Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1>CC#N>[Br:8][C:6]1[N:7]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Solvent: CC#N
Product: Nc1ncc(Br)nc1NCC1CCOCC1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
To a scintillation vial containing 3,5-dibromopyrazin-2-amine (500 mg, 1.977 mmol) and TEA (0.551 ml, 3.95 mmol) was added MeCN (6 ml) and (tetrahydro-2H-pyran-4-yl)methanamine (300 mg, 1.977 mmol). The homogenous reaction mixture was capped and heated to 80° C. in a oil bath for 36 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (30% EtOAc/Hexane) to yield 6-bromo-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (351 mg, 1.222 mmol, 61.8% yield).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20](Cl)[C:19]([C:23]([O-:25])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:26]([O-])(=O)[CH3:27].[K+]>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)[O-])c(Cl)n2)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 93 %

Procedure:
Then, 4.9 g (0.012 mole) of the obtained 2-(p-octyloxyphenyl)-4-chloropyrimidine-5-carboxylate was dissolved in 100 ml of ethanol, and was reduced with 0.3 g of Pd/BaSO4 in the presence of potassium acetate to give 4.0 g of ethyl 2-(p-octyloxyphenyl)pyrimidine-5-carboxylate (yield: 93%).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:2][C:3]#[N:4]
Reactant: Nc1cccc(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1cccc(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
2-Bromoacetonitrile (0.22 g, 1.83 mmol), 3-aminophenol (0.2 g, 1.83 mmol) and potassium carbonate (0.5 g, 3.67 mmol) were combined in dry DMF (10 ml). The reaction was stirred at room temperature for 24 hours. The reaction was diluted with water and ethyl acetate. The organic solution was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 50% ethyl acetate in dichloromethane to afford the title compound as a colourless oil (0.16 g, 58.9%). 1H-NMR (500 MHz, CDCl3): δ 3.76 (s, br, 2H), 4.69 (s, 2H), 6.29 (d, J=2.3 Hz, 1H), 6.37 (dd, J=2.3 Hz, 8.1 Hz, 1H), 6.41 (dd, J=2.3 Hz, 8.1 Hz, 1H), 7.1 (t, J=8.1 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].[CH3:21][S:22]CCl>CN(C)C=O.[Cl-].[Na+].O>[CH3:20][N:17]1[C:7]2[C:8](=[O:16])[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=3[N:5]([CH2:3][CH2:4][S:22][CH3:21])[C:6]=2[CH:19]=[N:18]1
Reactant: CSCCl
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 225 mg, 5.6 mmol), which was washed with hexane and dried in vacuo, in N,N-dimethylformamide (40 ml) was added a solution of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.80 g, 3.75 mmol) in N,N-dimethylformamide at 0° C. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 10.5 h. Further more, sodium hydride (60-72% in mineral oil, 68 mg, 2.8 mmol) and chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) were added. After 2 h, the mixture was heated at 50° C. for 15.5 h. The mixture was poured into brine (50 ml) and extracted with ethyl acetate (50 ml×2). The organic extracts were dried over magnesium sulfate and concentrated. Purification by column chromatography on silica gel eluting with ethyl acetate/hexane (1:1) gave 0.46 g (43%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N+](C1C=CC(C([O:19][CH2:20][C@@:21]2([CH3:24])[CH2:23][O:22]2)=O)=CC=1)([O-])=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Cl.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:23][C@:21]([OH:22])([CH3:24])[CH2:20][OH:19])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: C[C@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 91.7 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (600 g, 4.07 mol) and (R)-2-methyloxiran-2-ylmethyl 4-nitrobenzoate (1060 g, 4.47 mol) were dissolved in ethyl acetate (2124 ml), triethylamine (113.64 ml, 0.82 mol) was added to the solution, and the resulting mixture was stirred under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (530 ml) and toluene (5300 ml) were added to the residue. The resulting precipitates were filtered off and dissolved in methanol (10.6 1). Potassium carbonate (55.4 g, 0.4 mol) was added to the solution, the resulting mixture was stirred at room temperature for 1 hour, concentrated hydrochloric acid (66 ml) and magnesium sulfate (671 g) were added in this order with cooling on ice-bath, and the resulting mixture was stirred for 30 minutes. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue, ethyl acetate (530 ml) and toluene (5300 ml) were added. The resulting precipitates were filtered off and dried at 50° C. to afford (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole (879.1 g, yield 92%) as a light brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-1H-indole (6.7 g) in tetrahydrofuran (75 ml) was treated with sodium hydride (1.24 g) and stirred for 0.5 h at room temperature. The resulting suspension was treated with a solution of iodomethane (2.34 ml) in tetrahydrofuran (35 ml) at 0° C. and allowed to warm to room temperature over 1 h, whilst stirring. The reaction mixture was poured onto water and partitioned between dichloromethane and water. The organic phase was dried over (MgSO4) and concentrated in vacuo to afford the title compound (7.2 g). TLC Silica (cyclohexane-ethyl acetate [1:1]), Rf=0.55.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.[NH2:7][CH2:8][CH2:9][OH:10]>C(O)C>[OH:10][CH2:9][CH2:8][NH:7][C@@H:1]1[CH2:2][CH2:3][CH2:4][C@H:5]1[OH:6]
Reactant: C1CC2OC2C1
Reactant: NCCO
Solvent: CCO
Product: OCCN[C@@H]1CCC[C@H]1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-oxabicyclo[3.1.0]hexane (3.00 g, 35.7 mmol) and 2-aminoethanol (2.18 g, 35.7 mmol) in ethanol (15 mL) was stirred at 80° C. in a sealed tube for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification using silica gel chromatography (Eluant: methanol in dichloromethane) afforded the title compound. Yield: 1.6 g, 11 mmol, 31%. 1H NMR (400 MHz, DMSO-d6) δ 4.43-4.64 (br m, 2H), 3.68-3.75 (m, 1H), 3.44 (t, J=5.6 Hz, 2H), 2.71-2.77 (m, 1H), 2.58-2.63 (m, 2H), 1.73-1.89 (m, 2H), 1.47-1.64 (m, 2H), 1.34-1.44 (m, 1H), 1.17-1.28 (m, 1H).
Reaction SMILES: Cl[CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]([OH:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>C1C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:25]([CH:24]([O:32][CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC=CCC(O)CCCCCCC
Reactant: CCOC(=O)C(Cl)Sc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC=CCC(CCCCCCC)OC(Sc1ccccc1)C(=O)OCC

Procedure:
Part B. The method of Speckamp et al., Tetrahedron Letters, v. 32, p. 1491 (1991), is employed here. Thus, a solution of ethyl 2-chloro-2-(phenylthio)acetate [prepared according to the method of Bohme et al., Liebigs Annalen der Chemie, p. 51 (1977)], 7-heptadecen-10-ol, andcatalytic zinc acetate dihydrate in benzene is heated to reflux under a Dean-Stark trap until the formation of hydrogen chloride is complete. Workup according to the listed reference affords ethyl 2-(1-heptyl-3-decen-1-oxy)-2-(phenylthio)acetate.
Reaction SMILES: I[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C.[Cu]I>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[C:43][C:2]2[NH:16][C:15]3[C:17]4[C:3]=2[CH2:4][C@@H:5]2[C@@H:10]([C:11]=4[CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]2[CH3:26])=[CH:38][CH:37]=1)#[N:35]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Reactant: C#Cc1ccc(C#N)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#Cc5ccc(C#N)cc5)c(c34)C[C@H]2N(C)C1
Yield: 43.6 %

Procedure:
Under argon, 200 mg of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea is heated to 80°-90° C. in 4 ml of DMF with 4 ml of triethylamine, 4 mg of copper(I) iodide, 8 mg of palladium(O) tetrakis(triphenylphosphine) and 112 mg of 4-cyanophenylacetylene for 2 hours. After evaporation, the mixture is distributed in ethyl acetate and saturated sodium bicarbonate solution, and the organic phase is washed with saturated sodium chloride solution. After chromatography over silica gel with methylene chloride:ethanol=10:1, 87 mg of 3-[2-(4-cyanophenylethynyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea is obtained, mp 150°-151° C., [α]D =+139.5° (c=0.2; pyridine).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(F)c1
Yield: 38.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3-fluorobenzoyl chloride (64 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 34 mg of 3-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 39%).
Reaction SMILES: Cl[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:26].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[NH:4][C:3](=[O:26])[CH:2]=[CH:11]2
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)C(=O)N3)c1=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)ccc3cc2F)c1=O
Yield: 97.4 %

Procedure:
A stirred solution of 5.2 grams (0.013 mole) of 3-(3-chloro-6-fluoro-3,4-dihydroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil and 6.2 grams (0.061 mole) of triethylamine in 200 mL of tetrahydrofuran was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.5 grams of 3-(6-fluoroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, mp 179° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:38][CH:37]=[CH2:36])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: C=CCBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: C=CCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with allyl bromide
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:32]=[CH:31][C:10]([NH:11][C:12]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[CH:21][C:13]=3[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:11][C:12]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[CH:21][C:13]=3[C:14]([OH:16])=[O:15])=[CH:31][CH:32]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-morpholinoanilino)-4-phenylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-80% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-morpholinoanilino)-4-phenylbenzoic acid 31 mg of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.[BH4-].[Na+]>CO>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=Cc1ccccn1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reaction time: 1 h
Yield: 39.7 %

Procedure:
(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in MeOH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N.O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Br)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 8.8 g (21.3 mmol) of 1-[[(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole in 20 ml of N,N-dimethylformamide is treated with 3.6 ml (about 47 mmol) of a 25 percent aqueous ammonia solution and the mixture is stirred at room temperature for 1 hour. The mixture is then poured into 100 ml of water, the product is filtered off under suction after 15 minutes, rinsed with water and dried at 80° in a high vacuum. There is obtained (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of decomposition point 296°.
Reaction SMILES: [N:1]1[N:2]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19](Br)[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[N:1]1[N:2]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: C#C[Si](C)(C)C
Reactant: O=c1oc2cc(-n3nc4ccc5ccccc5c4n3)ccc2cc1Br
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc2ccc(-n3nc4ccc5ccccc5c4n3)cc2oc1=O

Procedure:
After charging 7.8 parts of 7-(naphtho[1,2]triazol-2-yl)-3-bromocoumarin synthesized by a known method, 2.4 parts of trimethylsilylacetylene, 0.46 parts of tetrakis(triphenylphosphine)palladium(0), 0.038 parts of copper iodide and 20 ml of triethylamine in 40 ml of THF, the mixture was refluxed for 9 hours. The reaction mixture was filtered and washed with THF, and the obtained filtrate was concentrated and then diluted with water and filtered. The obtained cake was recrystallized from methanol. Upon drying under reduced pressure there was obtained 4 parts of 7-(naphtho[1,2]triazol-2-yl)-3-trimethylsilylethynylcoumarin having a melting point of 250-252° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11]Cl)[N:9]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+].[I-].[K+]>O1CCCC1.CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CC(=O)Nc1nc(CCCl)cs1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
2-Acetylamino-4-(2-chloroethyl)thiazole (1 g), 3-(4-piperidyl)indole (0.98 g), sodium hydrogen carbonate (620 mg) and potassium iodide (810 mg) were refluxed in a mixture of tetrahydrofuran (14 ml) and N,N-dimethylformamide (10 ml) for 4 hours and 10 minutes. Thereafter, with additions of 2-acetylamino-4-(2-chloroethyl)thiazole (0.5 g) three times, the mixture was further refluxed for 2 hours and 20 minutes. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted with a mixture of chloroform and methanol (100 ml, 10:1 V/V) and the extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (10:1 V/V). The eluate gave 2-acetylamino-4-[2-[4-(3-indolyl)piperidino]ethyl]thiazole (500 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([N:24]2[C:28]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:27](=[O:34])[NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:31]1[CH2:30][CH2:29][C:28]2([N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][NH:26][C:27]2=[O:34])[CH2:33][CH2:32]1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (2.3 mL, 13 mmol) in dichloromethane (50 mL) was added with stirring to a mixture of 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (2.9 g, 13 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (250 mL) at room temperature. Stirring was continued for 2 h. Water (150 mL) was added, the phases were separated and the water phase was extracted twice with dichloromethane (100 mL). Organic phases were pooled, washed with brine (200 mL), dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (ethylacetate/n-hexane 1:1) yielded the desired product (5.3 g, 89%) m.p. 251° C. and MS: m/e=472.1 (M+H+).