Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN1C(=O)CCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:20][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Oc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dichloronitrobenzene (764 mg, 3.99 mmol), 3-bromo-5-chlorophenol (1.65 g, 7.98 mmol) and potassium carbonate (661 mg, 4.79 mmol) were suspended in NMP (5 mL) and placed in an oil bath at 120° C. After 2 hours, the reaction was allowed to cool to room temperature, saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with dilute brine (4×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by automated column chromatography on silica gel (80 g), eluting with 0-100% CH2Cl2/hexanes to yield the title compound. 1H NMR (CD3CN) δ 8.02 (dd, J=8.3 Hz, J=1.5 Hz, 1H), 7.88 (dd, J=8.2 Hz, J=1.6 Hz, 1H), 7.52 (dd, J=8.2 Hz, J=8.3 Hz, 1H), 7.38 (m, 1H), 7.07 (m, 1H), 6.97 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>CCOCC>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Br:34]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccccc1OC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccccc1CBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-trifluoromethoxybenzyl alcohol (0.81 g, 4.5 mmol) from Step 1 above in ether (20 mL) at 0° C. was added triphenylphosphine (2.4 g, 9.2 mmol) and CBr4 (3.0 g, 9.2 mmol). The mixture was warmed to ambient temperature and stirred for 18 h. The ether was decanted from the gummy precipitate of triphenylphosphine oxide and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using hexanes as eluant to give 2-trifluoromethoxybenzyl bromide as a colorless liquid (TLC Rf =0.80 (hexanes)).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[CH:12][C:11]([C:14](O)=O)=[CH:10][CH:9]=1.C[N:18](C=O)C.N1C(Cl)=NC(Cl)=NC=1Cl>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([C:14]#[N:18])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (40 mL) was added dropwise at 0° C. to a suspension of 6-chloropyridine-3-carboxylic acid (18 g, 114 mmol) in 300 mL of DCM with 3 mL of DMF. The mixture was stirred at 25° C. for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of anhydrous acetonitrile and then added to 500 mL of diluted aqueous NH3.H2O at 0° C. The mixture was stirred for 30 minutes then extracted with EtOAc twice. The combined EtOAc layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in 100 mL of DMF and cooled to 0° C. with ice/water bath. Cyanuric chloride (21.2 g, 114.9 mmol) was added and the mixture was stirred for 2 hours at 0° C. and then poured into ice/water. The resulting solid was collected by filtration, washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 6-Chloropyridine-3-carbonitrile.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][O:47][CH3:48].[I-].[K+]>CN(C)C=O.O>[F:37][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH2:45][CH2:46][O:47][CH3:48])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (81 mg) and potassium carbonate (105 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, 1-bromo-2-methoxyethane (84 mg) and potassium iodide (2.5 mg). The reaction mixture is stirred at 80° C. for 3 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (41 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.C(N(CC)CC)C.[N+:20]([CH3:23])([O-:22])=[O:21]>>[N+:20]([CH2:23][CH:7]([C:6]1[CH:5]=[N:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=1)[OH:8])([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 100 mL round-bottomed flask, 6-(trifluoromethyl)nicotinaldehyde (2.61 g, 14.9 mmol) was combined with nitromethane (20 ml) to give a light yellow solution. triethylamine (1.51 g, 2.08 ml, 14.9 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, 80 g, 0.2% to 1.2% MeOH in dichloromethane gradient) to afford 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (2.4 g) as an off-white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O1CCOCC1.[OH:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([O:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)COC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reaction time: 48 h

Procedure:
A solution of Boc-Ser(tBu)-Asp(OtBu)-Ala-OH.CHA (1.205 g, 2.0 mmol) was extracted with a mixture of EtOAc: 0.5N H2SO4 (10 mL-10 mL). The organic layer was retained, washed with saturated NaCl, dried (MgSO4) and evaporated in vacuo. The resultant free acid in EtOAc:dioxane (5 mL-10 mL) was treated with HOSu (230 mg, 2.0 mmol, 1 eq) and cooled to 0°. To the cold stirring solution DCC (412 mg, 2.0 mm, 1 eq) was added portionwise and stirring proceeded at 0° for 1 hr and at 25° for 48 hr. The reaction mixture was filtered and the filtrate evaporated to dryness and crystallized from isopropanol-petroleum ether. Yield: 631 mg (52.5%); mp 129°-136°; [α]D25 -32.74° (c 1, MeOH); Rf 0.86 (CHCl3 :MeOH:AcOH; 85-10-5); Rf 0.79 (CHCl3 :MeOH:AcOH; 80-5-2). Anal. calc. for C27H44N4O11 (600.67): C, 53.99; H, 7.38; N, 9.33. Found C, 53.85; H, 7.50; N, 9.29.
Reaction SMILES: S([O-])(=O)(C1C=CC([NH2:9])=CC=1)=O.[Na+].N([O-])=O.[Na+].[ClH:17].[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([S:30]([OH:33])(=[O:32])=[O:31])[CH:25]=[C:26]2[OH:29])=[CH:21][CH:20]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[ClH:17].[ClH:17].[NH2:18][C:19]1[C:28]([NH2:9])=[C:27]2[C:22]([CH:23]=[C:24]([S:30]([OH:33])(=[O:31])=[O:32])[CH:25]=[C:26]2[OH:29])=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A stirred solution of p-benzenediazonium sulfonic acid, was prepared by the addition of sodium sulfanilate (1.10 g, 5.2 mmole) to sodium nitrite (0.40 g, 5.7 mmole) in water (10 mL) followed by addition to ice (6.0 g) and concentrated HCl (1.1 mL, 37%). After 30 min. of standing at 0° C. 7-amino-1-hydroxy-3-naphthalene sulfonic acid (1.2 g, 5.2 mmole) was added in water (10 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was warmed to 50° C. and sodium hydrosulfite (3.0 g, 15.6 mmole) was added and the reaction was stirred for 4 hours. The reaction was filtered and the precipitate was washed with water, methanol, and ether to give the title compound (0.54 g; 45%) as a red solid. MS(ES) m/z 255 [M+H].
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([N:17]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18]1)[CH3:16]>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:15]([N:17]1[C:21]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:20]=2[C:19]([CH3:22])=[CH:18]1)[CH3:16]
Reactant: CCn1ccc(C)c1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(C)c2cnc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1-Ethyl-3-methyl-1H-pyrrole (6.7 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (˜200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Pure fractions were combined and evaporated to give the product methyl 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1N, 6.1 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.34 (t, J=7.20 Hz, 3H) 2.34 (d, J=1.01 Hz, 3H) 3.88 (s, 3H) 4.26 (q, J=7.24 Hz, 2H) 7.48 (d, J=1.01 Hz, 1H) 8.20 (d, J=1.01 Hz, 1H) 8.85 (d, J=1.01 Hz, 1H).
Reaction SMILES: [Br:1][CH:2]([CH:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(Br)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)C(Br)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 50 g of methyl 2,3-dibromo-3-phenylpropanoate 1B, 100 ml of triethylamine and 500 ml of toluene is heated to boiling for 1 h, then cooled to room temperature and filtered. The filtrate is evaporated in vacuo and the α-bromocinnamic acid 1C thus obtained is reused without purification. 0.2 mol of imidazopyridine, dissolved in 150 ml of anhydrous DMF, is added dropwise with stirring to a suspension of 4.7 g of NaH (80% strength in mineral oil) in 100 ml of anhydrous DMF. During this process, the temperature of the mixture is kept below 35° C. by cooling with ice. After addition is complete, the mixture is stirred at room temperature for 1 h. The α-bromocinnamic acid previously prepared is dissolved in 200 ml of anhydrous DMF and the solution of the azole sodium salt is added dropwise with stirring while cooling with ice. After stirring at room temperature for 2 hours, 10.8 ml of glacial acetic acid are added, the mixture is stirred into 1.5 l of ice water and extracted several times with ethyl acetate, and the organic phases are washed with water. The organic phases are dried and evaporated in vacuo, and the residue is crystallized from ethyl acetate. 37.0 g of 1D are obtained as pale yellow crystals.
Reaction SMILES: Br[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:24]1[C:31]2[CH2:30][CH2:29][CH2:28][N+:27]=2[CH2:26][CH2:25]1.Cl>CCOCC.CCCCC>[C:8]1([C:2]2[CH:7]=[C:6]([C:31]34[CH2:30][CH2:29][CH2:28][N:27]3[CH2:26][CH2:25][CH2:24]4)[CH:5]=[N:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrC1(c2ccccc2)C=CC=NC1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: c1ccc(-c2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
3-Bromo-3-phenylpyridine (200 mg, 0.85 mmol) was dissolved in Et2O and cooled to -30° C. A solution of 2.5M t-BuLi (1.1 mL, 1.90 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-Hexahydropyrrolizinium perchlorate (230 mg, 1.30 mmol) was added, and the reaction mixture was allowed to stir for 30 minutes at -30° C. then allowed to warm to room temperature and stir for 1 hour. Then 2N HCl was added, the phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford a clear oil (32.5 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC[CH:25]([O:28]C(CCl)CCl)CCl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:25]=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(C=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (1.0 g) and 1,1-dichloromethylmethylether (0.57 ml) in dichloromethane (5 ml) was added at 0° C. a solution of titanium tetrachloride (0.7 ml) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was added to stirred ice/water to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:4→1:2) to give pale yellow crystals of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]benzaldehyde (0.381 g). (469.4 mg of the starting materials were collected)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4.53 g, 19.8 mmol) and K2CO3 (4.146 g, 30 mmol) in THF (30 mL) was added phenyl chloroformate (4.071 g, 26 mmol). It was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. The crude product was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate as solid (5.12 g, 74%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 2.43 (s, 3H), 6.5 (s, 1H), 7.0 (s, 1H), 7.15 (d, 2H), 7.36 (m, 7H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([S:21][C:22](Cl)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([S:21][C:22](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)[CH3:20]
Reactant: CCSC(=O)Cl
Reactant: NCCOc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
6.4 g of 2-(p-benzoylphenoxy)ethylamine and 17.2 g of chlorothioformic acid S-ethyl ester are dissolved in 230 ml of acetone, 22.2 g of potassium carbonate are added to the solution. The mixture is heated under reflux for 6 hours. After cooling to room temperature, the mixture is filtered, the residue is washed with acetone and the filtrate is evaporated in vacuo. The residue is suspended in hot ether and filtered. The residue is then washed with ether and the filtrate is evaporated in vacuo. Recrystallization of the residue from ether yields 2-(p-benzoylphenoxy)ethylthiocarbamic acid S-ethyl ester, m.p.--90°-92° C. Recrystallization of the mother liquor yields a further 1 g of product.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:6]=[C:7](I)[N:8]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:23]=[C:22]([C:24]#[C:25][Si](C)(C)C)[CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:4]2[N:5]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:6]=[C:7]([C:25]#[C:24][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([CH3:17])[CH:23]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Reactant: Fc1ccc(-n2cc(I)nc2C2CC2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C3CC3)n2)ccn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2-Cyclopropyl-1-(4-fluoro-phenyl)-4-iodo-1H-imidazole (V-1) (150 mg, 0.46 mmol) and 2-methyl-4-trimethylsilanylethynyl-pyridine (113 mg, 0.59 mmol) were dissolved in 4 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. In a second reaction vessel triphenylphosphine (4 mg, 0.01 mmol), bis(triphenylphosphine)-palladium(II)chloride (16 mg, 0.02 mmol), copper(I)iodide (1 mg, 0.01 mmol) and triethyl amine (0.10 mL, 0.69 mmol) were dissolved in 2 mL dry THF. This mixture was also evacuated and backfilled with argon several times to remove oxygen from the solution. This mixture was heated to 40° C. and the solution of 2-cyclopropyl-1-(4-fluoro-phenyl)-4-iodo-1H-imidazole and 2-methyl-4-trimethylsilanylethynyl-pyridine was added dropwise. The reaction mixture was heated to 60° C. and tetrabutylammonium fluoride solution (1M in THF, 0.72 mL, 0.69 mmol) was added dropwise during 5 min. The reaction was than stirred at 40° C. for 2 hours. The mixture was taken up in 20 mL water and extracted three times with ethyl acetate (20 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (n-heptane/ethyl acetate 1:4) to obtain the desired title compound as a colorless solid (85 mg, 59%),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:39])=[C:15]([C:19]2[N:20]=[C:21]([C:35]([CH3:38])([CH3:37])[CH3:36])[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1>>[CH3:37][C:35]([C:21]1[S:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32]([N:40]3[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]3)=[O:33])[N:25]=2)=[C:19]([C:15]2[C:14]([F:39])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=2)[N:20]=1)([CH3:38])[CH3:36]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)O)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)N3CCS(=O)(=O)CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 254 using 3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoic acid (200 mg, 0.347 mmol) and thiomorpholine 1,1-dioxide (0.094 g, 0.694 mmol), the title compound was obtained as a white solid (108 mg, 36% yield). MS (ESI): 694 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCOC(=O)CN1CCC(O)C1=O
Product: CC(C)N(CCNC(=O)CN1CCC(O)C1=O)C(C)C

Procedure:
4.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetate are heated to 100° under nitrogen for 3.5 hours with 6.1 g of 2-(diisopropylamino)ethylamine. The crude product is chromatographed on aluminum oxide (neutral, activity grade III). With ethyl acetate/ethanol (1:1) and with ethanol there is eluted (R/S)-N-[2-(diisopropylamino)-ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide. After stirring in diethyl ether this has a melting point of 91°-93°; boiling point 230°-250°/0.01 mmHg (bulb-tube).