Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.N1CCCC1C(O)=O.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[C:21]([O:25][C:26](=[O:46])[CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:34]1[CH:43]=[C:42]2[C:37]([C:38]([Cl:45])=[CH:39][N:40]=[C:41]2Cl)=[CH:36][CH:35]=1)=[O:33])([CH3:24])([CH3:23])[CH3:22].O>CS(C)=O>[C:21]([O:25][C:26](=[O:46])[CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:34]1[CH:43]=[C:42]2[C:37]([C:38]([Cl:45])=[CH:39][N:40]=[C:41]2[NH:19][C:18]([NH2:20])=[NH:17])=[CH:36][CH:35]=1)=[O:33])([CH3:24])([CH3:22])[CH3:23]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: O=C(O)C1CCCN1
Solvent: CS(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
N-1(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline trifluoroacetate ##STR67## NaH (65 mg, 60% dispersion in mineral oil, 1.63 mmol) was added to a stirred solution of guanidine hydrochloride (154 mg, 1.61 mmol) in DMSO (5 mL) at 50° C. and the solution stirred for 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (253 mg, 0.64 mmol) was added and the mixture was heated at 80° C. overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with water, brine, dried over (MgSO4), and evaporated in vacuo. The residue was crystallised with CH2Cl2 -i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (241 mg, 0.58 mmol).
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[CH2:1]([N:3]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(CCC(=O)O)cc2)c1
Yield: 66 %

Procedure:
A solution of 400 mg (0.98 mmol, 1 eq) of (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylic acid (prepared in Example 27 g) in 10 mL of ethyl acetate in the presence of 0.2 ml of methanol is stirred for 4 hours at room temperature in the presence of 200 mg (50% by mass) of 10% palladium-on-charcoal under a hydrogen atmosphere. The reaction medium is filtered through Celite and then evaporated to dryness. After crystallization from ethyl ether/pentane, 265 mg of 3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=70° C.). Yield=66%
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(N(CC)CC)C>C(O)C>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncnc3c2nc(-c2ccc(Cl)cc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 70 °C

Procedure:
6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.07 mmol), piperidine-4-carboxylic acid ethyl ester (34 mg, 0.22 mmol), and triethylamine (20 μl, 0.29 mmol) were combined in ethanol (1 ml) and heated at 70° C. for 2 hours. The reaction mixture was concentrated under a stream of N2 and then extracted into ethyl acetate from saturated NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, evaporated to dryness, and then purified by preparative TLC using 4% methanol in methylene chloride as eluant to obtain title compound 7A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred and evaporated to dryness to afford the hydrochloride salt of compound 7A-1 (24 mg, 65%) as a solid: +ESI MS (M+1) 530.1; 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.50–7.45 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.68 (v br s, 2H), 2.85 (m, 1H), 2.16 (m, 2H), 1.89 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C.O>C1COCC1.[Cu](I)I.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>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: COC(=O)Nc1cc(C)c(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1cc(C)c(Br)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
(4-Bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester (605 mg, 1.64 mmol) was dissolved in THF (6 ml). (Trimethylsilyl)acetylene (0.70 ml, 4.95 mmol), copper iodide (33.5 mg, 0.175 mmol), Pd(PPh3)2Cl2 (56.5 mg, 0.081 mmol) and triethylamine (0.690 ml, 4.95 mmol) were added and the mixture was stirred at room temperature for four hours. Water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give (4-bromo-5-methyl-2-trimethylsilanylethynyl-phenyl)-carbamic acid methyl ester (548 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(Cl)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-5-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours, A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: CN(C)CCCN
Solvent: C1COCCO1
Product: CN(C)CCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
0.16 g (0.00041 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 6 ml of dioxane and treated with 0.52 ml of 3-dimethylamino-1propylamine. The mixture was stirred at 60° C. for 24 hrs., the solvent was removed and the residue was chromatographed on silica gel firstly with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The product-containing fractions were freed from solvent, the residue was dissolved in 1N HCl, filtered and the filtrate was adjusted to pH 9 with 1N NaOH. The precipitate which thereby resulted was filtered off under suction and dried in a high vacuum. There was obtained 0.072 g (43%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N',N'-dimethylpropane-1,3-diamine as pink coloured crystals; m.p.: >250° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:28]3[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]3)[S:8][C:7]=2[CH:35]=1.[BH4-].[Na+].O>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:28]3[CH2:29][CH2:30][CH:31]([OH:34])[CH2:32][CH2:33]3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCC(=O)CC3)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCC(O)CC3)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
50 mg of [6-methoxy-2-(4-oxocyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 4 ml of methanol and 0.5 ml of THF, followed by ice cooling, 6 mg of sodium borohydride was added, and the mixture was stirred at 0° C. for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resultant crude product was purified by TLC (developing solvent, chloroform:methanol=19:1) to obtain 32 mg of [6-methoxy-2-(4-hydroxycyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:13][C:14]#[C:15][CH3:16].[Br:17][C:18]1[NH:19][C:20]([C:25]#[N:26])=[C:21]([C:23]#[N:24])[N:22]=1>O.C(OCC)(=O)C>[Br:17][C:18]1[N:19]([CH2:13][C:14]#[C:15][CH3:16])[C:20]([C:25]#[N:26])=[C:21]([C:23]#[N:24])[N:22]=1
Reactant: CC#CCBr
Reactant: N#Cc1nc(Br)[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Br)nc(C#N)c1C#N
Temperature: 50 °C

Procedure:
69.8 g of potassium carbonate and 50 ml N,N-dimethylformamide solution of 74 ml of 1-bromo-2-butyne were added to a 520 ml N,N-dimethylformamide solution of 90.6 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS No 50847-09-1], and the mixture was heated at 50° C. for 8 hours. 1 L of ethyl acetate and 500 ml of water were added to the solution, and the organic layer was washed twice with 500 ml of water and then with 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 48.0 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:4).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](=O)[CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:19].O>CN(C)C=O>[CH3:19][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:31])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2.0 g (60%, 51 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, and 11.3 g (51 mmol) of ethyl diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 5.5 g (25 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetra-hydroquinolin-6-yl]ethanone. The obtained mixture was stirred at 60° C. for 48 hours, followed by the addition of water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (4% ethyl acetate/n-hexane) to give 4.0 g of the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][Cl:10])=[CH:2]1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl-:10].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: ClCc1cccc(-c2ccsc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Yield: 66.5 %

Procedure:
2.40 g of 3-(3-thienyl)benzyl chloride was dissolved in 40 ml of toluene, and 3.62 g of triphenylphosphine was added. The mixture was heated under reflux for 50 hours. The reaction mixture was allowed to cool, and the precipitated crystals were collected by filtration to give 3.60 g (yield 66%) of 3-(3-thienyl)benzyltriphenylphosphonium chloride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([OH:45])=O.[F:46][C:47]([F:68])([F:67])[C:48]1[CH:49]=[C:50]([S:54]([CH2:57][CH2:58][S:59][C:60]2[C:65]([NH2:66])=[CH:64][CH:63]=[CH:62][N:61]=2)(=[O:56])=[O:55])[CH:51]=[CH:52][CH:53]=1>C(Cl)Cl.CCCCCC>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([NH:66][C:65]1[C:60]([S:59][CH2:58][CH2:57][S:54]([C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([C:47]([F:67])([F:68])[F:46])[CH:49]=2)(=[O:56])=[O:55])=[N:61][CH:62]=[CH:63][CH:64]=1)=[O:45]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CC(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.7 g (4.0 mmol) HATU and 1.36 ml (8.0 mmol) DIPEA were added to a solution of 582 mg (3.5 mmol) 2-(2-methoxyphenyl)acetic acid in DCM (10 ml) and the mixture was cooled to 0° C. After stirring for 15 min a solution of 725 mg (2.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in DCM (6 ml) was added at 0° C. The mixture was then stirred for 16 h at room temperature. Then it was diluted with DCM and washed successively with a saturated aqueous NH4Cl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue yielded 827 mg (1.6 mmol, 81%) 2-(2-methoxyphenyl)-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 511.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12.[Cu][C:12]#[N:13].O>CN1CCCC1=O>[C:12]([C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12)#[N:13]
Reactant: Brc1ccn2ccncc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccn2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
2 g of 8-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 was added to a mixture of 2 g of copper(I) cyanide dissolved in 20 ml of N-methylpyrrolidone at 160° C. The reaction mixture was stirred for 10 minutes and cooled to room temperature. The reaction mixture was poured into 100 ml of distilled water, extracted with ethyl acetate (50ml×3), and then concentrated to dryness to obtain 1.2 g of yellowish brown title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CSc1ccc(C(=O)O)nc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A stirred mixture of 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (0-5% gradient, MeOH/CH2Cl2, 0-5% gradient, product eluted after 4.7 min). The product fractions were combined, concentrated and the residue was triturated in MeCN (50 mL) for 1.5 h. The product was isolated by filtration and dried in vacuo to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.52 g, 57% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.89 min (98.54%); mp: 210-212° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.97-2.12 (m, 1H), 2.53-2.78 (m, 6H), 4.62 (d, J=6.2 Hz, 2H), 7.68-7.90 (m, 4H), 7.91-8.04 (m, 1H), 8.52 (d, J=1.7 Hz, 1H), 9.51 (t, J=6.3 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.02, 28.57, 29.09, 42.35, 58.73, 121.75, 122.05, 123.15, 129.59, 131.34, 133.53, 133.82, 139.65, 145.00, 145.90, 147.39, 164.07, 167.73, 167.88, 172.15; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.24; H, 4.33; N, 12.16.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[N:13][CH:14]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])#[CH:24]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:24]#[C:23][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[CH:12]=[N:13][CH:14]=1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Reactant: C#Cc1cccc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C#Cc2cncc(F)c2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Add triethylamine (0.79 mL, 5.64 mmol), copper (I) iodide (15.43 mg, 0.08 mmol) and bis(triphenylphosphine)palladium (II) dichloride (49.48 mg, 0.07 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoropyridin-3-ylester, (prepared as described in PREPARATION 6), (345 mg, 1.41 mmol) and 3-ethynylbenzonitrile, prepared as described in PREPARATION 8), (230 mg, 1.41 mmol) in ethyl acetate (2 mL). Stir in a sealed tube at 70° C. for 18 h. Concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (109 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([O:14]CC)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:18][C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([NH2:27])=[CH:21][N:20]=1>C(O)C.C(O)(=O)C.ClCCl>[Cl:18][C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:12](=[O:14])[N:25]([CH3:26])[C:23]=2[N:24]=1
Reactant: CNc1nc(Cl)ncc1N
Reactant: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-c2nc3cnc(Cl)nc3n(C)c2=O)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-(3,5-dimethoxyphenyl)-2-oxoacetate (1 g, 4.2 mmol) and 2-chloro-N4-methylpyrimidine-4,5-diamine (600 mg, 3.8 mmol) in ethanol (100 mL) and acetic acid (2.5 mL) was stirred at 80° C. for 48 h and cooled to RT (5° C.). The mixture was diluted with dichloromethane and washed with brine. The organic layer was directly concentrated and purified by chromatography on silica gel to give the title compound (700 mg, 50%). MS (ES+) C15H13ClN4O3 requires: 332, 334. found: 333, 335 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC.[OH-].[Na+]>CC1C=CC=CC=1C.C1(C)C=CC=CC=1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:42][N:41]=[N:40][N:2]=2)=[CH:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
A solution of 1.6 g (4.5 mmol) of crude N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(2methoxyethyl)valeramide and 1.8 g (5.5 mmol) of tri-n-butyltin azide in 15 ml of o-xylene is heated under reflux for 20-24 hours while passing a gentle stream of nitrogen through. After cooling, the solution is diluted with about 30 ml of toluene, treated with 15 ml of 1N aqueous sodium hydroxide solution and intensively stirred for 2 hours. The aqueous phase is separated off and rendered acidic with 16 ml of 1N aqueous hydrochloric acid. The precipitated product is isolated by extraction with ethyl acetate. The crude title compound is thus obtained as an oil which crystallizes from a little ethyl acetate, m.p. 120°-122°.