Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)=[O:11])=[CH:5][CH:4]=1.[CH3:31][CH:32]([CH3:41])[CH2:33][C:34]1[O:35][CH2:36][C:37](=[O:40])[NH:38][N:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:26]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[C:37](=[O:40])[CH2:36][O:35][C:34]([CH2:33][CH:32]([CH3:41])[CH3:31])=[N:39]3)=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)=[O:11])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)CC1=NNC(=O)CO1
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CBr)cc3)C3CCCC3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(CC(C)C)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
100 mg (0.213 mmol) of methyl 4-({[4-(bromomethyl)phenyl](cyclopentyl)acetyl}amino)-2,3-dihydro-1H-indene-2-carboxylate were dissolved in 3.5 ml of DMF, and 55 mg (0.213 mmol) of 2-(2-methylpropyl)-4H-1,3,4-oxadiazin-5(6H)-one (Example 22A) and 76 mg (0.234 mmol) of cesium carbonate were added. The reaction mixture was stirred at room temperature for 3 d. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC. This gave 8 mg (8% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:27]1([CH2:26][O:16][C:13]2[CH:14]=[C:15]3[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]3=[N:11][CH:12]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrCC1CCCCC1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(OCC4CCCCC4)cc23)cn1
Yield: 52.2 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), (bromomethyl)cyclohexane (146 μL, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4M (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux for 24 h. Standard workup and purification by PTLC using 80% AcOEt in hexane gave 28t as a clear oil (40 mg, 52%); 1H NMR (400 MHz, CDCl3) δ-0.059 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), 1.09 (dq, J=12.2 Hz, J=3.3 Hz, 2H), 1.17-1.40 (m, 2H), 1.65-1.95 (m, 7H), 3.56 (t, J=8.3 Hz, 2H), 3.84 (d, J=6.3 Hz, 2H), 3.99 (s, 3H), 5.64 (s, 2H), 7.38 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.59 (s, 1H), 7.75 (d, J=0.3 Hz, 1H), 8.13 (d, J=2.6 Hz, 1H).
Reaction SMILES: [O-]CC.[Na+].C(O)(=O)C.[CH3:9][CH:10]([CH3:15])[CH2:11][C:12](=[NH:14])[NH2:13].Cl.C(O[C:20](=[NH:27])[CH2:21][C:22](OCC)=[O:23])C.Cl>C(O)C.O>[NH2:27][C:20]1[N:13]=[C:12]([CH2:11][CH:10]([CH3:15])[CH3:9])[N:14]=[C:22]([OH:23])[CH:21]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CC(C)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)Cc1nc(N)cc(O)n1
Yield: 43.5 %

Procedure:
Sodium ethoxide (210 mL of a 21% solution in ethanol, 563 mmol) was diluted with absolute ethanol (290 mL). To the sodium ethoxide solution were then sequentially added 3-methylbutanimidamide acetate (45 g, 281 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (59 g 85% purity, 256 mmol) and the mixture was heated to reflux overnight. The mixture was cooled down, solvent was stripped off and the residue was diluted with water (100 mL). pH was adjusted to 6-7 with 2 N HCl and the slurry was heated to reflux. Water (350 mL) was added although total dissolution of the solids was not achieved. The solids were collected by filtration and dried under vacuum to yield 18.6 g of the title compound. Upon cooling additional product precipitated, that was isolated by filtration and dried under vacuum to yield additional 8.18 g of product. The combined solids accounted for a total of 26.8 g (yield: 62%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1.CO.C1(C)C=CC=CC=1>[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Agent: O=C(O)CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a cooled solution of piperazine (10 eq) in toluene/methanol (5:1 toluene/methanol (v:v); 5 mL/g piperazine) was added slowly a solution of trityl chloride 10 (1.0 eq) in toluene (5 mL/g trityl chloride). Upon reaction completion (1-2 hr), this solution was washed four times with water. To the resulting organic solution was added an aqueous solution of succinic acid (1.1 eq; 13 mL water/g succinic acid). This mixture was stirred for 90 min, and the solid product was collected by filtration. The crude solid was purified by two reslurries in acetone. Yield=70%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)o2)cc1
Yield: 95.7 %

Procedure:
A mixture of methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.600 g), 1 M aqueous sodium hydroxide solution (3.6 ml), tetrahydrofuran (6 ml) and ethanol (3 ml) was heated under reflux for 1.5 hrs. After cooling, 1 M hydrochloric acid was added to acidify the mixture. The crystals were collected by filtration to give 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.550 g, yield 95%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 284–286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]#[N:10])[C:3]=1[O:11][CH3:12].[H-].[Na+].[CH2:15](I)[CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:15][CH3:16])[C:9]#[N:10])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(Cl)ccnc1CC#N
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C#N)c1nccc(Cl)c1OC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-3-methoxy-2-pyridinyl)-acetonitrile (7.06 g) is dissolved in THF (40 ml) and 60% sodium hydride (1.62 g) is added followed by 3.25 ml of ethyl iodide. The reaction is allowed to stir at 45° C. for 1.5 hour then the reaction mixture is diluted with water and extracted with ethyl acetate. The desired product is purified by chromatography using hexane/ethyl acetate 4/1 as solvent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
1-tert-Butoxycarbonyl-piperazine (5.6 g) was dissolved in dry DCM (100 ml) followed by the addition of cyclobutanone (2.10 g). The reaction mixture was stirred at rt for 30 min. Sodium triacetoxyborohydride (6.37 g) was added portion-wise over 15 min. The mixture was then stirred at rt overnight to give a black solution. The reaction mixture was washed with 1N NaOH (70 ml) and the DCM layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give the subtitled compound as an oil (6.1 g) 1H NMR δ [DMSO-d6]: 1.39 (6H, s), 1.68-1.87 (4H, m), 1.9-2.01 (2H, m), 2.15-2.2 (3H, m), 2.5 (1H, m), 2.6-2.78 (1H, m), 3.18-3.3 (4H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22]1([N:32]=[C:33]=[O:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4cccc5ccccc45)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 1-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.40 g of the product in 56% yield: 1H NMR (DMSO-d6) δ 2.00-2.09 (m, 1H), 2.35-2.42 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.44 (d, J=17.2 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 4.58 (d, J=17.2 Hz, 1H), 5.16 (dd, J=13.1 Hz, J=5.1 Hz, 1H), 7.11 (t, J=5.8 Hz, 1H), 7.09-7.67 (m, 7H), 7.90 (dd, J=6.6 Hz, J=2.9 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 8.09 (t, J=9.0 Hz, 1H), 8.66 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 40.0, 46.2, 51.6, 117.0, 121.4, 121.6, 122.4, 125.5, 125.8, 125.9, 128.3, 128.4, 130.4, 131.7, 133.7, 134.9, 135.5, 140.0, 155.7, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.64; H, 4.99; N, 12.28.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[Na].C(O)(=O)[CH2:22][C:23](CC(O)=O)(C(O)=O)[OH:24]>C(O)C>[N+:17]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:24][CH2:23][CH3:22])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-nitro-N-phenyl-benzamide from Example 9 (2.34 g, 9 mmol) was added all at once to a solution prepared by dissolving sodium metal (2.29 g, 100 mmol) in ethanol (100 mL). The reaction mixture was stirred 1 hour at room temperature, then citric acid solution (10% aqueous, 4 mL) was added, and the mixture allowed to stand overnight. The reaction mixture was then concentrated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate, 1:1, as eluant to afford the product as an orange solid (1.09 g); m.p. 189-190° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: NCCCNc1nsc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)propane-1,3-diamine (600 mg, 2.8 mmol) and 4′-methoxy-biphenyl-4-carboxaldehyde (614 mg, 2.8 mmol) were combined in 1,2-dichloroethane (20 mL) and treated with sodium triacetoxyborohydride (1.2 g, 5.7 mmol) and acetic acid (160 μL, 5.6 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution. The crude product was extracted with ethyl acetate (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography, on silica gel, eluting with 98:2 methylene chloride: methanol to yield N1-(benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (330 mg) as a light yellow foam. 1H NMR (CDCl3): 7.80 (d, 1H), 7.75 (d, 1H), 7.25-7.45 (m, 8H), 6.90 (d, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.70 (t, 2H), 3.00 (t, 2H), 2.30-2.40 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=1.C(OC(=O)C)(=[O:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:19])[CH:8]=1
Reactant: [O-][n+]1ccc(OCc2cccc(Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2cccc(Cl)c2)cc[nH]1
Temperature: 25 °C

Procedure:
To 4-((3-chlorobenzyl)oxy)pyridine 1-oxide (2.0 g) was added acetic anhydride (20 ml), and the solution was heated at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH/NaOH (1:1, 150 ml) and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined DCM layer was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (984 mg) as an off-white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:19][CH2:20][CH2:21][N:22]=2)[CH:8]=[CH:9][CH:10]=1.[H][H].Cl[C:28](OCC)=[O:29]>O1CCCC1.O.C(O)(=O)C>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3=[N:19][CH2:20][CH2:21][N:22]3[C:28]2=[O:29])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(Nc2ccccc2C2=NCCN2)c1
Reactant: [H][H]
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N2CCN=C2c2ccccc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3.26 g (75 mmol) of sodium hydride were added to a solution of 10.4 g (34 mmol) of 2-(2-(3-trifluoromethylphenylamino)-phenyl)-2-imidazoline in 100 ml of absolute tetrahydrofuran, and the mixture was warmed to 50° to 60° C. until evolution of hydrogen had ceased (5 to 6 hours). After the reaction mixture had cooled to room temperature, 16 ml (0.166 mol) of ethyl chloroformate were added dropwise to it and it was boiled under reflux for one hour. The mixture was allowed to cool, the pH was adjusted to 4-5 with glacial acetic acid, and the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated, and the residue was subjected to chromatography over silica gel (running agent ethyl acetate/methanol 7:3), and the residue from the evaporation of the product-containing fractions was thoroughly stirred with ether/petroleum ether 1:3.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[N:17]=[C:16]([NH:18][CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(N)n1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(NC=O)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To stirred neat formic acid (3.83 mL, 101.7 mmol) was added acetic anhydride (6.98 mL, 74.0 mmol). The reaction mixture was heated under stirring at 70° C. for 2 hrs and allowed to room temperature. A solution of 6-methylpyridin-2-amine (5.00 g, 46.23 mmol) in tetrahydrofurane (30 mL), was added dropwise in order to prevent temperature from rising above 45° C. The reaction mixture was allowed to room temperature and stirred for further 1 hr. The reaction mixture was concentrated in vacuo and the residue was diluted in 100 mL of ethanol. The reaction mixture was stirred for 2 hrs at room temperature concentrated in vacuo, yielding to N-(6-methylpyridin-2-yl)formamide as a yellow solid [2.00 g, yield 32%; HPLC/MS: m/z=137 (M+H); logP(HCOOH)=0.45].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[C:38](O)(=[O:41])[CH2:39][CH3:40]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:28])([F:29])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][NH:26][C:38](=[O:41])[CH2:39][CH3:40])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanamine (0.1 g) and triethylamine (0.05 g) were added to dichloromethane (20 mL), and then dichloromethane solution (10 mL) comprising anhydrous propionic acid (0.05 g) was added dropwise thereto under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.1 g, 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>C(O)C.O>[CH2:20]([NH:27][C:28](=[S:29])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:18]=[CH:19][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccc(NC(=S)NCc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (1.5 g, 0.005 mole) was dissolved in hot ethanol (30 ml) under a nitrogen atmosphere. Benzyl isothiocyanate (0.82 g, 0.0055 mole) and potassium acetate (0.6 g, 0.006 mole) were added and the mixture was refluxed under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (10-15 ml.) and chilled in ice. The product was filtered off, washed with ethanol and dried. Recrystallization of the product from acetonitrile gave an off-white solid. Yield 1.25 g (62%), m.p. 197°-199° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1)[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[Br-:17].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:13]=[CH:12][N:11]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH:10]=2)=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-n2ccnc2)c(C(=O)O)c1
Reactant: CCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCn1cc[n+](-c2ccc(CC)cc2C(=O)O)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 4.60 mmol (1.00 g) 1-(4-ethylcarboxyphenyl)imidazole and 5.50 mmol (1.50 g, 1.5 ml) 1-bromotetradecane are dissolved in 5 ml THF and heated for 68 h to 90° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14]N)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24](C1C=CNN=1)=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].C[N:39](C)C=O>>[C:29]([O:28][C:26]([N:25]([O:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:24]([NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[NH:39])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: NOCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)c1cc[nH]n1
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)N(OCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2-(benzyloxycarbonylamino)ethoxyamine (780 mg, 3.7 mmol), as prepared in the preceding step, in N,N-dimethylformamide (20 mL) was added [N,N'-di(tert-butoxycarbonyl)]amidinopyrazole (1.25 g, 4.0 mmol). The mixture was stirred at room temperature overnight, the solvent was evaporated under high vacuum. The residue was purified by flash column chromatography (0-5% ethyl acetate in methylene chloride) to give the title compound as a colorless oil (1.55 g, 93%). 1H-NMR (300 MHz, CDCl3) δ9.08 (s, 1H), 7.67 (s, 1H), 7.33 (m, 5H), 6.21 (br s, 1H), 5.21 (br s, 1H), 5.11 (s, 2H), 4.12 (t, J=4.8 Hz, 2H), 3.54 (q, J=4.9 Hz, 2H), 1.49 (s, 9H), 1.46 (s, 9H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.CCN(C(C)C)C(C)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].CO>CN(C=O)C>[CH3:31][N:32]([CH3:36])[C:33]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)=[O:34]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (253.6 mg, 0.809 mmol) in DMF (6 mL), DIPEA (0.7 mL, 4 mmol) was added at rt. The solution was cooled to 0° C. and N,N-dimethylcarbamoyl chloride (107.7 mg, 1.002 mmol) in DMF (1 mL) was added. The reaction was stirred from 0° C.→rt for 30 min. MeOH was added and all organic solvent was concentrated in vacuo to dryness. The residue was dissolved in CH2Cl2, washed once with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, giving the title compound as a waxy white solid that solidified upon drying. The material was used without further purification. 1H NMR (400 MHz, CDCl3): δ=1.32 (s, 12H), 1.94-2.07 (m, 2H), 2.16 (dd, J=12.3, 2.4 Hz, 2H), 2.85 (s, 6H), 2.87-2.95 (m, 2H), 3.78 (d, J=13.4 Hz, 2H), 4.24-4.34 (m, 1H), 7.76 (s, 1H), 7.80 (s, 1H). MS (AP+): m/z 349.13 (100) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).