Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:42][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methylaniline (108 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 548.2 (M+H), 526.0 (M+H-MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH2:10]Cl)[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH2:10][N:21]1[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]2[C:17]1=[O:27])[CH3:2]
Reactant: CCOc1ccccc1OCC(O)CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: CCOc1ccccc1OCC(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 30 g. (0.12 mole) of 1-(2-ethoxyphenoxy)-4-chloro-2-butanol and 18.5 g. (0.10 mole) of potassium phthalimide was heated slowly to 130° C. for 10 min. and at 160° C. for one hour with stirring. The reaction mixture was extracted with 250 ml. of hot toluene. A crystalline solid separated from the toluene extract when cooled to room temperature. The solid was recrystallized from toluene and melted at 93°-95° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:33][CH3:34])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][C:8]1([F:32])[F:31]>CN(C)C=O>[CH3:34][O:33][C:7]1([O:6][CH3:5])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][C:8]1([F:31])[F:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2)CC1(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1(F)F
Temperature: 70 °C
Yield: 88 %

Procedure:
The mixture of sodium azide (26.0 mmol) and (R)-{3-[4-(4,4-dimethoxy-3,3-difluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (12.0 mmol) in dimethylformamide was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 88% yield.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110 %

Procedure:
(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (13.6 g, 50 mmol) was dissolved in anhydrous THF (200 mL) and cooled to −10° C. (ice/MeOH bath). Phenylmagnesium bromide solution in THF (100 mL of 1.0 M, 100 mmol, 2 equiv) was added slowly. After 15 min, the reaction mixture was warmed up to rt slowly and stirred for 1 hour. LC-MS showed the reaction was complete. 5% Aq HCl (100 mL) was added slowly to quench the reaction and the mixture was stirred for 20 min. After separation, the aqueous layer was extracted with ether (2×200 mL). The combined organic layers were washed with satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded crude (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (16.45 g, 110%) as a clear oil which was used for the next step without further purification. LC-MS (3 min) tR=1.91 min, m/z 302 (M+Na). 1H NMR (CDCl3) □ 7.94 (d, 2H), 7.54 (t, 1H), 7.47 (t, 2H), 4.28 (br d, 1H), 4.09 (d, 1H), 3.38 (t, 1H), 2.92 (br t, 1H), 2.72 (t, 1H), 2.01 (d, 1H), 1.79-1.45 (m, 3H) 1.42 (s, 9H). Chiral HPLC indicated 100% purity.
Reaction SMILES: [Br-].[CH3:2][C:3]([CH3:11])=[CH:4][CH2:5][S+]1CCCC1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1.[H-].[Na+]>>[CH3:11][C:3]([CH3:2])=[CH:4][CH:5]1[O:19][CH:18]1[C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccncc1
Reactant: CC(C)=CC[S+]1CCCC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CC1OC1c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1-(3-methyl-but-2-enyl)-tetrahydrothiophenium bromide (381 mg in 5 mL dry tetrahydrofuran) at 0° C. was added 0.31 mL pyridine-4-carboxaldehyde followed by 111 mg sodium hydride and the mixture allowed to warm to room temperature. After 1.5 hours, an additional 0.15 mL pyridine-4-carboxaldehyde was added and after 30 minutes the reaction quenched by the addition of water. The mixture was partitioned between ethyl acetate and water and the organic portion washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (138 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:3]2[CH2:4][NH:5][CH2:6][CH2:7][N:2]2[CH3:1])=[CH:13][C:12]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCNCC1c1ccc([N+](=O)[O-])c(-c2nc3ccccc3o2)c1
Temperature: 90 °C

Procedure:
1.01 g (0.010 mol) of N-methylpiperazine were added to the mixture of 1.29 g (0.005 mol) of 2-(2′-nitro-5′-fluorophenyl)benzoxazole and 1.04 g (0.0075 mol) of K2CO3 in 9 ml of dimethyl sulfoxide. The reaction was stirred magnetically and heated at 90° C., the progression thereof being verified by TLC.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(N2CCOCC2)ccc1Br
Temperature: 80 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
4-Bromo-3-chloroaniline (500 mg) was dissolved in DMF (10 ml), and bis(2-bromoethyl)ether (1.12 g), K2CO3 (1.34 g), and potassium iodide (80 mg) were added thereto, followed by stirring at 80° C. for 2 days. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 20% EtOAc/hexane) to obtain 4-(4-bromo-3-chlorophenyl)morpholine (263 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.[CH3:24][N:25]([O:29][CH3:30])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:26]([N:25]([CH3:24])[O:29][CH3:30])=[O:27])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)Cl
Reactant: Cc1ccc(C(=O)CCc2ccc(N)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)Nc1ccc(CCC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
15.3 g of sodium bicarbonate were added to a solution, in 250 ml of tetrahydrofuran, of 36 g of the 1-(4-methylphenyl)-3-(4-aminophenyl)-n-propan-1-one prepared as described in Example A, and 18.5 g of N-methyl-N-methoxycarbamyl chloride were added dropwise at 10°-15° C., while cooling with ice. The mixture was stirred for 6 hours at 25° C., after which it was filtered and the filtrate was evaporated down under reduced pressure. The oil obtained crystallized after trituration with diisopropyl ether, and 38.5 g (79% of theory) of product of melting point 73°-74° C. were obtained.
Reaction SMILES: [C:1]([N:4]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][C:19]=2[CH2:28][NH:29][CH3:30])[CH2:14][CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([O:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:13][CH2:14]2)=[C:19]([CH2:28][NH:29][CH3:30])[CH:20]=1)(=[O:33])[CH3:32]
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1
Reactant: CC(=O)Cl
Product: CNCc1cc(CCCOC(C)=O)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1

Procedure:
from trans-N-acetyl-N-benzyl-4-[4-(3-hydroxypropyl)-methylaminomethylphenyl]cyclohexylamine and acetylchloride. Oil. Rf value: 0.67 (alumina, ethyl acetate/petroleum ether=1:1, v:v).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([N:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:34])C(=O)C1.O>CN(C=O)C>[Br:34][C:23]1[CH:24]=[CH:25][C:26]2[N:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazole (6 g, 17.17 mmol) was dissolved in 100 mL of DMF. The solution was cooled to 0° C. To the solution was added NBS (3.36 g, 18.89 mmol) in 20 mL of DMF dropwise. After stirring at this temperature for 1 h, HPLC indicated there was very little reaction. The reaction was warmed to room temperature and monitored by HPLC. After 24 h, 500 mL of water was added to the reaction and stirred at room temperature for 2 h. The white precipitate was filtered and washed with water. The solid was dissolved in DCM and washed with water and dried over MgSO4. The residue was used directly for the next step. The product contains 10% of starting material, 80% of desired product and 10% of dibrominated product.
Reaction SMILES: COCN[C:5]([C:7]1[C:12]([N:13]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)(=[O:19])=[O:18])COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:13][C:12]2[C:7]([C:5]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:6])=[N:8][CH:9]=[CH:10][CH:11]=2)(=[O:18])=[O:19])=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCNC(=O)c1ncccc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxymethyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(c2ccncc2)CC1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) and triethylamine (0.7 ml) in dry dichloromethane (20 ml) was treated slowly with a solution of 4-bromophenylsulphonyl chloride (0.77 g) in dry dichloromethane (10 ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were washed with water, brine, dried (MgSO4) and evaporated to yield a white crystalline solid which was recrystallised from ethyl acetate to give 1-(4-pyridyl)-4-(4-bromophenylsulphonyl)piperazine (0.84 g) as a solid, m.p. 199-200° C.: microanalysis, found: C, 47.3; H, 4.1; N, 10.9%; C15H16BrN3O2S requires: C, 47.1; H, 4.22; N, 11.0%; NMR: (CDCl3) 3.13(t,4H), 3.42(t,4H), 6.62(dd,2H), 7.67(q,4H), 8.29(d,2H): MS: m/z 382 (MH)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=1)[CH3:2].[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].Cl[Sn](Cl)(Cl)Cl>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:19]=[N+:20]=[N-:21])[O:14][CH2:15][CH2:16][OH:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(OCC2OCCO2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-([1,3]-dioxolan-2-ylmethoxy)-benzoic acid ethyl ester (2.02 g, 8 mmol) and azidotrimethylsilane (1.17 ml, 8.8 mmol) was added SnCl4 (60 μl) at room temperature under nitrogen. After 2 hr, 2% aqueous methanol (10 ml) was added to the reaction mixture and the reaction was stirred at room temperature for 30 minutes. All the solvents were evaporated under reduced pressure. The residue was co-evaporated with ethanol (2×10 ml). The residue was purified by a column chromatography (3×20 cm). The product was eluted with 0 to 1% methanol in DCM. The title compound was obtained as a colourless oil (2.01 g, 85.1%). APCI-MS, m/z 267.90 (M-N2+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17](#[N:20])[CH:18]=[CH2:19].C(N(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[CH:18][C:17]#[N:20])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Reaction time: 7 h
Yield: 16.1 %

Procedure:
6.76 g (0.02 mol) of 4,4'-dibromostilbene, 1.06 g (0.02 mol) of acrylonitrile, 4.08 g (0.022 mol) of tri-n-butylamine, 0.0898 g (0.4 mmol) of palladium acetate and 0.2098 g (0.8 mmol) of triphenylphosphine are added under argon to 10 ml of toluene. The reaction mixture is stirred at 100°-115° C. for 7 hours. Working up gives 1 g (16% of theory) of 4-bromostilbene-4'-acrylonitrile in the form of a pale yellow powder. Melting point 258° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][NH:18][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: CC(C)CCN
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Product: CSc1nc(NCCC(C)C)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of isopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 39 mg (38%), m.p. 157°-158° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[F:12][C:13]([F:17])([F:16])[CH:14]=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:17])([F:16])[CH:14]([OH:15])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=CC(F)(F)F
Reactant: C=CCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC#CC(O)C(F)(F)F
Yield: 72 %

Procedure:
1-hexene (6.2 g, 76 mmol) and n-butyllithium (52 ml, 1.5 M in hexane) and trifluoroacetaldehyde (7 g, 71 mmol) were reacted 3 hours under the action of ultrasonic irradiation (as generated by a commercially available ultrasonic cleaner 220H manufactured by Branson Cleaning Equipment Company). The reaction mixture was poured into aqueous 2% HCl solution and diethyl ether was used for extraction of the oily layer. The extracts were then distilled to give 1,1,1-trifluoro-3-octyne-2-ol (b.p.: 83-85° C./21 mmHg) in a yield of 72%. This hydroxyalkyne gave the following analytical data:
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>>[Br:45][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][C:11]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:38])(=[O:39])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1
Reactant: CCCCc1nn(-c2cc(N)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 77 %

Procedure:
Propionyl bromide was reacted with 2-(5-amino-2-bromophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) according to the procedure of Example 26 to give a 77% yield of the title compound as a stiff, off-white foam, mp 119°-121° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 686,688 (M+1)+.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[NH:9][CH:8]=[CH:7][N:6]=[C:5]1[C:10]([O:12][CH3:13])=[O:11].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([N:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ncc[nH]c1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH was added to the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, benzyl chloride (0.15 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product, which was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2, 0.102 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.35-7.40 (m, 6H), 7.29 (d, 1H), 5.14 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>C1COCC1>[NH2:34][C:33]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Reactant: N#Cc1ccncc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cccnc3[nH]2)c(=O)[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20 minutes, a solution of 3-aminopyridine-4-carbonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred 3 hours, and then refluxed overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. A precipitate formed, was filtered off, and was washed repeatedly with ether to yield the desired compound as a brown solid. Purification by reverse phase chromatography afforded the desired product as a yellow solid. LC/MS m/z 279.0 (MH+), Rt 1.29 minutes.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]4[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=4[C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])[CH:15]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>>[NH2:8][C:9]1[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=3[C:32]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:33])[CH:15]=2)[N:10]=1
Reactant: COc1ccc(CNc2nc3ccc(-c4c(C)cccc4C(=O)N4CCCC4)cc3cc2N2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reaction time: 3 h

Procedure:
A solution of (2-(2-(4-methoxybenzylamino)-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone (30 mg, 0.056 mmol) and TFA (2 mL) was heated at 90° C. After 3 h, the reaction mixture was concentrated in vacuo, diluted with DCM and concentrated again. The crude product was dissolved in MeOH and filtered through an SCX (1 g) column then eluted with a 2M ammonia methanol solution to release the product. This filtrate was concentrated in vacuo to give a light orange solid that was washed with ether and decanted to remove most of the remaining starting material. The remaining solid was dissolved in DCM and purified by preparative thin layer chromatography (5×20 cm, 1000 um, 10% MeOH:DCM) to give (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as a white solid. MS (ESI, pos. ion) m/z: 417 (M+1).