:28]([NH:32][C:56]([N:55]([CH3:58])[CH:54]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:57])[N:29]=[CH:30][N:31]=2)[CH:51]=[CH:52][C:21]=1[NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(Oc2cc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)ncn2)cc1F)OCc1ccccc1
Reactant: CN(C)C=O
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ncn2)CC1
Reaction time: 2 h

Procedure:
After adding a solution of 1-methyl-4-methylaminopiperidine (0.355 ml) in N,N-dimethylformamide (2.5 ml) to crude phenyl N-[6-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyrimidin-4-yl]-N-(phenoxycarbonyl)carbamate (358 mg) at room temperature, the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N aqueous sodium hydroxide and brine in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the title compound (189.4 mg) as white powder.
Reaction SMILES: N#N.[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][CH:10]=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl>O.ClC1C=CC=CC=1Cl>[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][C:10]([CH:28]=[O:31])=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc2c(c1)ccc1c3ccccc3ccc21
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reaction time: 4 h

Procedure:
A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser and N2 line was charged with chrysene (Eastman Kodak Co., Rochester, NY., 14650, 100 g, 0.438 mol) and o-dichlorobenzene (2.5 L). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich Chemical Co., Milwaukee, WI, 53201, 98%, 228.2 g, 0.876 mol, 102.4 mL) was added in one portion. No temperature change occurred. The reaction mixture was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 70.48 g, 0.613 mol, 55.45 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h, the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was split into 2 portions and each passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted chrysene (3 g) from the aldehyde and a nore polar product. Fractions containing the aldehyde were combined and the PhCH3 removed. Crystals formed during this process and were removed periodically by filtration. After drying (at 60°) the yield of 6-chrysenecarbaldehyde was 89.46 g (79.7%) mp 167°-169°, (C,H), (lit. 168°, N. P. Buu Hoi, J.-P. Hoffinger, and P. Jacquignon, Bull. Soc. Chim. Fr. 3808 (1968)).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])C#C.CC(=CCCC(CCO)C)C.P(Cl)(Cl)Cl.P(Br)(Br)Br.C(OCC)(=O)CC(C)=O>>[CH3:15][CH:8]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:7][CH2:6][CH2:5][C:2](=[O:16])[CH3:1]
Reactant: C#CC(C)(O)CCCC(C)CCC=C(C)C
Agent: BrP(Br)Br
Agent: CC(C)=CCCC(C)CCO
Solvent: ClP(Cl)Cl
Solvent: CCOC(=O)CC(C)=O
Product: CC(=O)CCCC(C)CCC=C(C)C

Procedure:
3,7,11-trimethyldodeca-1-yn-10-en-3-ol can easily be synthesized by halogenating citronellol, which is used as a perfume, with phosphorus trichloride or phosphorus tribromide, reacting the halogenation product with ethyl acetoacetate to form 6,10-dimethylundeca-9-en-2-one, and subjecting it to ethynylation in the same manner as described above.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20]2[N:25]=[C:24](N)[CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)C.BrCC(O[CH2:34][CH3:35])=O.C(=O)([O-])[O-].[K+].[K+].[OH2:42]>C(#N)C>[CH3:21][C:20]1[NH:25][C:34]([CH3:35])=[CH:12][C:13]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:13]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:19]=3[C:10]([O:9][CH2:8][C:7]([O:6][CH2:5][CH3:4])=[O:42])=[CH:11][CH:12]=2)[N:25]=1
Reactant: O
Reactant: CCN(CC)CCOCCOc1ccc(-c2cccc(N)n2)c2c1CCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(-c2cccc(-c3cc(C)[nH]c3C)n2)c2c1CCCC2
Yield: 83.5 %

Procedure:
Prepared from 2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine (from Example 1) by alkylation with ethyl bromoacetate, using potassium carbonate, in acetonitrile. The mixture was refluxed 12 hours, cooled, poured into water, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to an 83.5% yield of the product as an oil. 1H-NMR (δ, CDCl3): 1.31 (t, J=7, 3H), 1.71 (m, 2H), 1.83 (m, 2H), 2.19 (s, 6H), 4.26 (q, J=7, 2H), 4.66 (s, 2H), 5.90 (s, 2H), 6.64 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.82 (t, J=8, 1H); 13C-NMR (δ, CDCl3): 13.4, 14.2, 22.3, 22.9, 23.7, 28.7, 61.2, 65.5, 106.7, 107.8, 119.6, 123.0, 126.9, 127.7, 128.5, 133.4, 137.0, 138.1, 151.3, 156.0, 160.1, 169.0; MS (%): 405 (parent+1, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.C[C:18]1(C)[C:27]2[C:22](=CC(Br)=CC=2)[C:21]([S:29]C2C=CC=CC=2)=[CH:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([S:29][C:21]2[CH:22]=[CH:27][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Product: CC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C

Procedure:
Employing the procedure used for the preparation of 4,4-dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (Compound C1) 1.2 g, (3.5 mmol) of 4,4-dimethyl-7-Bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35) was converted to the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:33][NH2:34]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:33][N:34]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-3-trifluoromethyl-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-trifluoromethyl-phenyl)-amine as brown solid in 34% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.C=O.[C:27]([BH3-])#[N:28].[Na+].[C:31](O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:28]([CH3:27])[CH3:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-bromo-1-(aminomethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-bromo-1-[ (dimethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CO>C1(C)C=CC=CC=1>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: c1csc(-c2ccno2)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C=C(C#N)C(=O)c1cccs1
Yield: 87.3 %

Procedure:
A mixture of 5-(2-thienyl)isoxazole (4.3 kg) and dimethylformamide dimethylacetal (6.1 kg; Lancaster) in toluene (12 L; Barton) is heated at reflux. As methanol forms it is removed by distillation. Solid forms from the reaction mixture. The reaction mixture is cooled and diluted with methyl-t-butyl ether (8 L; Van Waters). The precipitate is collected by filtration and washed with methyl-t-butyl ether (4 L). The solid is slurried with acetone (10 L; Batron) and hexanes (10 L; Mallinckrodt), then filtered and washed with hexanes (4 L). After drying in vacuo there is obtained 5.124 kg of α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropane-nitrile (87% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C=[O:32])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH:16]=[O:32])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CC1(c2ccc3ccccc3c2)CCCC1
Reactant: O=CC1(c2cc(Cl)ccc2Cl)CCCC1
Product: O=CC1(c2ccc3ccccc3c2)CCCC1
Yield: 82.77 %

Procedure:
1-Naphthalen-2-yl-cyclopentanecarbaldehyde (212) (21.0 g, 82.77%) was synthesized as a colourless liquid from 1-naphthalen-2-yl-cyclopentanecarbonitrile (211) (25.0 g, 113.12 mmol) following the procedure described for 1-(2,5-dichlorophenyl)-cyclopentanecarbaldehyde (199).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13](O)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12])=[CH2:14]
Reactant: CCO
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4-methyl-2-benzofuran-1(3H)-one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmol), PdCl2(dppf)-CH2Cl2 Adduct (182 mg, 0.223 mmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140° C. for 20 min. Analysis by LC-MS showed product peak. The reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness. The crude product was purified by MPLC chromatography using a 120 g Redi-sep column and 0-80% ETOAC/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): δ ppm 7.76 (d, J=8 Hz, 1H), 7.03 (dd, J=11, 17 Hz, 1H), 5.84 (d, J=17 Hz, 1H), 5.55 (d, J=11 Hz, 1H), 5.29 (s, 2H), 2.34 (s, 3H). LC-MS: M+1=175; tR=2.42 min
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C1[N:16]2[C:17]3C(C=CC2=CN=1)=CC=CC=3.C(OC(=O)C)(=[O:27])C.C(OC(=O)CC)(=O)CC>>[N:1]1([C:17]([NH2:16])=[O:27])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: c1ccc2c(c1)ccc1cncn12
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1=O
Agent: CCC(=O)OC(=O)CC
Product: NC(=O)N1C(=O)C(=O)c2ccccc21

Procedure:
CHART B discloses one of the general processes for the transformation of isatin (III) to amide or ketone (VI) and the subsequent conversion of this compound to imidazo[1,5-a]quinoline (I). The substituted isatin precursors (III) are either commercially available or are known to those skilled in the art. Following the general procedure of Camp (Arch. Pharm., 237, 687 (1899)) the appropriately substituted isatin (III) was acylated with either acetic anhydride or propionic anhydride to provide isatin amide (IV). Generally these reactions were carried out in a solvent such as THF in the presence of dimethylaminopyridine, between 20-25° and that of the solvent system at reflux. Reaction of isatin amide (IV) with 1 N sodium hydroxide or 1 N potassium hydroxide at reflux, in the presence or absence of THF, provides the appropriately substituted 2-hydroxyquinoline-4-carboxylic acid (V). Alternatively, the substituted 2-hydroxyquinoline-4-carboxylic acid (V) may be formed directly from isatin (III) by reaction of isatin (III) with malonic acid in THF at reflux and then removal of the solvent under reduced pressure, heating the crude material in water at reflux. This is the preferred method when R4 and R6 are hydrogen and R7 is --Cl. Reaction of the acid (V) with thionyl chloride at reflux provides an intermediate acid chloride (V-A) upon concentration. Exposure of this crude acid halide (V-A) to the desired amine in an inert solvent such as methylene chloride or THF in the presence of an acid scavenger such as Hunig's base or triethylamine between 0→25° gives the desired amide intermediate (VI).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][CH2:33][CH2:34][CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCOCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 92.8 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.52 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.64 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (452 mg) as yellow oil.