Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([O-])(=O)C.[Li+]>CO>[CH2:1]([O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 96.5 %

Procedure:
109 g (0.374 mol) of β-(3,5-di-tert-butyl4-hydroxyphenyl)propionic acid methyl ester, 92.5 g (0.34 mol) of stearyl alcohol and 0.1 g of lithium acetate in the dihydrate form (0.001 mol) are introduced into a vessel and melted and stirred at 100° C. under nitrogen. As soon as a melt is obtained, cautiously evacuation is carried out and at the same time the melt is heated to an internal temperature (IT) of from 150 to 160° C. The methanol formed is distilled off and condensed in a cold trap. As soon as an internal pressure of <10 mbar is reached, the internal temperature (IT) is increased to from 170 to 180° C. and further evacuation to <1 mbar is carried out. As soon as IT=180° C. and a pressure of <1 mbar is reached, those conditions are maintained for one hour and then, in the course of from 1 to 2 hours at IT=200-210° C., the excess β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester is removed by distillation. The reaction melt then contains <0.2% starting materials and has a content of >98% β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid octadecyl ester. The reaction melt is cooled, and left to stand for crystallisation. Yield 96.5%; m.p. 51° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[F:10][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[F:10][C:5]1[S:1][C:2]([NH:6][C:7](=[O:9])[CH3:8])=[N:3][CH:4]=1
Reactant: CC(=O)Nc1nccs1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(=O)Nc1ncc(F)s1
Temperature: 80 °C
Yield: 41.4 %

Procedure:
To a solution of N-(thiazol-2-yl)acetamide (150 g, 1056 mmol, Combi-Blocks, San Diego, Calif.) in acetonitrile (3 L) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (486 g, 1373 mmol, Air Products, Allentown, Pa.) and the mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and water (2 L) was added. The mixture was extracted with ethyl acetate (2×1.5 L). The combined organic extract was washed with saturated aqueous NaHCO3 (1.5 L) and 2N HCl (1 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude N-(5-fluorothiazol-2-yl)acetamide (70.0 g, crude) which was used for next reaction without any purification. m/z (ESI) 161.0 (M+H)+
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C(OCC)(=O)C>O>[CH:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][C:4]([Br:20])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
First, 25 g (100 mmol) of triphenylamine, 18 g (100 mmol) of N-bromosuccinimide, and 400 mL of ethyl acetate were put in a 1000-mL Erlenmeyer flask, and the mixture was stirred at room temperature in the air for 18 hours. After the reaction was terminated, the mixture was washed with a saturated sodium carbonate aqueous solution twice to obtain an organic layer and a water layer. Then, the water layer was extracted twice with ethyl acetate, and the extract was combined with the organic layer and washed with a saturated saline solution. The solution was dried with magnesium sulfate and filtered naturally, and the filtrate was concentrated. An obtained colorless solid was recrystallized with ethyl acetate-hexane; thus, 22 g of a colorless powdered solid of 4-bromotriphenylamine was obtained (yield: 66%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=1[CH2:49][C:50]([O:52][CH3:53])=[O:51])#[CH:38]>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>[CH3:53][O:52][C:50](=[O:51])[CH2:49][C:40]1[CH:41]=[C:42]([C:45]([F:47])([F:46])[F:48])[CH:43]=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Product: COC(=O)Cc1cc(C(F)(F)F)ccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.300 g, 0.656 mmol), PdCl2(PPh3)2 (0.046 g, 0.066 mmol), t-Bu3PH.BF4 (0.019 g, 0.066 mmol), CuI (0.013 g, 0.022 mmol) and methyl 2-(2-ethynyl-5-(trifluoromethyl)phenyl)acetate (A105) (0.191 g, 0.657 mmol) in dry degassed DMF (4 mL) and Et3N (4 mL) was heated at 120° C. for 20 minutes under nitrogen. The volatiles were evaporated under reduced pressure and the residue adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A106 as a yellow solid (0.196 g, 45%); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.60-7.53 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 4.25 (s, 2H), 3.99 (s, 2H), 3.72 (s, 3H), 2.80 (t, J=11.9 Hz, 2H), 2.64 (m, 1H), 1.82 (d, J=12.8 Hz, 2H), 1.68-1.53 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.109 min; m/z 663.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]#[CH:15])=[CH:4][C:5]2[C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:3]([C:14]#[C:15][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:12])([CH3:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#Cc1cc2c(cc1C)CCCC2(C)C
Product: Cc1cc2c(cc1C#Cc1ccc(C#N)cc1)C(C)(C)CCC2

Procedure:
Using a process similar to that described in Example 1c, 4.4 g (22 millimoles) of (5,6,7,8-tetrahydro-3,8,8-trimethylnaphth-2-yl)-ethyne and 2.7 g (15 millimoles) of 4-bromobenzonitrile were converted to the title compound. 1.3 g (29%) of product of melting point 128°-130° C. were obtained after recrystallization from ethanol.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=[C:1]([Br:5])[Br:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CCCOC1CCCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCCOC1CCCCC1
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
Subsequently, to a solution of carbon tetrabromide (36.5 g, 0.11 mol) in dichloromethane (120 ml) was added a solution of triphenylphosphine. (57.7 g, 0.22 mol) in dichloromethane (120 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred for 5 minutes. After stirring, to the reaction mixture was added a solution of the crude 3-cyclohexyloxypropionaldehyde (8.60 g) obtained above in dichloromethane (90 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 25 minutes. After stirring, the reaction mixture was diluted with dichloromethane and washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (100:1–33:1) as the eluent to afford 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, overall yield in two steps: 55%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CN(C)C1CCCCC1

Procedure:
26 gm of N-methyl-cyclohexylamine were added to 29 gm of 2-acetylamino-4-tert.butyl-5-chloro-benzyl bromide in 1.5 liters of carbon tetrachloride, and the mixture was refluxed for 2 hours. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, and the filtrate was evaporated. The residue was taken up in 2 N acetic acid, the solution was extracted with chloroform, and the acid phase was made alkaline with concentrated ammonia, extracted three times with chloroform, and the organic phase was evaporated. After column-chromatographic purification on silicagel with ethyl acetate/chloroform (1:1), the 2-acetylamino-4-tert.butyl-5-chloro-N-cyclohexyl-N-methylbenzylamine thus obtained was crystallized from absolute ethanol and recrystallized from ethanol, whereupon it had a melting point of 174°-175.5°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm3 of benzyl alcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm3 of toluene is refluxed for 2 hours while removing the water formed. After cooling, treating with 3 g of animal black and filtering, the reaction mixture is concentrated to 150 cm3 and 300 cm3 of isopropyl oxide are added. The crystals obtained by cooling to 0° C. are drained, washed and dried to give 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassium carbonate are added to a solution of 153 g of this ester in a mixture of 500 cm3 of 1,3-dibromopropane and 2500 cm3 of acetonitrile, and the mixture is refluxed for 17 hours. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of ethyl acetate and the organic phase is washed with 400 cm3 of water twice and twice with 250 cm3 of a saturated solution of sodium chloride and then dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm, height 55 cm), eluting with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 500 cm3. Fractions 12 to 18 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 g of benzyl 2-(3-bromopropoxy)phenyl-acetate in the form of a yellow oil. A solution of 40 g of this product in 500 cm3 of acetonitrile is heated in an autoclave with 27 g of sodium iodide and 90 g of dimethylamine for 16 hours at 80° C. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by acid-base treatment to give 29.3 g of benzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellow oil. Hydrogenation of this ester, at atmospheric pressure at 40° C. in ethyl acetate in the presence of palladium hydroxide followed by crystallization from ethyl acetate, yield 17.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid in the form of white crystals; melting point 98° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][CH2:8][C:7]2=[O:18])([O-:3])=[O:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][N:22]([CH:24]=[C:8]1[C:7](=[O:18])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9]1)[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.976 g), N,N-dimethylformamide dimethyl acetal (8.568 g), and triethylamine (1.818 g) in benzene (24 ml) was refluxed with stirring for 2.5 hours and cooled to room temperature. The resulting precipitates were collected by filtration, washed with cold ethyl acetate, and dried to give 3-dimethylaminomethylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.345 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].Cl.O[NH:27]/[C:28](=[N:37]\[H])/[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:37]=[C:28]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:27]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/COc1ccccc1)NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(COc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
To ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (26 mg, 0.073 mmol) and (1Z)—N-hydroxy-2-(phenyloxy)ethanimidamide hydrochloride (16 mg, 0.079 mmol) in EtOH (1 ml) was added 21% wt. ethanolic sodium ethoxide solution (0.068 ml, 0.183 mmol) and the mixture was heated under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase dried (Na2SO4) evaporated and purified by MDAP to give title compound as a gum which solidified upon trituration with ether (5.9 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:32][NH:17][CH2:16][C:13]2[N:12]=[C:11]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])([CH:19]3[CH2:31][C:22]4[NH:23][C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=5[C:21]=4[CH2:20]3)[F:18])[O:15][N:14]=2)=[CH:35][CH:36]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a stirred solution of 50 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL MeOH at 0° C. was added 19 mg (0.1 mmol, 1 eq) of methyl 4-formylbenzoate, 7 mg (0.1 mmol, leg) sodium cyanoborohydride and one drop of acetic acid. The reaction mixture was stirred at 0° C. for 20 minutes and then the temperature was raised to RT and the reaction quenched with saturated aqueous solution of NaHCO3. The reaction mixture was poured on water and extracted with EtOAc. The organic phase were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:1) yielded 30 mg (45%) of (RS,SR)-4-[({5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:26][O:27][C:28]([CH2:30]Br)=[O:29]>CC(C)=O>[CH3:26][O:27][C:28](=[O:29])[CH2:30][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 72.3 %

Procedure:
To a mixture of 7-Hydroxy isoflavone (35 grams, 147 mmol), anhydrous K2CO3 (84 grams, 608 mmol) in anhydrous acetone (500 mL) was added ethyl bromo acetate (29 grams, 174 mmol) and refluxed for 8 hours. Acetone was distilled and water (500 mL) was added. Crude 49 was filtered, dried, and recrystallized from toluene to give pure 49 (33 grams, 72.4%) as a white shining powder. The melting point was found to be 105-106.5° C. The structure was confirmed with IR and NMR. IHNMR (CDCl3) δ 1.31 (t, 3H,OCH2,CH3), 4.30(q, 2H, OCH2, CH3), 4.70(s, 2H,OCH2), 6.84 (d, 1H,Ar), 7.05 (dd,1H,Ar), 7.41 (m, 3H,Ar), 7.57 (m, 2H,Ar), 7.97(s, 1H, Pyran), 8.24(d,1H,Ar).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:16]3([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:11][CH:12]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:28][CH2:27]2)[CH2:31][CH2:30]1
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Reactant: O=CC1CC1
Product: c1cc(C2(CN3CCN(CC4CC4)CC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 14 %

Procedure:
The title compound (26 mg, 14%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and cyclopropane carboxaldehyde similarly to the procedure used for example 54. 1H NMR (400 MHz, CDCl3) δ 0.02 (q, 2H), 0.43 (q, 2H), 0.76 (m, 1H), 1.74-1.76 (m, 4H), 1.83-1.89 (m, 2H), 1.95-1.99 (m, 2H), 2.03-2.06 (m, 3H), 2.13 (d, 2H), 2.19-2.21 (m, 4H), 2.26-2.40 (m, 5H), 2.47-2.51 (m, 4H), 2.59 (t, 2H), 3.49 (t, 2H), 3.68-3.72 (m, 2H), 3.98 (t, 2H), 6.82 (d, 2H), 7.17 (d, 2H). HRMS ESI+ m/z 442.3412 [MH]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[N:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:28][NH:27][C:12]([C:11]1[N:10]=[CH:9][N:8]2[C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][C:5]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)=[N:6][C:7]=12)=[NH:13]
Reactant: NO
Reactant: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 20.3 %

Procedure:
A stirred mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carbonitrile [CAS-No. 851263-42-8] 1.16 g, 3.26 mmol), hydroxylamine hydrochloride (0.46 g, 6.62 mmol) and potassium carbonate (1.35 g, 9.77 mmol) in ethanol (50 ml) was heated under reflux conditions for 3 h. The precipitate was collected by filtration and washed with ethanol, the combined filtrates were evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/ethanol 95:5) and crystallization from diethyl ether/hexane to yield the title compound (257 mg, 20%) as a red solid. MS (ISN) 388.2 [(M−H)−]; mp 213° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: C1CCNC1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: Fc1ccc(-c2csc3cc(OCCCN4CCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and pyrrolidine were converted to yield 1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-pyrrolidine as colorless oil, MS: 356 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[S:10]1[C:14]([CH:15]=O)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2>>[S:10]1[C:14]([CH2:15][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=Cc1cc2ccccc2s1
Product: Cc1cc(Br)cc(Cc2cc3ccccc3s2)c1

Procedure:
3,5-Dibromotoluene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.[H-].[Na+]>O1CCCC1>[CH:3]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)=[CH2:2]
Reactant: ClCCn1cnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cn1cnc2ccccc21
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To 3.61 g (20 mmoles) of 1-(2-chloroethyl)benzimidazole in 50 ml of tetrahydrofuran was added in portions 960 mg (20 mmoles) of 50% sodium hydride and the mixture allowed to stir for 3 hours. The solids were filtered, washed with tetrahydrofuran and the washings and filtrate evaporated to dryness. The residue was dissolved in acetonitrile, washed with hexane and the acetonitrile concentrated to give 2.77 g of product as a yellow oil.