Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34](Cl)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([O:7][CH2:6][C:5]#[C:4][CH:1]5[CH2:3][CH2:2]5)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2
Reactant: OCC#CC1CC1
Reactant: NC1=N[C@@](c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@](c2cc(NC(=O)c3cnc(OCC#CC4CC4)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 57.5 %

Procedure:
To a solution of 3-cyclopropylprop-2-yn-1-ol (205 mg, 2.137 mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil; 8.6 mg, 0.214 mmol) at rt. After 15 min N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide (Example 261, 88 mg, 0.214 mmol) was added and the reaction mixture was stirred at 60° C. for 50 min. Water (1.0 mL) and aqueous, saturated NaHCO3 solution (1 mL) were added. The resulting mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM) to give 58 mg of the title compound as an off-white solid. MS m/z=472 [M+H]+
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.O1CCN(NC(=S)[S-])CC1>CO>[C:6]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Agent: S=C([S-])NN1CCOCC1
Solvent: CO
Product: O=C(O)Cc1ccccc1

Procedure:
A solution of 1.85 g (0.01 mole) of 4-chloromethylphenyl acetic acid and 6.25 g (0.025 mole) of freshly prepared morpholinodithiocarbamate salt in 250 ml of methanol was stirred under nitrogen for 20 hours at room temperature. The solvent was evaporated, water was added and the solution was acidified to pH 1 using aqueous 10% hydrochloric acid then extracted with ethylacetate, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ethylacetate to give p-morpholinodithiocarbamatemethyl)phenylacetic acid. M. P. 163° C.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h

Procedure:
A suspension of CuBr2 (20.88 g, 93.5 mmol) and HMTA (13.1 g, 93.5 mmol) in degassed DCM (250 ml) was treated with DBU (14.0 ml, 93.5 mmol) and the dark solution formed was stirred in a water bath for 5 minutes. A solution of ethyl (4S)-2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-4,5-dihydro-1,3-oxazole-4-carboxylate (preparation 152) (9.24 g, 23.4 mmol) in degassed DCM (30 ml) was added dropwise to the reaction mixture and stirred at room temperature for a further 3 hours. The solvent was removed under reduced pressure. The resdue was dissolved in EtOAc and washed with a 1:1 solution of NH3(aq):NH4Cl. The aqueous extract was washed with EtOAc (2×380 ml). The combined organic extracts were washed with 2M HCl (500 ml), sat. NaHCO3 (500 mL) and brine (500 ml). The organic extracts were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (0:100) gradually changing to (25:75) to afford the title compound as colourless oil which formed needles on standing (7.39 g, 80%).
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5])=[CH:10][C:9]=1[CH3:16]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C[C@@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Temperature: 25 °C

Procedure:
(S)-3-Bromo-2-methyl-1-propanol (150 mg), 4-bromo-3,5-dimethylphenol (98.5 mg) and potassium carbonate are stirred in 5 mL of acetonitrile at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give a solid, used in the next step without further purification. Yield: 130 mg.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:23][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:24]=[C:25]([NH2:27])[S:26][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1-c1csc(N)n1
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.20 g, 5.68 mmol) and thiourea (0.43 g, 5.68 mmol) in 95% EtOH (8.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)thiazol-2-amine (1.30 g) as yellow solids in 63% yield: 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 2 H), 7.05 (d, J=8.5 Hz, 2 H), 6.76 (s, 2 H), 6.32 (s, 1 H), 5.03 (s, 2 H), 2.17 (s, 6 H).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:48])([CH3:47])[NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)=[O:39]>>[CH3:35][Si:36]([CH3:48])([CH3:47])[N:37]=[S:38]([Cl:1])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39]
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)c1ccccc1

Procedure:
The reactants used in the general procedure were hexachloroethane (0.1353 mol, 32.68 g), triphenylphosphine (0.1367 mol, 36.22 g), triethylamine (0.1353 mol, 19.2 ml), and N-trimethylsilylsulfonamide (3b) (0.1353 mol, 31.0 g).
Reaction SMILES: [CH2:1]([C@@H:5]([C:11]([OH:13])=[O:12])[C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]1C=CC(S(O)(=O)=O)=C[CH:20]=1>COC(OC)(C)C.C(Cl)Cl>[CH3:14][C:15]1([CH3:20])[O:8][C:7](=[O:9])[CH:6]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11]([OH:13])=[O:12])[O:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid B-4 (300 mg, 1.58 mmol) in 2,2-dimethoxypropane (10 mL) is added p-TSA (20 mg) and the reaction is stirred at rt for 16 hours. The solution is diluted with DCM and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:13]1[C:26]2[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.[C:35]([NH2:52])([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36]>C(O)(=O)C>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:52][CH:13]3[C:26]4[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=4[O:20][C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCCCOc1ccc2c(c1)C(O)c1ccccc1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1ccc2c(c1)C(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1O2
Reaction time: 14 h

Procedure:
A solution of p-toluenesulfonic acid (30 mg, 0.015 mmol) in glacial acetic acid (3 mL) was added dropwise at 25° C. over 15 minutes to a solution of 5-(9-hydroxyxanthen-2-oxy)valeric acid (0.2 g, 0.64 mmol) prepared as described above and Fmoc-NH2 (184 mg, 0.76 mmol) in glacial acetic acid (12 mL). This mixture was stirred continuously for 14 hours, filtered, and the resultant white solid washed with water (3×5 mL) and n-hexane (2×5 mL). The solid was dried in vacuo over P2O5 at 25° C. for 6 hours. Yield: 200 mg (69%), TLC-pure Rf : 0.53 EtOAc/MeOH 10:2. 1H-NMR (CDCl3, 300 MHz) δ7.76 (d, 7.4 Hz 2H), 7.59 (d, 7.4, 2H), 7.40 (t,J=7.4, 2H), 7.31 (t,J=7.4 2H), 4.69 (s, broad, 1H), 4.40 (d, J=6.9, 2H), 4.24 (t,J=6.9, 1H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=[O:9])=CC=1.[NH2:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:17]=[C:16]([C:31]#[N:32])[C:15]=1[C:33]#[C:34][CH3:35].C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:13][C:14]1[N:18]([C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:23][C:24]=2[Cl:25])[N:17]=[C:16]([C:31]#[N:32])[C:15]=1[C:33](=[O:9])[CH2:34][CH3:35]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Toluenesulphonic acid monohydrate (2.92 g) was added to a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(prop-1-yn-l-yl)pyrazole (WO-A-97107102; 2.1g) in acetonitrle (40 ml) and the mixture stirred at room temperature for 1 hour. Further p-toluenesulphonic acid monohydrate (1.0) was added and this mixture stirred at room temperature for 16 hours. Further acetonitrile (20 ml) and yet more p-toluenesulphonic acid monohydrate (1.0 g) were added and stirring continued for 1 hour, then the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (500 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and evaporated under reduced pressure, then the residue purified by column chromatography on silica gel (70 g), using dichloromethane as eluant, to yield the title compound as a pale brown solid, m.p. 167-169° C. δ(CDCl3): 1.26 (t,3H), 3.03 (q,2H), 5.83 (br.s,2H), 7.80 (s,2H). MS (thermospray): M/Z [M+H] 377.2; C14H9Cl2F3N4O+H requires 377.0.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[I:18]CI.N(OCCC(C)C)=O>CC#N>[I:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1ccc(-n2nc(C)c(C#N)c2I)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.30 g, 5.70 mmol) in MeCN (8 mL) was added diiodomethane (1.93 mL, 23.9 mmol) followed by isoamyl nitrite (0.19 mL, 1.42 mmol). The reaction vessel was heated using a heating gun to initiate the reaction. After the rest of isoamyl nitrite (1.72 mL, 12.8 mmol) was added and the reaction was stirred for 1 hour at 50° C. The reaction was concentrated into silica and purified using silica gel (Heptane-CH2Cl2 1:0 to 0:1) gave 5-iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.45 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: Nc1ccc(F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
4-Fluoroaniline (0.178 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.125 g, 0.268 mmol, 50%).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3 g (0.014 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 30 ml of dichloromethane, are added dropwise at 15 to −20° C. to a solution of 2.65 ml (0.013 mol) of 4-amino-1-benzyl-piperidine and 6 ml (0.043 mol) of triethylamine in 100 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is extracted with a mixture of I molar sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml of ethanol.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH3:24]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6]([O:9][CH3:24])=[CH:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.3 g, 0.96 mmol) in dimethylformamide (3 mL) at 0° C. under an argon atmosphere was added potassium t-butoxide (0.11 g, 0.96 retool) and, 0.5h later, dimethyl sulfate (0.09 mL, 0.96 mmol). After 5 min, ammonium chloride was added, the mixture was extracted three times with ether, the organic extract was washed three times with water, once with brine, was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 9:1 hexanes/ethyl acetate, provided a white solid (0.06 g, 19%): m.p. 123°-125° C. Analysis Calc. for C20H25NO3 ·0.35 H2O:C 71.98, H 7.76, N 4.20; found: C 71.98, H 7.66, N 3.95
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=[O:20])[C:17]([CH3:19])=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:17]([CH3:19])[C:16]2=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(Nc2ccccc2N)cc1
Product: Cc1nc2ccccc2n(-c2ccc(N)cc2)c1=O

Procedure:
Preparation as in Example 1 but using N-(4-aminophenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 269°-271° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(OC(=O)C)(=O)C>[Cl:10][C:5]1[N:4]=[CH:3][C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(N)cnc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(-n2cccc2)cnc1Cl
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution of 5-amino-2-chloronicotinonitrile (5.0 g, 0.033 m), 2,5-dimethoxytetrahydrofuran (11 g, 0.085 m) and acetic anhydride (20 ml) was heated at reflux with stirring. After two hours, the solution was concentrated to dryness under reduced pressure (20 mm). The residue was triturated with CCl4 and filtered to yield 5.2 g (78% yield) of 2-chloro-5-(1-pyrrolyl)nicotinonitrile, m.p.=144°-146°.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:31]4[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (88 mg, 0.23 mmol), 2-methoxypyridine-3-boronic acid (46 mg, 0.3 mmol), K2CO3 (95 mg, 0.69 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.4 mg, 0.012 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (82.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.06 Hz, 6H) 2.13-2.32 (m, 2H) 2.89 (s, 3H) 3.43 (dd, J=10.48, 6.95 Hz, 1H) 3.48-3.56 (m, 1H) 3.69-3.76 (m, 2H) 4.09 (s, 3H) 4.99 (dt, J=12.38, 6.19 Hz, 2H) 6.62 (d, J=9.85 Hz, 1H) 7.04 (dd, J=7.45, 4.93 Hz, 1H) 7.79 (d, J=9.85 Hz, 1H) 8.13-8.19 (m, 2H) 8.86 (dd, J=7.71, 1.64 Hz, 1H). LRMS (ESI) m/z 411.2 [(M+H)]+, calc'd for C21H26N6O3: 410.48.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:15]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CI
Reactant: CCOC(=O)CNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)c1ccccc1
Temperature: 70 °C

Procedure:
Ethyl N-Phenylglycinate (2 g, 11.1 mmol) was dissolved in toluene (4.5 mL) and iodomethane (0.35 mL, 5.6 mmol) added. After warming at 70° C. over 4 hours, the reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed several times with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10:1 hexanes/EtOAc) afforded a quantitative yield of the title compound as a light yellow oil. MS (ES+) m/z 194 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[CH3:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH3:25])[CH:27]=3)[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Dimethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.03 (d, 1H), 6.94 (br s, 1H), 6.84 (br s, 1H), 5.38 (s, 2H), 3.68 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 6H), 2.14 (s, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16](=[O:24])[C:17]([Cl:23])=[C:18]([Cl:22])[C:19]([OH:21])=O)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][CH3:40].CC1NC2C(C=1)=CC=CC=2>>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16]2([C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH2:29][C:28]4[CH:41]=[CH:42][CH:43]=[C:26]([Cl:25])[CH:27]=4)[C:31]=3[CH2:39][CH3:40])[O:24][C:19](=[O:21])[C:18]([Cl:22])=[C:17]2[Cl:23])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(=O)C(Cl)=C(Cl)C(=O)O)c2cc(OC)ccc21
Reactant: CCc1cc2ccccc2n1Cc1cccc(Cl)c1
Agent: Cc1cc2ccccc2[nH]1
Product: CCCCn1cc(C2(c3c(CC)n(Cc4cccc(Cl)c4)c4ccccc34)OC(=O)C(Cl)=C2Cl)c2cc(OC)ccc21

Procedure:
Following a procedure similar to that described above in part B of this example by using 4-(1-n-butyl-5-methoxy-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid instead of 4-(1-ethyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-(3-chlorobenzyl)-2-ethylindole is substituted for 2-methyl-indole, there is obtained 5-(1-n-butyl-5-methoxy-3-indolyl)-5-[1-(3-chlorobenzyl)-2-ethyl-3-indolyl]-3,4-dichloro-2(5H)-furanone (Formula V: R=CH3 (CH2)2CH2 ; R1 =Y1 =H; R2 =3-ClC6H4CH2 ; R3 =CH3CH2 ; Y=5-CH3O).