Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][NH:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:25][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:25][CH2:24]2)[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (144 mg, 0.272 mmol) in DCM (2.72 mL) at 0° C. was treated with pyridine (66.0 μL, 0.816 mmol), followed by acetic anhydride (51.3 μL, 0.544 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure and taken up in MeOH, filtered through a 0.45 μm Millipore® syringe filter, and purified via HPLC Method A to give the title compound, as a TFA salt, as a yellow solid (74.9 mg, 48.2%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.82 (m, 2H), 1.97 (m, 2H), 2.11 (m, 4H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.45 (m, 2H), 2.73 (t, J=5.9 Hz, 0.7H), 2.84 (t, J=5.9 Hz, 1.3H), 3.11 (m, 2H), 3.47 (m, 2H), 3.81 (t, J=5.9 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H), 4.40 (m, 1H), 4.49 (m, 1H), 4.59 (s, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 458.00.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=C>O>[O:17]([C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCC(=O)Oc1ccccc1)Nc1ccc(C=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: NC(=O)NCC(=O)Oc1ccccc1

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-phenoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-allyloxyiminomethyl)phenyl]-N'-phenoxycarbonylmethylurea.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:40][CH2:39][O:13][C:12]([C:10]1[S:11][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][C:9]=1[N:15]([C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[O:14])=[O:46]
Reactant: CC1CCC(C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(C)CC2)CC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)OCOC(=O)C(C)(C)C)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.27 mmol) in 5.0 mL of dry dimethylformamide under nitrogen was added cesium carbonate (351 mg, 1.08 mmol) and 2,2-dimethyl-propionic acid chloromethyl ester (45 mg, 0.297 mmol). The mixture was stirred for 120 min at 60° C. The mixture was partitioned between ethyl acetate and water. The EtOAc layer was separated and was washed 3 times with water, dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 120 mg (79%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[N:35]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]2[N:32]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:33]=1
Reactant: Cc1cnc(N)c(C)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)n1
Temperature: 130 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (770 mg, 1.61 mmol, 1.0 eq), 3,5-dimethylpyrazin-2-amine (CAS-Nr. 91678-81-8, 218 mg, 1.77 mmol, 1.1 eq) and diisopropylethylamine (0.28 mL, 1.61 mmol, 1.0 eq) in 10 mL isopropanol was added 3 Å molsieves. The reaction mixture was heated to reflux temperature for 2 h. No conversion was observed under these conditions (UPLC-MS). Therefore, the reaction mixture was heated to 130° C. for 1 h under microwave conditions (single mode microwave oven). The reaction mixture was filtered to remove the molsieve and the filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera, 25 g Snap cartridge, DCM→DCM/ethanol 95/5) to deliver 249 mg (31%) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1CNCCN1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 74.9 %

Procedure:
A suspension of 0.80 g (2.69 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.08 g (10.8 mmol) of 2-methylpiperazine, and 20 ml of acetonitrile was refluxed for three hours, then cooled in an ice bath. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.76 g of the title compound, mp 187°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[Li]CCCC.[Cl:28]N1C(=O)CCC1=O>C1COCC1.CCCCCC>[Cl:28][C:13]1[S:14][C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncsc1C#Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(Cl)sc1C#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
2.63 g (8.26 mmol) of tert-butyl N-{5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}carbamate are dissolved in 100 ml of dry THF in a dried Schlenk flask under nitrogen and cooled to −78° C. 11 ml of a 15% solution of n-BuLi in n-hexane are then slowly added dropwise, and the mixture is stirred at −78° C. for 20 min. 1120 mg (8.38 mmol) of N-chlorosuccinimide dissolved in 1 ml of dry THF are subsequently added dropwise, and the mixture is stirred at −78° C. for 15 min, then quenched using 10 ml of n-butanol and warmed to RT. The solvent is removed in vacuo, and the residue is purified directly by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 99/1), giving 2.3 g (6.51 mmol, 78%) of tert-butyl N-{2-chloro-5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}-carbamate as beige solid from PE; ESI-MS: m/e: 353 ([M+H]+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)=[O:26])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A solution of the carbonate(45 g, 0.13 mol) produced in Example 1 in 250 mL of methylene chloride was added dropwise under nitrogen over three hours to a solution of 4-hydroxypiperidine (14.3 g, 0.14 mol) and triethylamine (19.7 mL, 0.14 mol) in 250 mL of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 4 hours and at room temperature overnight. The reaction was extracted one time with 1N HCl and then multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 39.27 g of a light yellow solid. Recrystallization from diisopropyl ether-methanol gave 31.78 g (79%) of the title compound as an off-white crystalline solid, mp 130-133° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: COc1cccc2c1CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCc1cc(Nc3ccc(F)cc3F)ccc1C2=O

Procedure:
For the synthesis of the title compound, 0.54 g (0.0020 mol) of 8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.26 g (0.0020 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). C22H17F2NO2 (Mr=365.38)
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@@H:25]([C:33]([OH:35])=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH2:46][C@@H:47]([C:55]([NH:57][C@H:58]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@@H:25]([C:33]([NH:46][C@@H:47]([C:55]([NH:57][C@H:58]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:59][O:60][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:35])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.71 ml of N-ethylmorpholine and 7.98 g of DCC are added at 0° C. to a solution of 10.69 g of Z-D-Phe-OH, 14.5 g of H-D-Phe-Ser(tBu)-OtBu.HCl and 4.89 g of HOBt in 150 ml of dimethylformamide. The mixture is left to stir at 0° C. for 1 hour and to stand at room temperature overnight. The precipitate is filtered off with suction, and the filtrate is concentrated. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking successively with saturated NaHCO3 solution, KHSO4 /K2SO4 solution and water, dried over Na2SO4 and concentrated. The oil crystallizes from isopropanol/petroleum ether.
Reaction SMILES: [C:1]([C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:12].C(N(CC)CC)C.[Cl-]>CN(C=O)C.C(Cl)Cl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[C:12][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)c1cccnc1Br
Reactant: C#Cc1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cccnc1C#Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg 3-Acetyl-2-bromopyridin, 550 μL 2-ethynyl-pyridine, 765 μL triethylamin, 255 mg triphenylphosphinpalladium(II) chlorid, 17 mg Cu(I)I were suspended in 10 mL DMF under argon atmosphere and stirred for 2 h at 25° C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and saturated NH4Cl solution. The organic phase was concentrated and the mixture separated via FCC (100 g SiO2, cyclohexane→cyclohexane/ethylacetate 35:65) to yield 455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone as solid. Analysis: HPLC-MS: Rt=0.88 min (method E) M+H=223.
Reaction SMILES: Cl.[F:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[F:2][C:3]12[CH2:11][CH:7]3[CH2:6][C:5]([NH:12][CH2:20][C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]#[N:29])=[O:22])([CH2:4]1)[CH:9]([CH2:8]3)[CH2:10]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(F)(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K2CO3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl) glycyl]pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38% yield. m/z (M+1) 292; 1H NMR (CDCl3) 300 MHz δ 4.80-4.73 (m, 1H), 3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, 1H), 2.87-2.08 (m, 6H), 2.0-1.60 (m, 6H), 1.50-1.42 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CO.O>[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([OH:23])=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
NaOH (0.12 g, 3 mole) was added in one portion to a stirred solution of 2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.59 g, 1.4 mole) dissolved in 6 mL of 5:1 CH3OH-H2O at room temperature. After stirring for 3 hours, the mixture was concentrated, diluted with H2O, acidified with 6N HCl (pH 1) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration afforded 0.5 g (91%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][CH2:20][C:21]([OH:23])=O)[NH:17][CH:18]=2)[CH:9]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:24]1([C:21](=[O:23])[CH2:20][S:19][C:16]2[NH:17][CH:18]=[C:14]([C:10]3[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=3)[N:15]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C(O)CSc1nc(-c2cccnc2)c[nH]1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2cccnc2)c[nH]1)N1CCCCC1

Procedure:
32 mg (0.069 mmol) of (4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid trifluoroacetic acid salt from step (b), 8.8 mg (0.1 mmol) of piperidine, 24.9 mg (0.076 mmol) TOTU and 15.9 mg (0.138 mmol) NEM in 4 ml of DMF were stirred at room temperature for 4 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 7 mg.
Reaction SMILES: [CH2:1]([S:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O-:11])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:18][C:19]1[C:20]([S:28][CH3:29])=[N:21][C:22]([CH3:27])=[CH:23][C:24]=1[S:25][CH3:26].C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][S:28][C:20]1[C:19]([NH:18][C:9](=[O:11])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[C:24]([S:25][CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: CCCCCCSC(C(=O)[O-])c1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCSC(C(=O)Nc1c(SC)cc(C)nc1SC)c1ccccc1
Yield: 7.6 %

Procedure:
To a stirred solution α-hexylthio-phenylacetate (204 mg) and 3-amino-2,4-bis(methylthio)-6-methyl-pyridine (146 mg) in methylene chloride (5 ml) was added dropwise 2M solution of trimethylaluminum in toluene (0.4 ml), and the mixture was refluxed for 16 hours. After cooling to 0° it was acidified slowly with 1N hydrochloric acid, and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried (magnesium sulfate) and evaporated to give a solid residue. It was purified by a column chromatography on silica gel with elution by 2:8 ethyl acetate-hexane to give a solid residue. Crystallization from ethyl ether and hexane to provide pure N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-α-hexylthio-phenylacetamide (24 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:6][CH:5]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>CC#N.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:23]2[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)cc2C)cc1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a stirring solution of 4-[Chloro-(3-methoxy-phenyl)-methyl]-benzoic acid methyl ester (5.0 g, 17.3 mmol) in 87 mL CH3CN was added 3,5-dimethyl pyrazole (5.0 g, 51.8 mmol) and tetra-n-butyl ammonium iodide (3.2 g, 8.6 mmol). The mixture was heated to reflux for 24 h, cooled to room temperature and concentrated under reduce pressure. The crude oil was purified by flash chromatography with 30% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated under reduce pressure to give the desired product (1.8 g, 30%) as a clear yellow oil. 400 MHz 1H NMR (CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.19-7.25 (m, 3H), 6.81-6.83 (m, 1H), 6.68-6.73 (m, 2H), 6.52 (s, 1H), 5.85 (s, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H); MS (M+1) 351.2.
Reaction SMILES: CO[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].C(O)(=[O:18])C>Br>[N+:13]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:3]=1)([O-:15])=[O:14]
Reactant: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: CC(=O)O
Agent: Br
Product: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1
Yield: 83 %

Procedure:
A solution of 6-methoxy-5-nitrobenzotrifluoride (24.73 g, 110.7 mmol) in acetic acid (260 ml) and aqueous HBr solution (62%, 130 ml) was heated to reflux for 96 h, cooled, evaporated and taken up in aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 19.27 g (83%) of 4-nitro-2-trifluoromethyl-phenol as yellow solid, MS: 207 (M+), MP: 103-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]#[N:22]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:20][C:21]#[N:22])[C:7]=2[CH:12]=1
Reactant: N#CCBr
Reactant: COc1ccc2c(c1)NCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: COc1ccc2c(c1)N(CC#N)CCO2
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The compound obtained in Step D (400 mg; 2.42 mmol) is suspended in 10 ml of water. Potassium carbonate (10 eq.; 24.2 mmol; 3.35 g), tetrabutylammonium bromide (0.05 eq.; 0.12 mmol; 40 mg) and bromoacetonitrile (8 eq.; 19.37 mmol; 1.35 ml) are then added. The mixture is stirred vigorously for 12 hours at 70° C. After returning to ambient temperature, the product formed is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered, and then concentrated under reduced pressure. The residue obained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/1)). The title product is obtained in the form of a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[F:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:18]([N:17]([CH3:20])[CH3:16])=[NH:19])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C#N
Reactant: Nc1ccccc1-c1cccc(F)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CN(C)C(=N)Nc1ccccc1-c1cccc(F)c1

Procedure:
A mixture of 2-amino-3'-fluorobiphenyl hydrochloride (3.6 g), N,N-dimethylcyanamide (1.7 g) and m-cresol (25 ml) was heated at 90°-95° C. for 8 hours to give N-(3'-fluoro-2-biphenylyl)-N',N'-dimethyl guanidine (m.p. 109°-110° C.) as a colourless solid which was recrystallised from hexane.