Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[N+:29]([CH3:32])([O-:31])=[O:30]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])([CH2:32][N+:29]([O-:31])=[O:30])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=C1CCN(Cc2ccccc2)C1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC1(C[N+](=O)[O-])CCN(Cc2ccccc2)C1
Yield: 100 %

Procedure:
A solution of methyl (1-benzylpyrrolidin-3-ylidene)acetate a45 (3 g, 1.2 mmol, 1 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.7 g, 4.6 mmol, 3.8 eq) in nitromethane (30 ml) is refluxed for 30 h. The solution is concentrated in vacuum and the resulting oil is purified by chromatography over silicagel (ethyl acetate/hexane 30/70) to afford 3.7 g of methyl [1-benzyl-3-(nitromethyl)pyrrolidin-3-yl]acetate a46 as a black oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.I[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CC(C)([O-])C.[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][NH:1][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:5]=1
Reactant: NCCc1cccnc1
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cccc(NCCc2cccnc2)c1
Reaction time: 16 h
Yield: 17.3 %

Procedure:
To a mixture of 244 mg of 3-(2-aminoethyl)pyridine (2.0 mmol) and 604 mg of t-butyl 3-iodobenzoate (2.0 mmol) in 10 mL of toluene was added 250 mg of sodium t-butoxide (2.5 mmol), 30 mg of tri-t-butylphosphonium tetrafluoroborate (0.1 mmol) and 50 mg of tris(dibenzylidineacetone)dipalladium(0) (0.055 mmol). The mixture was stirred for 16 h and filtered through celite. The celite was washed with 3×5 mL of toluene and the filtrate was concentrated in vacuo. The residue was purified by column chromatography using 35%-45% EtOAc in hexanes as eluant to give 103 mg of t-butyl N-(2-(3-pyridyl)ethyl)-3-aminobenzoate as a bright yellow oil (17% yield).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>CS(C)=O.O>[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of (3-carboxypropy)triphenylphosphonium bromide (25 g, 58.3 mmol) in DMSO (53 mL) was added t-BuOK (12.4 g, 110.7 mmol). The mixture was stirred at rt for 20 min. Then a solution of 3-Bromo-benzaldehyde (9.3 g, 50.3 mmol) in DMSO (15 mL) was added dropwise. The reaction mixture was stirred at rt for 4 h. The mixture was poured in water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a solvent system of 5:1 petroleum ether/EtOAc to give 5-(3-Bromo-phenyl)-pent-4-enoic acid (4.8 g, 38%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.45 (s, 1H), 7.2-7.25 (m, 1H), 7.1-7.15 (m, 2H), 6.4-6.45 (m, 1H), 6.23-6.3 (m, 1H), 2.4-2.6 (m, 4H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[C:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([OH:34])=[O:33].C([O-])([O-])=O.[Na+].[Na+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:39]4[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=4)[C:32]([OH:34])=[O:33])[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)O)c3)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Yield: 67.8 %

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (200 mg, 0.39 mmol) (approx 3:1 mix of 5-Br & 5-Cl) and 3-carboxyphenylboronic acid (85.0 mg, 0.51 mmol) in 1,2-DME (4 mL) were added Pd(Ph3P)4 (22.8 mg, 0.02 mmol) and 2.0 M aqueous Na2CO3 (0.8 mL, 1.6 mmol). The reaction mixture was heated at 90° C. overnight then cooled to room temp and diluted with water. The pH was adjusted to 6 with 1.0 M HCl before extracting with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0% to 4% MeOH/CH2Cl2 (0.5% NH4OH)) to afford 145 mg (67%) of 3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid as a white foamy solid.
Reaction SMILES: [N+:1]([CH2:4][C@@:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[CH:8][CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][CH2:4][C@@:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[CH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC=C[C@@H]21
Reaction time: 4.5 h

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.98 g, 7.41 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (2.07 g, 37.0 mmol) and ammonium chloride (392.7 mg, 7.41 mmol) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow solid (1.99 g, this compound was used directly in the next reaction without being purified).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>C1COCC1.CO.[Pt](=O)=O>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:17]3=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4C(F)(F)F)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccccc4C(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Platinum(IV) oxide (20.0 mg) was added to a solution of 9-{4-[2-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in THF (dry) (10 mL) and MeOH (10 mL) and the mixture was stirred at room temperature under hydrogen overnight. The insoluble solid was removed by filtration through Celite-pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give 9-{4-[2-(trifluoromethyl)phenoxy]phenyl}-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (77.3 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:14])[S:10][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(Br)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid 156 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.18 g, 0.52 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.29 g, 0.62 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-60% EtOAc/hexane) affording the title compound (0.281 g, 86%). LC-MS (ES) m/z=632 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(OCC2C=CC=CC=2)=O)=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=3[F:41])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=3[F:41])=[CH:30][CH:31]=2)[CH2:23][CH2:24]1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCN(Cc2ccc(Oc3cc(F)c(F)cc3F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)cc1C1CCN(Cc2ccc(Oc3cc(F)c(F)cc3F)cc2)CC1
Yield: 100.2 %

Procedure:
N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl](phenylmethoxy)carboxamide (4.88 g, 8.68 mmol) was dissolved in ethanol (150 mL) and hydrogenated over palladium on carbon (10%, 980 mg) for 2.5 h. The reaction mixture was filtered through celite filter aid, washing with ethanol and the filtrate was concentrated in vacuo. Flash column chromatography (silica gel 60) eluting with cyclohexane:ethyl acetate (1:1 then 1:4) provided 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenylamine (3.71 g, 100%). LCMS (method B): 2.14 min, 427.0 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 7.63 (d, 2H, J=7.2 Hz), 7.41-7.33 (m, 2H), 7.27-7.23 (m, 2H), 7.15 (d, 1H, J=8.0 Hz), 7.09 (d, 2H, J=8.0 Hz), 4.36 (s, 2H), 3.61 (d, 2H, J=12.0 Hz), 3.22 (t, 3H, J=12.0 Hz), 2.42 (s, 3H), 2.15-2.02 (m, 4H).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O.C([BH3-])#N.[Na+].Cl>CO.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][CH:13]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH3:15]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCN(C(C)C)CC1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A solution of ethyl 1-piperazinylcarboxylate (25.0 mL, 0.171 mole) and acetone (37.7 mL, 0.513 mole) in methanol (MeOH) (500 mL) was cooled to 0°-5° C. Sodium cyanoborohydride (10.7 g., 0.171 mole) was added in two portions. The so-formed mixture was stirred at 0°-5° C. for 8 hours while maintaining the pH at 4-6 by dropwise addition of 6N HCl. The temperature of the reaction mixture was allowed to slowly rise to RT overnight. The reaction mixture was evaporated in vacuo to provide a residue which was dissolved in H2CCl2 (500 mL) and 5% NaHCO3 (500 mL). The H2CCl2 layer was separated, washed with brine (500 mL), dried over anhydrous MgSO4, and evaporated in vacuo. The so-formed residue was chromatographed on silica gel, eluting with 1% MeOH/H2CCl2 (v/v) containing 1 mL of conc. NH4OH per liter of solution to give 18.9 g of the title compound of Example 67(a) as a gum, M/e, M+ 201.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH3:12])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1ccccc1N
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (587 mg, 2.78 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (2.5 ml) and TEA (400 μl, 2.87 mmol) was added. To this solution, 2-methoxyaniline (340 mg, 2.76 mmol) in 3 ml DCM was added dropwise and the mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (10% to 40%, hexane-ethyl acetate) to obtain 630 mg (77% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][CH:7]([CH:14]1[CH2:17][CH2:16]C1)[C:6]([CH:18]=[O:19])=[CH:5]2.[BH3-]C#N.[Na+]>C1COCC1.CC(O)=O>[OH:19][CH2:18][C:6]1[C:7]2([CH2:16][CH2:17][CH2:14]2)[O:8][C:9]2[C:4](=[C:3]([CH3:20])[C:2]([OH:1])=[C:11]([CH3:12])[C:10]=2[CH3:13])[CH:5]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C=C(C=O)C(C1CCC1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)C=C(CO)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To a stirred solution of 6-hydroxy-5,7,8-trimethyl-2-cyclobutyl-chromene-3-carbaldehyde (250 mg) in 10 mL of THF and 1 mL of AcOH was added NaCNBH3 (305 mg). The reaction mixture was allowed to stir at room temperature for 6 h. The mixture was concentrated and the residue was purified by flash chromatography eluted with 30% ethyl acetate in hexane to give 135 mg of 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol as a light yellow solid. 1H-NMR (300 MHz, MeOD) δ=6.52 (s, 1H, C═CH), 4.35 (s, 1H), 2.36 (m, 4H), 2.20-1.75 (m, 11H) ppm. 13C-NMR (75 MHz, MeOD) δ=146.5, 144.5, 137.6, 124.9, 122.2, 119.3, 118.4, 117.0, 80.7, 62.0, 32.7, 14.3, 12.2, 11.2, 10.7 ppm. MS:(m/z)=243.2 (M−18+), 283.1 (M+Na+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[I:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:32]2[CH2:31][CH2:30][CH:29]([N:25]3[C:24]4[CH:35]=[CH:36][C:21]([I:20])=[CH:22][C:23]=4[NH:27][C:26]3=[O:28])[CH2:34][CH2:33]2)=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2cc(I)ccc2n1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(I)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane, 6.84 parts of 1,3-dihydro-5-iodo-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 1-{1-[4,4-bis(4-fluorophenyl)-butyl]-4-piperidinyl}-1,3-dihydro-5 -iodo-2H-benzimidazol-2-one; mp. 179.3° C.
Reaction SMILES: S([O-])(O)(=O)=O.[CH3:6][N+:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH3:13])[CH:8]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>O>[C:14]([O-:17])(=[O:16])[CH3:15].[CH3:6][N+:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH3:13])[CH:8]=1
Reactant: CC(=O)O
Agent: CCn1cc[n+](C)c1
Agent: O=S(=O)([O-])O
Solvent: O
Product: CC(=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
149.8 g (0.72 mol) of 1-methyl-3-ethylimidazolium hydrogensulfate are dissolved in 600 ml of water, and 226.8 g (0.72 mol) of Ba(OH)2 (octahydrate) are subsequently added in portions over a period of 30 minutes. The temperature is increased to 60° C. and the reaction mixture is stirred for 2 hours at this temperature. It is allowed to cool overnight and the precipitated BaSO4 is filtered off using Celite as filter aid. After addition of 43.5 g (0.72 mol) of glacial acetic acid, the water is removed on a rotary evaporator and the oil which remains is extracted with ethyl acetate. To remove residual water, the oil is admixed with n-butanol and the n-butanol is subsequently distilled off under reduced pressure. This gives 108.3 g (0.636 mol) of 1-methyl-3-ethylimidazolium acetate (yield: 88% based on 1-methyl-3-ethylimidazolium hydrogensulfate). The chloride content is 4 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5](Br)=[CH:4][N:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC.[Cl-].[Na+].O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1Cc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-bromopyrazine (c-10) (1.66 g, 6.27 mmol) was dissolved in 1,2-dimethoxyethane (17 mL) and ethanol (13 mL) and to this were sequentially added 2 M aqueous solution of sodium carbonate (31.4 mL, 62.8 mmol), dichlorobis(triphenylphosphine) palladium(II) (221 mg, 315 μmol), and phenyl boronic acid (996 mg, 8.16 mmol) while stirring at room temperature and then stirred at 90° C. for 2.5 h. After cooling to room temperature, to this were added saturated brine and ethyl acetate to stop the reaction. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. After purifying the residue by column chromatography (50 g, n-hexane/ethyl acetate=3/2→1/1), the obtained solid was recrystallized twice from ethyl acetate to give 2-amino-3-benzyl-5-phenylpyrazine (c-41) as a yellow solid (982 mg, 59.9%). Rf=0.30 (n-hexane/ethyl acetate=3/2). 1H NMR (400 MHz, DMSO-d6) δ 4.07 (s, 2H), 6.41 (s, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 3H), 7.34 (d, J=7.3 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 8.41 (s, 1H). IR (KBr, cm−1) 596, 664, 694, 716, 733, 754, 773, 908, 937, 1070, 1152, 1217, 1233, 1396, 1427, 1450, 1462, 1493, 1543, 1636, 3024, 3125, 3291, 3487. HRMS (EI+) m/z 261.1269 (M, C17H15N3 requires 261.1266).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:17]>[OH-].[Na+].O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][NH2:17])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: Sc1nc(-c2ccccc2)ns1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2)ns1
Reaction time: 0.17 h

Procedure:
A solution of 30 g of 5-mercapto-3-phenyl-1,2,4-thiadiazole in 500 ml of 5% sodium hydroxide and a solution prepared by diluting 310 ml of 5.25% NaOCl to 500 ml with water were added dropwise simultaneously to 1325 ml of an ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 18.5 g of powder. Recrystallization of 8.2 g of this material from benzene (300 ml) gave 4.8 g of crystals, m.p.>142° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: CON(C)C(=O)c1cc(-n2cccn2)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1cc(-n2cccn2)ccc1Cl
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-5-pyrazol-1-yl-benzamide (280 mg, 1.05 mmol) was added DIBAL-H (1.16 mL, 1.16 mmol) slowly at −78° C. T he reaction was stirred 2 h, quenched with water, extracted with ether, concentrated, and purified by flash chromatography to give 2-chloro-5-pyrazol-1-yl-benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)COc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
10 g of 3-aminophenoxyacetic acid methylester are solved in 19 g benzyl chloride. Subsequently, 14 g of sodium carbonate are added portionwise and the temperature is raised to 100° C. The reaction mixture is stirred at this temperature for 3 hours. The insoluble salt is filtered off and washed with 100 ml of ethyl acetate. The combined filtrates are kept at 5° C. for 12 h. After the extraction with water and brine, the organic phase is dried with sodium sulfate and the solvent is removed in vacuum (50° C., 10−2 mbar). Yield: 22 g (dark oil).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6].[CH3:19][CH:20](O)[CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:20]([CH3:19])[CH2:21][CH2:22][CH3:23])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: CCCC(C)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCC(C)OC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
Thionyl chloride in an amount of 60 ml was added to 10.8 g (0.06 mol) of 4-acetoxy-2-fluoro-benzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excessive thionyl chloride was distilled off, and then 10 ml of pyridine and 3.5 g (0.0402 mol) of 2-pentanol were dropwise added.