Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12][OH:13].C(O)C.[OH-].[K+]>[Fe].CCCCCC>[ClH:1].[OH:13][CH2:12][C:4]1[C:3]([CH3:2])=[C:8]([CH:7]=[CH:6][CH:5]=1)[NH2:9]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: Cc1c(N)cccc1CO
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (5.2 ml) was slowly added to a stirred and refluxing mixture of 41.8 g (0.25 mole) of 2-methyl-3-nitrophenylmethanol, 85.0 g of iron powder, and 100 ml of 50% aqueous ethanol. Refluxing and stirring was continued for 2 hours, then the mixture was made just basic by the addition of a 15% ethanolic solution of potassium hydroxide. The hot mixture was filtered through diatomaceous earth, and the filter cake was washed with ethanol. The ethanol washings were combined with the filtrate, and the whole was made acidic with hydrogen chloride and allowed to stand for 16 hours. The solution was concentrated under reduced pressure to give a residue. Hexane was added and the water-hexane azeotrope was removed by distillation. The azeotropic distillation was repeated twice to give an undetermined amount of 3-hydroxymethyl-2-methylaniline hydrochloride, which was used in the next reaction in this sequence without further characterization.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:15]=[C:3]12.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:3]12
Reactant: CCOC(=O)c1cc2n(C)c3ccccc3c(=O)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c2ccccc2c(=O)n2nc(C(=O)O)cc12

Procedure:
A mixture of 5.8 g of 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester, 50 ml of 1 N aqueous sodium hydroxide and 400 ml of methanol is heated at reflux until complete solution is attained (about 30 minutes). The solution is evaporated at reduced pressure to remove methanol; the residue is diluted with water and acidified with 1 N hydrochloric acid. The resulting precipitate is 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid is collected by filtration, washed with water and dried; mp 265° C., after crystallization from dimethylformamide/methanol.
Reaction SMILES: ClC1C=CC2OC(C3C=CC=CC=3)=CC=2C=1.COC1C=CC(S(Cl)(=O)=O)=CC=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:35]([S:44]([C:47]3[CH:52]=[CH:51][C:50]([O:53]C)=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:34]=2[CH:55]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:35]([S:44]([C:47]3[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:34]=2[CH:55]=1
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Clc1ccc2oc(-c3ccccc3)cc2c1
Product: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with 4-methoxybenzenesulfonyl chloride as described in Example 1 followed by demethylation of the 5-chloro-3-(4-methoxyphenylsulfonyl)-2-phenylbenzofuran thus formed also as described therein, gives 5-chloro-3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:12]=3[C:11]=2[N:10]=1.[C:26]([CH:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)#[CH:27].C(N(C(C)C)CC)(C)C.O=O>O1CCCC1.Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:27]#[C:26][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:4][C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:12]=3[C:11]=2[N:10]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(I)ccc3Cl)ncc1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
2.0 g (4.0 mmol) N-[8-(2-chloro-5-iod-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide are placed in 50 mL tetrahydrofuran under an argon atmosphere and combined with 1.5 g (7 mmol) tert-butyl 4-ethynyl-piperidine-1-carboxylate and 0.5 ml (3 mmol) diisopropylethylamine. The mixture is kept free from oxygen and 78 mg (0.1 mmol) triphenylphosphine palladium(II)-chloride and 21 mg (0.1 mmol) copper(I)-iodide are added. The mixture is stirred for 5 hours at 80° C. After cooling to ambient temperature the reaction mixture is combined with dichloromethane and washed with dilute ammonia solution. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography, corresponding fractions are combined and freeze-dried. The intermediate product obtained is stirred for 2 hours in ethereal hydrochloric acid, suction filtered and dried. Yield: 65 mg (m.p.: 162° C.; MH+=430; RT=3.72; Method A)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>C(O)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Reactant: COc1ccc(N)cc1Cl
Solvent: CCCCO
Product: COc1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of compound, 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (3.97 g, 13.7 mmol), 3-chloro-4-methoxyaniline (2.13 g, 13.7 mmol) in 1-butanol (30 mL) was stirred at 120° C. for 12 hours. The mixture was then cooled to temperature in the range of 20-40° C. The solid precipitated was filtered, collected, stirred in isopropanol (10 mL), filtered, and dried to give the desired compound as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Cl.N1C=CC(CCl)=CC=1.C(NCC)C>>[CH2:2]([N:1]([CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)[CH2:6][CH3:5])[CH3:3]
Reactant: c1cc(CN2CCOCC2)ccn1
Agent: Cl
Agent: ClCc1ccncc1
Solvent: CCNCC
Product: CCN(CC)Cc1ccncc1
Yield: 88 %

Procedure:
In a manner similar to the procedure described for the synthesis of 4-(4-morpholinyl)methylpyridine, 4-picolylchloride hydrochloride (6.00 g, 0.0366 mol) and diethylamine (10.68 g, 0.146 mol, 4.0 equiv.) provided 5.28 g (88%) of 4-(N,N-diethylaminomethyl)pyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN(C=O)C>[C:7]([O:6][C:5]([N:4]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:1][CH2:2][CH2:3]1)=[O:11])([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate 38.1 (9.00 mL, 58.2 mmol) in DMF (50.0 mL) was cooled in a ice bath and treated portion wise with sodium hydride (60% in mineral, 5.12 g, 128 mmol). The mixture was stirred in ice bath for 15 minutes and then treated with 3-chloro-2-(chloromethyl)prop-1-ene (7.07 mL, 61.1 mmol). After addition was complete, the ice bath was removed and the reaction mixture was stirred was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an oil which purified by flash chromatography (gradient EtAOAc/hexane 5%-40%) to afford the desired product (4.6, 37% yield) clear oil. LCMS 114.10[M-tBuCO2]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[S:12])[NH2:11])[CH3:9])(C)(C)C.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[N:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[S:12][CH:15]=1)=[O:18])[CH3:21]
Reactant: CC(NC(=O)OC(C)(C)C)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C(C)N)n1
Yield: 14.6 %

Procedure:
(1-Thiocarbamoyl-ethyl)-carbamic acid tert-butyl ester (8.7 g, 42.5 mmol) and ethyl bromopyruvate (90% Tech., 9.21 g, 42.5 mmol) were heated at reflux in ethanol (200 mL) for 12 hours. The ethanol was removed in vacuo and the residue was purified by flash chromatography (5:95 MeOH:CH2Cl2) to afford the title compound (1.24 g, 15% over two steps): 1H NMR (400 MHz, d6-DMSO): 8.37 (s, 1H), 4.28 (qd, 2H), 4.24 (q, 1H), 2.60 (br s, 2H), 1.37 (d, 3H), 1.29 (t, 3H); MS (ESI-LCMS) for C8H13N2O2S: 201 (MH+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=1/[CH:6]=[N:7]/[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=1[CH:6]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][NH:7]1)[CH3:2]
Reactant: CCOC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SCC
Reaction time: 3 h

Procedure:
To 35B (23.4 mmol) in CH2Cl2 (200 mL) at −15° C. was added Et3N (5.7 mL, 41 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 41 mL, 41 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (200 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet Celite®, extracted with CH2Cl2 (3×60 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio, LC-MS 325 (M+H). To the above ethyl 2-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate in THF (100 mL) was added Et3N (3.3 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 24 mL, 24 mmol). The mixture was stirred at rt for 3.0 h before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was first triturated with EtOAc, the precipitate was collected by filtration and washed with EtOAc to give the trans 35C (1.7 g). The filtrate was concentrated and further purified by flash silica gel column chromatography using gradient EtOAc in hexane to give predominantly cis isomer 35D (1H NMR indicated presence of 30% trans isomer). To this cis isomer was added mixture of EtOAc/hexane (1:3), the precipitate was collected and washed with the same mixture of EtOAc/hexanes (1:3) to give a second crop of the trans 35C (0.8 g, total 2.5 g, 25% yield). The filtrate was concentrated to give enriched cis isomer 35D (3.0 g, >92% purity, 30% yield). 35C: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 1.20 and 1.23 (m, 12H) 1.33 (t, J=7.42 Hz, 3H) 2.08-2.19 (m, 2H) 2.90 (br s, 1H) 3.15 (q, J=7.15 Hz, 2H) 3.48-3.58 (m, 1H) 3.70 (m, 1H) 4.10-4.19 (m, 2H) 5.31 (br s, 1H) 7.58 (d, J=8.79 Hz, 1H) 7.84 (s, 1H) 8.02-8.09 (m, 1H). LC-MS 425 (M+H). 35D: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 0.86 (t, J=6.87 Hz, 3H) 1.18 (s, 9H) 1.34 (t, J=7.15 Hz, 3H) 2.12-2.22 (m, 2H) 3.09-3.17 (m, 2H) 3.56-3.67 (m, 3H) 3.69-3.83 (m, 2H) 5.43 (d, J=8.79 Hz, 1H) 7.50-7.58 (m, 1H) 7.81 (s, 1H) 8.03 (d, J=8.79 Hz, 1H); LC-MS 425 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 ML isopropyl acetate. The mixture was heated slowly to 80° C. After 5 hours, high performance liquid chromatography showed reaction to be 90% complete. After being left overnight at 80° C., reaction was complete. The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added. The mixture was stirred until all solids dissolved. The aqueous layer was separated and discarded.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1.[C-:13]#[N:14].[K+].Cl>C(O)COCCOCCO>[C:13]([CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1)#[N:14]
Reactant: [C-]#N
Reactant: CNS(=O)(=O)c1cscc1CCl
Agent: Cl
Agent: [K+]
Solvent: OCCOCCOCCO
Product: CNS(=O)(=O)c1cscc1CC#N
Temperature: 0 °C

Procedure:
26.5 g (0.109 mol) of 3-chloromethyl-N-methyl-4-thiophenesulfonamide and 21.3 g (0.328 mol) of potassium cyanide are warmed to 80° C. for 20 minutes in 130 ml of triethyleneglycol. Thereafter, the mixture is poured into 200 ml of 2-N hydrochloric acid and 200 g of ice and extracted with three 250 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, stirred with 3 g of active carbon, filtered and evaporated. There is obtained 3-cyanomethyl-N-methyl-4-thiophenesulfonamide in the form of a non-crystallizing oil which is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH:16][C:17](=O)[CH2:18][CH3:19]>C(O)C>[CH2:18]([C:17]1[N:4]([O:3][CH3:2])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH3:19]
Reactant: CCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCc1nc2cnc3ccccc3c2n1OC
Temperature: 25 °C
Yield: 86.7 %

Procedure:
O-methylhydroxylamine hydrochloride (1.51 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)propionamide (2.5 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.10 g of 2-ethyl-1-methoxy-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>>[N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1nc2ccccc2[nH]1
Product: N=C(NCCSCc1nc2ccccc2[nH]1)N[N+](=O)[O-]

Procedure:
Reacting 2-[(2-aminoethyl)thiomethyl]benzimidazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(2-benzimidazolylmethylthio)ethyl]-N'-nitroguanidine. Treatment with hydrochloric acid gives the hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[Br:9]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:9][C:7]1[NH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=[N+]([O-])c1cc[nH]c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c[nH]c(Br)c1

Procedure:
To a tetrahydrofuran solution (10 mL) of 3-nitro-1H-pyrrole (520 mg, 4.64 mmol), 1,3-dibromo-5,5-dimethylhydantoin (730 mg, 2.55 mmol) was added at −78° C. and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the resultant residue, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:18])=[CH:13][CH:14]=2)[O:3]1
Reactant: C1COCCN1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(CC(=O)N3CCOCC3)cc2)OC1(C)C
Yield: 34.8 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (786 mg, 3.0 mmol) and morpholine (1.3 mL, 15.0 mmol), the desired title compound (346 mg, yield 35%) was obtained by the same method as the amidation step in Example 4 (4b).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][Si:18]([C:16]#[C:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn2cc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1cn2cc(C#C[Si](C)(C)C)ccc2n1
Temperature: 50 °C
Reaction time: 50 h

Procedure:
A mixture of 4 g of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 2.63 mL of ethynyltrimethylsilane and 888 mg of dichlorobis(triphenylphosphine)palladium is degassed under vacuum. 240 mg of degassed N,N-dimethylformamide and 3.52 mL of triethylamine are added. The reaction mixture is degassed under argon, stirred at 50° C. for 50 hours and then cooled and diluted with 20 mL of water. The precipitate is filtered off by suction and washed with 5 mL of water and then chromatographed on silica, eluting with mixtures of ethyl acetate and hexane (from 50/50 to 90/10). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 3.6 g of ethyl 6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in the form of an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH:28]1[CH:35]=[CH:34][C:32]([NH2:33])=[N:31][C:29]1=[O:30].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:33][C:32]2[CH:34]=[CH:35][NH:28][C:29](=[O:30])[N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]c(=O)n2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (4 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30 min. The resulting reaction mixture was then treated with a solution of cytosine (101 mg, 0.91 mmol) and pyridine (0.245 mL, 3.03 mmol) in N,N-dimethylformamide (10 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 95/5 methylene chloride/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide (145 mg, 57%) as a white solid: mp>200° C.; EI-HRMS m/e calcd for C19H22ClN3O4S (M+) 423.1019, found 423.1015.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[Cl:15][C:7]([C:6]([CH3:11])([CH3:10])[CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acetoxy-2,2-dimethyl-propionic acid (example 40, step 1) (2.2 g, 13.75 mmol) in CH2Cl2 (25 ml), were added oxalyl chloride (2.62 ml, 27.50 mmol) and 2-4 drops of DMF and stirred at 25° C. for 3 hours. The solvent was evaporated and the resulting acetic acid 2-chlorocarbonyl-2-methyl-propyl ester (2.4 g) was used directly in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCCC(O)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCCC(O)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(3-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(C)(C)C(=O)O)cc1
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(C)(C)C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2-(4-acetyl-phenyl)-2-methyl-propionic acid (Ex-77A) and 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. White foam. 1H-NMR (CCDl3) δ 8.11–7.86 (m, 5H), 7.62–7.46 (m, 3H), 7.42 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.3, 1H), 7.10–7.08 (m, 1H), 6.54 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). MS m/z=436 (M+, 55%), 405 ([M−OCH3]+, 100%).