Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH3:11][C:12]([CH3:23])([CH3:22])[CH2:13][CH2:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17].[SiH4]>C(O)C.O1CCCC1>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Si:15]([CH2:14][CH2:13][C:12]([CH3:23])([CH3:22])[CH3:11])([O:18][CH3:19])[O:16][CH3:17])[CH3:10]
Reactant: CO[Si](CCC(C)(C)C)(OC)OC
Reactant: CCc1ccccc1Br
Agent: [Mg]
Agent: [SiH4]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccccc1[Si](CCC(C)(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
Under an atmosphere of dry nitrogen a magnetically stirred suspension of anhydrous tetrahydrofuran (Aldrich, 300 mL) and magnesium turnings (Aldrich, 1.2 g, 49 mmol) was treated dropwise at room temperature with 1-bromo-2-ethylbenzene (Aldrich, 6.1 mL, 44 mmol). After 10 minutes the reaction mixture began to reflux mildly. After the addition was complete the reaction mixture was heated to reflux overnight (18 h). A separate flask was flushed with dry nitrogen and then charged with anhydrous tetrahydrofuran (Aldrich, 100 mL) and 3,3-dimethylbutyl-trimethoxysilane (Huls, 11.4 mL, 49 mmol). The Grignard solution was cooled to room temperature and then added to the silane solution at room temperature via stainless steel cannula. The reaction mixture stirred at room temperature overnight (18 h). Ethyl alcohol (Aldrich, 5 mL) was added to quench any remaining Grignard. The reaction mixture was concentrated on a rotary evaporator and distilled in vacuum to give 3.7 g (30%) of the title compound as a colorless oil (b.p. 107-108° C. at 0.5 mm Hg, 99% GC-purity): C16H28O2Si (Mw=280).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Br:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1>CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:5][C:3](=[O:4])[CH:2]([C:6]3[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=3)[C:20]=2[CH:21]=1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: Oc1ccc(Br)cc1
Solvent: CO
Product: CC(C)c1ccc(C2C(=O)Oc3ccc(Br)cc32)cc1
Yield: 30 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 4-bromophenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 30%. Melting point: 157-158° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:11][C:12]1[C:13]([CH2:19]Cl)=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1>CS(C)=O>[Cl:11][C:12]1[C:13]([CH2:19][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S)cc1
Reactant: ClCc1nc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reaction time: 15 h

Procedure:
p-Aminothiophenol (6.25 grams; 0.05 mole) was dissolved in 40 ml. of dimethylsulfoxide and powdered dry sodium hydroxide (2.0 grams; 0.05 mole) added thereto. The resulting mixture was warmed slightly, stirred and an additional 20 ml. of dimethylsulfoxide added thereto to clear the solution. A solution of 3,6-dichloro-2-chloromethylpyridine (8.6 grams; 0.05 mole) in 20 ml. of dimethylsulfoxide was added thereto slowly, with stirring, over a period of about one hour. The temperature of the reaction mixture increased to about 30°-45° C. during the addition. Following the completion of the addition, the reaction mixture was cooled and poured over ice and allowed to stand for about 15 hours. The aqueous layer was then decanted and the residue extracted with 5-500 ml. portions of hexane and the product precipitate recovered therefrom. Recrystallization of the precipitate from benzene gave the desired N-(4-((3,6-dichloro-2-pyridinyl)methylio)benzenamine compound as a crystalline solid having a melting point of 110°-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6]CC)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.CCO>[CH2:16]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Product: C=CCOc1cccc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
Under N2, the mixture of ethyl 2-hydroxy-6-methyl-benzoate (5.00 g, 27.75 mmol), allyl bromide (5.08 g, 3.55 ml, 42.00 mmol) and potassium carbonate (4.42 g, 32.00 mmol) in dry 2-Butanone (100 ml) was heated to reflux for 48 h. After the reaction mixture cooled down to 25° C., the suspended inorganic salt was removed by filtration. The concentration of the resulting solution by rotary evaporation yielded pale yellowish syrup, which was then mixed with 2N NaOH (20 ml, 40 mmol) and EtOH (30 ml). After this mixture was stirred for 48 h at 80° C., ethanol was removed at reduced pressure. After the aqueous solution was acidified by 6N HCl to pH 2 at 5° C., the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 2-Allyloxy-6-methyl-benzoic acid as oil (4.44 g, 23.10 mmol). The title compound was then treated with of 1M sodium trimethylsilanolate (21.0 ml, 21.0 mmol) to give sodium 2-allyloxy-6-methyl-benzoate (4.65 g) as white powder. 1H-NMR (400 MHz, D2O): 7.06 (m, 1 arom. H); 6.73 (m, 2 arom. H); 5.92 (m, —CH═CH2); 5.29, 5.14 (2 d-like, CH═CH2); 4.47 (d-like, CH2—CH═CH2); 2.10 (s, —CH3). 13C-NMR (100 MHz, D2O): 176.86 (CO);=153.10; 134.09; 133.61; 131.33; 127.99; 122.84; 117.22; 110.91; 69.60; 18.36.
Reaction SMILES: C(O)C.[OH:4][C@@:5]([C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48]([NH:50][CH3:51])=[O:49])[CH:44]=2)[CH:39]=1)([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:6][C:7]([O:9][C:10](C)(C)[CH3:11])=[O:8].Cl.[Cl-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C>[OH:4][C@@:5]([C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48]([NH:50][CH3:51])=[O:49])[CH:44]=2)[CH:39]=1)([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.67 h
Yield: 79.5 %

Procedure:
150 mL of ethanol and 6.9 mL (23.5 mmol, 3 eq) of titanium tetraisopropoxide were added to 5 g (7.84 mmol) of tert-butyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate. The mixture was stirred at 60˜65° C. for 28 hours and 40 minutes. 50 mL of 1N hydrochloric acid was added to at 0˜10° C., followed by dilution with 150 mL of ethyl acetate. 50 mL of an aqueous saturated sodium chloride solution was added, and the layers were separated. The organic layer was washed successively with a mixed solution of 25 mL of 1N hydrochloric acid and 65 mL of an aqueous saturated sodium chloride solution two times, 25 mL of an aqueous saturated sodium bicarbonate solution, and 50 mL of an aqueous saturated sodium chloride solution two times. After concentrated under reduced pressure, 50 mL of ethyl acetate, 10 mL of THF and 10 mL of water were added to the concentration residue and the layers were separated. The organic layer was washed with 10 mL of an aqueous saturated sodium chloride solution two times. After concentrated under reduced pressure, 15 mL of IPE was added to the concentrated residue, crystals were loosened, filtered, and washed with 5 mL of. IPE two times. Vacuum drying (40° C.) to a constant weight afforded 3.8 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 80%, enantiomer excess 94.8% ee).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@H:29]([CH2:28][NH:27][CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:31])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.535 g, 1.730 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chloropheny)propanoic acid (0.6122 g, 1.730 mmol) were combined in methylene chloride (15 mL) and treated with diisopropylethylamine (0.9041 ml, 5.191 mmol). HBTU (0.6579 g, 1.730 mmol) was then added. The reaction was stirred at ambient temperature for 16 hours. ESI MS looked excellent for desired product. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion was washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was applied to a 40 mm samplet and air-dried. This was placed on top of a column (Biotage 40S) and eluted with 3:2 hexane/EtOAc. The major spot was collected to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (955 mg, 96%). LC/MS (APCI+) m/z 571.9 [M+H]+
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH2:7]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+].[Cl-]>C1COCC1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:24][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: c1cn[nH]c1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(OCC(O)Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.091 g (3.96 mmol) sodium is mixed with 5 ml absolute THF and with a solution of 0.268 g (3.94 mmol) pyrazole in 15 absolute THF. Having stirred at room temperature for 2 hours, a solution of 0.690 g (2.63 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml THF is added drop-wise and boiled under reflux for 8 hours. The cooled reaction mixture is poured into semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator. Washing using a semi-saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 85:15) and recrystallized from petroleum ether and yields the product as a white solid.
Reaction SMILES: CO[CH:3](OC)[CH:4]([NH:6][C:7]1[CH2:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[N:8]=1)[CH3:5]>C(COC)OC.[Ti](Cl)(Cl)(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]2[N:8]3[CH:3]=[C:4]([CH3:5])[N:6]=[C:7]3[CH2:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10]=2[CH:20]=1
Reactant: COC(OC)C(C)NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COCCOC
Product: Cc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2

Procedure:
A solution of 2-[[7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]amino]propionaldehyde dimethyl acetal in monoglyme is treated with titanium tetrachloride first at room temperature, then under reflux. The reaction mixure is cooled, neutralized, and extracted with chloroform. The chloroform layer is concentrated in vacuo and the resulting residue crystallized to give 8-chloro-2-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: C([O:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)(=O)C.Cl>[OH-].[Na+]>[OH:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)Cc1ccc(C2=NNC(=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(O)Cc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
4,5-Dihydro-6-[4-(2-acetoxypropyl)phenyl]-3(2H)pyridazinone (0.73 g) was heated under reflux in 2N sodium hydroxide solution for 2 hr, cooled, neutralised with 2N hydrochloric acid, and extracted into ethyl acetate. The organic extract was dried (MgSO4) and evaporated to an oil which was chromatographed on silica gel. Elution with methanol-chloroform (4:96) gave 4,5-dihydro-6-[4-(2-hydroxypropyl)phenyl]-3(2H)pyridazinone as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].Cl.[NH2:11][OH:12].C([O-])(O)=O.[Na+]>CO>[OH:12][NH:11][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][N:9]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C#N)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)ccn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 130.4 %

Procedure:
To a solution of 2-methyl-isonicotinonitrile (330 mg, 2.79 mmol) in methanol (12 mL), hydroxylamine hydrochloride (388 mg, 5.59 mmol) and NaHCO3 (469 mg, 5.59 mmol) is added. The mixture is stirred in a sealed vial at 60° C. for 16 h before the solvent is evaporated. The residue is dried to give N-hydroxy-2-methyl-isonicotinamidine (550 mg); LC-MS: tR=0.55 min, [M+1]+=152.25.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]([CH3:50])[C:43]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=[O:44]>[Cu]I>[CH3:41][N:42]([CH3:50])[C:43]([CH:45]1[CH2:49][CH2:48][N:47]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]3=[N:6][CH:7]=2)[CH2:46]1)=[O:44]
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Reactant: CN(C)C(=O)C1CCNC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(N3CCC(C(=O)N(C)C)C3)cc12
Yield: 36.2 %

Procedure:
To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (228 mg, 0.53 mmol), copper(I)-iodide (20 mg, 0.11 mmol), proline (24.4 mg, 0.21 mmol), potassium carbonate (220 mg, 1.6 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (150 mg, 1.05 mmol) obtained in step 1. The mixture was flushed with nitrogen, and dimethylsulfoxide (1.5 ml) was added. The mixture was sealed and placed under microwave irradiation at 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 ml). The combined organic layers were dried over Sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0% to 100% ethyl acetate in hexanes) to give 95 mg (36%) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrrolidine-3-carboxylic acid dimethylamide. MS: m/z 495.5 (M+H+).
Reaction SMILES: [OH-:1].[K+].C([O:5][C:6](=[O:43])[C:7]([CH3:42])([CH3:41])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C>O.C(O)C>[CH3:41][C:7]([CH3:42])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:6]([OH:5])=[O:43]
Reactant: [OH-]
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCCC(=O)CCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 57.3 %

Procedure:
To a solution of KOH (85%, 8.4 g, 127.3 mmol) in deionized water (3.6 mL) and ethanol (11.5 mL) was added 208i (15.0 g, 25.3 mmol) and the mixture was heated to reflux for 7 h. The reaction mixture was diluted with water (40 mL) and extracted with MTBE (2×30 mL). The aqueous layer was cooled with an ice-bath and the pH was adjusted to 1 by addition of 5 N sulfuric acid (45 mL). The aqueous layer was extracted with MTBE (3×30 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give a crude oil (12.5 g). Purification by chromatography (silica gel, ethyl acetate/hexanes=10% to 100%) and recrystallization from MTBE/hexanes (4 mL/50 mL) yielded 210i (5.37 g, 57%) as a white powder. Mp 74.5-76.0° C. 1H NMR (CDCl3): δ (ppm): 12.40-11.20 (br, 2H), 2.39 (t, J=7.3, 4H), 1.62-1.48 (m, 8H), 1.38-1.22 (m, 12H), 1.11 (s, 12H). 13C NMR (CDCl3=77.02 ppm): δ (ppm): 211.88, 184.93, 42.70, 42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83. HRMS (LSIMS, gly): Calcd for C21H39O5 (MH+): 371.2797, found: 371.2804.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:16]([CH3:18])[CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:16]([CH3:18])[CH3:17])=[C:11]([CH2:13][CH2:14][O:15][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Reaction time: 5 h
Yield: 49 %

Procedure:
In a mixture of methylene chloride (1 mL) and pyridine (2 mL) was dissolved 2-[2-(2-chlorophenyl)-5-isopropyloxazol-4-yl]ethanol (159 mg, 0.598 mmol). Under cooling with water, to the solution was added p-toluenesulfonyl chloride (125 mg, 0.658 mmol). The mixture was stirred for 5 hours. The reaction mixture was poured into 1N HCl and extracted with chloroform. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate=2/1), to obtain the desired compound (123 mg, 49%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:15]=1.[NH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH2:34][CH2:35][C:36](=[O:41])[N:37]2[CH3:40])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:29][C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][C:36](=[O:41])[N:37]3[CH3:40])=[CH:32][CH:31]=2)=[O:20])=[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:15]=1
Reactant: O=C(O)c1ccc(Cl)cc1NC1CCCC1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NC3CCCC3)cc21
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (250 mg) was added to a chloroform (15 mL) solution of 4-chloro-2-(cyclopentylamino)benzoic acid (250 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (184 mg), followed by stirring at room temperature for 26 hours. The reaction liquid was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (chloroform:methanol, 1:0 to 9:1), 4-chloro-2-(cyclopentylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide was obtained. By treating this with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-2-(cyclopentylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide hydrochloride (97 mg) was obtained as a solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].[H][H]>CO>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
A solution of 14.7 g (60 mmol) of (S)-3-azido-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 200 ml of methanol was treated with 1.0 g of Raneynickel and shaken in a hydrogen atmosphere at pressures of 49.5-51 psi and temperatures of 25.3°-29.4° for nine hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 13.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:20][C:21]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:21]=2[CH3:20])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Product: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Yield: 82 %

Procedure:
The product from Example 61C and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound (7.20 g, 82%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:37])=[N:4][CH:5]=1)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (40 mg, 0.096 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (11 mg). MS 434.3 (M+H); UV 204.2, 265.8, 298.4, 357.9 nm; t 0.453 min.