Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:16]=1[NH2:17].O>CC(C)=O>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:16]=1[NH:17][C:11]([NH2:12])=[S:10]
Reactant: N#C[S-]
Reactant: Nc1c(F)cccc1F
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: NC(=S)Nc1c(F)cccc1F

Procedure:
Benzoyl chloride (5.44 g, 38 mmol) was added dropwise to a solution of ammonium thiocyanate (2.55 g, 42.6 mmol) in acetone. Solution was refluxed for 10 minutes at which time a solution of 2,6-difluoro-aniline (5.0 g, 38.8 mmol) in acetone was added dropwise and the solution refluxed for approximately 5 minutes. The solution was then poured into 500 mL of water and a resulting solid precipitated out. The separated crystalline solid was collected by filtration and then heated in a NaOH solution (3 g in 50 mL H2O). The solution was acidified with conc. HCl, then made slightly basic using conc. NH4OH. Crystalline solid was seen and collected to obtain (2,6-difluoro-phenyl)-thiourea. A mixture of the thiourea (5.7 g, 30.3 mmol), AcONa (2.43 g) and ClCH2CO2H (2.86 g) in AcOH (20 mL) was heated to reflux at 130 C.° for four hours. The mixture was poured onto water and the formed solid was isolated by filtration. It was washed with water to give the desired thiazolidinone (a compound of formula IV in which R is 2,6-difluorophenyl) (6.75 g, 29.6 mmol). A mixture of the thiazolidinone (200 mg, 0.8 mmol), 6-formyl quinoline (137 mg, 0.8 mmol) and AcONa (211 mg, 2.4 mmol) in AcOH (10 mL) was heated to reflux at 130 C.° for 2 days. Water was added to the solution and generated a solid that was collected by filtration and washed with water, followed by desiccation in vacuo to afford the title compound as a yellow solid. ES (±) MS m/e=368.0 (M+H). HPLC (rt)−4.53 m
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-:35].[Na+].[CH3:37]O>>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([CH:12]([O:35][CH3:37])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: [OH-]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Reactant: CO
Agent: [Na+]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(OC)c3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)1-(methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4- carboxylic acid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL), 10N sodium hydroxide (10 mL), tetrahydrohydrofuiran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (53%). white solid mp 207° C., MS: 462.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.O1CCCC1.C(OCC)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([Cl:13])=[O:9]
Reactant: Cc1[nH]cnc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1[nH]cnc1C(=O)Cl
Temperature: 25 °C

Procedure:
Under a dry nitrogen atmosphere, a stirred suspension of 5-methyl-1H-imidazole-4-carboxylic acid (12.6 g, 0.10 mole) and several drops of dimethylformamide in 125 ml of dry tetrahydrofuran was cooled in an ice bath. Oxalyl chloride, 20 ml, in 50 ml of tetrahydrofuran was carefully added dropwise. Upon complete addition the reaction mixture was heated under reflux for two hours, cooled to ambient temperature and diluted with 100 ml of diethyl ether. A solid precipitated and was collected by filtration, washed with diethyl ether, and dried to give 5-methyl-1H-imidazole-4-carboxylic acid chloride.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.N1C=CC=CC=1.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][O:15][C:35](=[O:37])[O:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C(CO)CO)cc2C2=CCCCC2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3COC(=O)OC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (as prepared in the previous step, 5.4 mg, 0.015 mmol) and pyridine (3.0 μL, 0.037 mmol) in 0.5 mL of THF at −78° C. was added a solution of triphosgene (1.8 mg, 0.0061 mmol) in 0.5 mL of DCM. The resulting mixture was warmed to RT and continued to stir for 1 h under Ar. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH-DCM) gave 2.8 mg (48%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.01 (s, 1H), 7.66 (dd, 1H, J=8.6, 2.3 Hz), 7.59 (d, 1H, J=2.3 Hz), 7.29 (d, 1H, J=8.6 Hz), 5.66 (m, 1H), 4.65 (dd, 2H, J=10.9, 10.9 Hz), 4.45 (dd, 2H, J=10.9, 4.9 Hz), 3.72 (m, 1H), 2.24 (m, 4H), 1.70-1.88 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H20N4O4, 393.2 (M+H). found 393.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:12]#[N:13]>C(O)(=O)C>[ClH:10].[Cl:10][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([O:8][CH3:9])[CH:6]=1)[NH:1][C:12](=[NH:13])[CH2:11]2
Reactant: COc1cc(Cl)cc(CC#N)c1N
Solvent: CC(=O)O
Product: COc1cc(Cl)cc2c1NC(=N)C2
Product: Cl
Yield: 126 %

Procedure:
In accordance with Example No. 3, 15 g of (2-amino-5-chloro-3-methoxyphenyl)acetonitrile were brought to reflux in 150 ml of acetic acid. 11.2 g of 5-chloro-7-methoxy-1,3-dihydroindol-2-ylideneamine hydrochloride were obtained (yield=63.6%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:12][C:13]1[CH:20]=[C:19]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([C:8]([F:9])([F:11])[F:10])[C@@H:2]2[CH3:1])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: C[C@@H]1NCC[C@@]1(O)C(F)(F)F
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)C(F)(F)F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-3-ol 0.5 oxalate (200 mg), 2-chloro-4-fluorobenzonitrile (289 mg) and lithium carbonate (138 mg), the title compound was obtained as a colorless solid (yield: 100 mg, yield: 35%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In a 2 L three-necked round bottomed flask was added piperidine (85.15 g, 1.0 mol) acetone (1000 mL), and anhydrous potassium carbonate (276.42 g, 2.0 mol, 2.0 equiv.). The flask was equipped with a mechanical stirrer and a condenser. 4-chloro-1-bromo-butane (188.6 g, 1.1 mol, 1.1 equiv.) was added dropwise under continuous stirring at room temperature over a period of 30 min. The suspension mixture was then stirred at 40° C. The progress of the reaction was monitored by TLC, which confirmed the reaction was completed after 4 hours. The mixture was cooled to room temperature and the insoluble materials were removed by filtration and washed with dichloromethane (2×100 mL). The combined filtrates were concentrated under vacuum until it became dry. The residue was then mixed with dichloromethane (500 mL). Insoluble materials were removed by filtration and washed by dichloromethane (2×100 mL). The combined filtrate and washings were concentrated and purified through a flash silica gel column, which gave the expected product as light yellow oil (98.39 g, 56% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]2[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC(C)C)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:192-194° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.73 (1 H, s), 8.33 (1 H, s), 8.17-8.22 (2 H, m), 7.94-7.96 (1 H, d, J=7.2 Hz), 7.76 (1 H, s), 7.54-7.57 (1 H, d, J=7.8 Hz), 7.45-7.48 (1 H, d, J=8.4 Hz), 7.15-7.18 (1 H, d, J=7.5 Hz), 6.79-6.82 (1 H, d, J=9.0 Hz), 4.14-4.20 (1 H, m), 2.56 (3 H, s), 2.19 (3 H, brs), 1.20-1.22 (6 H, d, J=6.3 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H26F3N6O: 519.2115. found: 519.2121.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Br[CH:17](Br)[CH3:18].Br[C:21]1[S:22][C:23](Br)=[CH:24][CH:25]=1.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[C:21]1[S:22][C:23]([C:3]2[S:4][CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:17][CH3:18])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccsc1Br
Reactant: CC(Br)Br
Reactant: Brc1ccc(Br)s1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCc1ccsc1-c1ccc(-c2sccc2CCCCCCCC)s1
Reaction time: 3 h
Yield: 134.5 %

Procedure:
0.53 g (21.8 mmol) of magnesium turnings were introduced in a 100 ml flask and suspended in 30 ml of anhydrous diethyl ether. To the resulting suspension, maintained under an argon (Ar) atmosphere, was slowly added a solution of 3.0 g (3.9 mmol) of 2-bromo-3-octylthiophene having formula (1) and 0.93 ml (10.9 mmol) of dibromoethane in 20 ml of anhydrous diethyl ether. The obtained reaction mixture was sonicated for 30 minutes and subsequently heated at the boiling point of the solvent, for 1.5 hours. After the elimination of the excess of magnesium turnings by filtration, the solution containing 2-(3-octylthienyl)magnesium bromide having formula (2), was slowly added, at 0° C., to a mixture of 0.4 ml (3.6 mmol) of 2,5-dibromothiophene and 0.18 g (0.3 mmol) of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) [Ni(DPPP)Cl2] in 30 ml of anhydrous diethyl ether. The resulting reaction mixture was heated at the boiling point of the solvent, for 18 hours, and poured into a mixture of crushed ice and hydrochloric acid (HCl) (2 M) obtaining an organic phase and an aqueous phase which were separated. The aqueous phase was then extracted with diethyl ether (3×20 ml). The overall organic phase (obtained by joining the organic phases obtained as described above) was dried over anhydrous magnesium sulfate (MgSO4), at room temperature (25° C.), for 3 hours. The solvent was subsequently evaporated at reduced pressure and the obtained residue was purified by chromatography on silica gel using petroleum ether as eluent obtaining 1.24 g (67% yield) of 3,3″-dioctyl-2,2′:5′,2″-terthiophene having formula (3), as yellow liquid, which was characterized by 1H NMR (300 MHz, CDCl3) obtaining the following spectrum: 7.18 (d, 2H), 7.05 (s, 2H), 6.94 (d, 2H), 2.77 (t, 4H), 1.65-1.59 (m, 4H), 1.39-1.26 (m, 20H), 0.87 (t, 6H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[NH:20][C:19](=O)[NH:18]C(=O)[CH:16]=2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].[CH2:28]([Cl:30])Cl>>[Cl:3][C:19]1[N:18]=[C:28]([Cl:30])[CH:16]=[C:15]([CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[N:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(CSc2ccc(F)cc2)[nH]c(=O)[nH]1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1ccc(SCc2cc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (15.2 g, 99.1 mmol) was added to 6-[(4-fluorophenyl)sulfanylmethyl]-1H-pyrimidine-2,4-dione (2.5 g, 9.91 mmol), and the resulting solution was stirred at reflux for 7 hours. The reaction was allowed to cool and the phosphorus oxychloride removed under reduced pressure to give a brown oil. This was dissolved in DCM and ice water (50 mL) added followed by solid sodium bicarbonate (until effervescence stops). The aqueous layer was extracted with DCM (2×50 mL) and the organics dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.11 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.O[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][N:10]([CH2:25][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:9]2(=[O:15])=[O:14])=[CH:16][CH:17]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccncc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccncc3)S2(=O)=O)cc1
Temperature: 0 °C

Procedure:
The title B compound, 2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (128 mg, 0.5 mmol), 4-hydroxypyridine (109 mg, 1 mmol) and triphenylphosphine (262 mg, 1 mmol) are put into a small reaction vessel under argon and dissolved in 10 mL of THF. This solution is stirred in an ice/water bath and diethyl azodicarboxylate (174 mg, 1 mmol) diluted with an equal volume of THF is added dropwise to the stirred cold solution. The reaction is allowed to stir 16 h while the ice bath slowly warms to RT. The solvent is evaporated on the rotary evaporator, then the residue is taken up in a minimal amount of CH2Cl2 and chromatographed on a 10 g RediSep silica gel column, using a gradient from 1 to 5% EtOAc in CH2Cl2 over 15 to 20 min to afford 2-(4-methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one: [M+1]+=348.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][N:7]=1.O.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].[CH2:18](N(CC)CC)C>C(OCC)(=O)C=C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:10][C:3]1[C:2](/[CH:18]=[CH:13]/[C:12]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: CCOC(C)=O
Reactant: COc1cnc(Cl)c(N)n1
Reactant: CCN(CC)CC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C=CC(=O)OCC
Solvent: O
Product: CCOC(=O)/C=C/c1ncc(OC)nc1N
Temperature: 125 °C
Reaction time: 2 h

Procedure:
To a solution of 3.15 g of 3-chloro-6-methoxypyrazin-2-amine in 20 mL of triethylamine, 2.6 mL of ethyl acrylate and 0.50 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at an external temperature of 120 to 130° C. for 2 hours in a sealed tube. Thereto was further added 5 mL of triethylamine, and the mixture was stirred at the same temperature for 4 hours 50 minutes. The reaction mixture was cooled to room temperature and left overnight, then 0.5 mL of ethyl acrylate and 0.25 g of bis(tri-tert-butylphosphine)palladium(0) were added thereto and the mixture was stirred at an external temperature of 115 to 125° C. for 9 hours 20 minutes in a sealed tube. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=4:1 to obtain 2.55 g of ethyl (2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate as a yellow solid.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:7]1=O.C(=O)=O.CC(C)=O>CCOCC.CCCCCC>[C:1]([C:14]1[C:9]2[CH:8]=[CH:7][O:6][C:10]=2[CH2:11][CH2:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccccc2O1
Reactant: [Li]C(C)(C)C
Agent: O=C=O
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)C1=CCCc2occc21
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A 2000-mL 3-neck flask fitted with nitrogen inlet, low temperature thermometer, and 500-mL pressure equilibrated dropping funnel is flame dried and charged with dry hexane (freshly distilled from calcium hydride, 200 mL). The flask is cooled with an external dry ice/acetone bath then tert-butyl-lithium (1.7 M in pentane, 200 mL, 340 mmol) is added via double ended needle transfer. The resulting solution is cooled to -65° C. internal temperature then a solution of 43 (40.00 g, 294 mmol) in a mixture of ether (100 mL) and hexane (300 mL) is added dropwise over 1 hour at a rate such that the reaction temperature does not exceed -55° C. Upon completion of the addition the reaction mixture is stirred with dry ice/acetone cooling for 10 minutes, the cooling bath is removed and the reaction allowed to gradually warm. After 1 hour the temperature reaches about 5° C. The reaction is quenched by dropwise addition of water (40 mL), followed immediately by 2N HCl (200 mL) and tetrahydrofuran (200 mL). The reaction mixture is then poured into a 4000-mL Erlenmeyer flask containing 2N HCl (200 mL) and the resulting mixture diluted to a total volume of 2800 mL with tetrahydrofuran. The elimination is allowed to proceed for 2.5 hours then 20% NaCl (500 mL) was added and the layers separated. The aqueous layer was reextracted with ether (500 mL) and the combined organic layers washed with 20% NaCl (500 mL), dried (Na2SO4) and concentrated to a reddish oil (48.7 g) which is distilled. The total distillate is chromatographed (Water Prep 500A) using hexane as eluant to afford 4-tert-butyl-6,7-dihydrobenzofuran as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12]Br)[CH:5]=1.[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][N:18]2[C:19]3[C:24](=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:16]([CH3:15])=[C:17]2[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: COC(=O)c1cccc(OCCBr)c1
Product: COC(=O)c1cccc(OCCn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)c1

Procedure:
3-(2-Bromo-ethoxy)-benzoic acid methyl ester and 5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processed according to the method described in Example 59 to give 3-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 2.26 (s, 3H), 3.90 (s, 3H), 4.22 (t, J=4.9 Hz, 2H), 4.60 (t, J=5.1 Hz, 2H), 6.91 (dd, J=7.8, 2.3 Hz, 1H), 7.21-7.24 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.52-7.59 (m, 2H), 7.65 (dd, J=7.8, 5.1 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.98-8.09 (m, 2H), 8.56-8.77 (m, 2H). HRMS (ESI) m/z 412.1664 [(M+H)+ Calcd for C25H22N3O3: 412.1661].
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)C>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)[N:20]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (20.4 g, 163 mmol) and 4-nitrophenylhydrazine (25.0 g, 163 mmol) in anhydrous EtOH (300 mL) was added acetic acid (3.4 mL, 60 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between EtOAc (500 mL) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 80:20 hexanes/EtOAc) to give 36.0 g (85%) of the desired product. 1H-NMR (DMSO-d6) δ 8.28 (d, J=6.9 Hz, 2H), 7.93 (d, J=6.9 Hz, 2H), 5.55 (s, 2H), 5.46 (s, 1H), 1.20 (s, 9H); MS LC-MS [M+H]+=261, RT=2.74 min.
Reaction SMILES: CC(C)(O[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)C.F[C:40](F)(F)C(O)=O>ClCCl>[CH3:40][N:7]([CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Solvent: ClCCl
Product: CN(C)CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Yield: 97 %

Procedure:
9.6 g (18.3 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were stirred overnight in 200 ml of a 5% solution of trifluoroacetic acid in dichloromethane. The reaction mixture was then evaporated down in vacuo. 13.47 g (97% of theory) of the desired 1-[N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were obtained as the trifluoroacetate salt. Then 7.0 g (9.1 mmol) of the crude product were dissolved in 200 ml of water and 4.1 ml of a 40% formaldehyde solution (45.6 mmol) were added whilst cooling with an ice bath. The reaction mixture was stirred for 10 minutes at room temperature, carefully mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath, then mixed with 4.1 ml of a 40% formaldehyde solution (45.6 mmol) whilst cooling externally with ice, after which the reaction mixture was stirred for a further 10 minutes at room temperature and again mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath. The pH of the reaction mixture was monitored continuously during the reaction and kept between pH 3 and pH 6 by dropwise addition of trifluoroacetic acid. The mixture was then stirred for 30 minutes at 5° C., adjusted to pH 10 by the addition of potassium carbonate and extracted four times with 50 ml of ethyl acetate. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=6.5/3/0.3 (v/v/v)). 2.3 g (56% of theory) of a colourless oil were obtained.