Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:21][CH2:20][C@@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Yield: 95.6 %

Procedure:
tert-Butyl [(1R,3S)-3-(4-[3-(trifluoromethyl)phenyl]-piperazin-1-ylcarbonyl)-cyclopentyl]-carbamate (82 mg, 0.18 mmol) was treated with trifluoroacetic Acid (3 mL, 0.04 mol) in methylene chloride (3 mL) at room temperature for 1 h. The mixture was concentrated to provide the desired product (98 mg, 93%). MS calculated for C20H28F3N3O: (M+H) 384.3; found 384.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([CH2:16]O)[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1(C)C=CC=CC=1>[Cl:3][CH2:16][C:14]1[O:13][N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:15]=1
Reactant: OCc1cc(-c2ccccc2)no1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: ClCc1cc(-c2ccccc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Thionyl chloride (2.41 ml) was added to a solution of (3-phenyl-5-isoxazolyl)methanol (2.89 g) in toluene (10 ml) and stirred at 60° C. for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 5-(chloromethyl)-3-phenylisoxazole (2.75 g, yield 86%) as pale-brown crystals. m.p. 69-70° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:40])[C:28]=1[O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:5][CH:6](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:47]([C:51]1[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>C(#N)C.C(OCC)(=O)C>[C:47]([C:51]1[CH:52]=[CH:53][C:54]([CH2:55][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2/[CH:18]=[CH:17]/[CH:6]([CH2:5][C:4]2[CH:26]=[C:27]([F:40])[C:28]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:32])[CH3:33])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:57][CH:58]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C

Procedure:
1.7 g (3 mmol) of 4-[(4E)-3-{3,5-difluoro-4-[(triisopropylsilyl)oxy]benzyl}-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzonitrile in 35 ml of acetonitrile are mixed with 627 mg (4.5 mmol) of potassium carbonate and 1 g (4.5 mmol) of 4-tert-butylbenzyl bromide and stirred under reflux for 12 hours. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed once with sodium bicarbonate solution and once with sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 628 mg (85% purity, 0.76 mmol, 25% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:71][C:72]1[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][CH:73]=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:76][C:75]2[CH:77]=[CH:78][C:72]([F:71])=[CH:73][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.1 mg, 58%). LC-MS m/z 633 (M+H)+.
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:39])[CH3:38])=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(CCCCC(C)=O)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(CCCCC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (1.45 g, 4.40 mmol) and DBU (1.54 mL, 10.20 mmol) were added to a stirred suspension of copper (II) bromide (2.28 g, 10.20 mmol) in deoxygenated dry CH2Cl2 (30 mL). After 20 min, a deoxygenated solution of 2-(5-oxo-hexyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (931 mg, 4.10 mmol) in CH2Cl2 (11 mL) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EA (50 mL), and 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (50 mL) and the combined organic layers were washed with 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:4 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:4 hept-EA)=0.37. LC-MS-conditions 02: tR=0.78 min, [M+H]+=226.47.
Reaction SMILES: O.[S:2]([O-:5])([O-:4])=[O:3].[K+:6].[K+].S(S([O-])=O)([O-])(=O)=O.[K+].[K+].[C:17]([F:26])([O:21][C:22]([F:25])([F:24])[F:23])=[C:18]([F:20])[F:19]>O>[F:19][C:18]([F:20])([S:2]([O-:5])(=[O:4])=[O:3])[CH:17]([F:26])[O:21][C:22]([F:25])([F:24])[F:23].[K+:6]
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: O=S([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)OC(F)(F)F
Temperature: -35 °C

Procedure:
A 1-gallon Hastelloy C276 reaction vessel is charged with a solution of 114 g potassium sulfite hydrate (KHSO3·H2O, 95%, Aldrich, 0.72 mol), 440 g potassium metabisulfite (K2S2O5, 99%, Mallinckrodt, 1.98 mol) and 2000 mL of deionized water. The pH of this solution is 5.8. The vessel is cooled to −35° C., evacuated to −3 psig (81 kPa), and purged with nitrogen. This evacuate/purge cycle is repeated two more times. 600 g perfluoro(methyl vinyl ether) (PMVE, 3.61 mol) is added to the vessel, which is heated to 125° C. at which time the internal pressure is 462 psig (3290 kPa). The reaction temperature is maintained at 125° C. for 6 hr. The pressure drops to 25 psig (275 kPa) at which point the vessel is vented and cooled to 25° C. Once cooled, a white crystalline precipitate of the forms, leaving clear colorless liquid above it (pH=7). 19F NMR of the white solid shows it to be the desired product in high purity (>98%). 19F NMR of the liquid shows a small but detectable amount of the hydration product of Equation (3), above.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)[CH3:4].C(N(CC)C(C)C)(C)C.[N:23]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[C:24]=[O:25]>ClCCCl>[CH:26]1([NH:23][C:24](=[O:25])[NH:2][CH:3]([C:5]2[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=2)[CH3:4])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(C)N)s1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(C)NC(=O)NC2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (33.2 mg, 0.150 mmol) and N,N-diisopropylethylamine (104 μL, 0.60 mmol) dissolved in 1,2-dichloroethane (1 mL) was added isocyanatocyclopentane (24 mg, 0.22 mmol). The reaction solution was shaken at room temperature overnight. The solution was further diluted with DCE (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The layers were separated and the organic layer concentrated to afford methyl 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylate as an oil residue. LC-MS: (FA) ES+ 297.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:34]2[CH2:35][CH:36]3[CH:32]([CH2:37]3)[CH2:33]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 5 h
Yield: 23.9 %

Procedure:
In absolute THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (200 mg, 0.45 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride salt (81 mg, 0.68 mmol). Triethylamine (137 mg, 1.35 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 5 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give a yellow solid (50 mg, 24% yield).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:45][CH3:46])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[C:43]=1[F:44])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:44][C:43]1[C:39]2[CH2:40][CH2:41][O:42][C:38]=2[C:37]([O:45][CH3:46])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCO2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 105 mg of {2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give 5-{(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (76 mg) as a light brown solid.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(Cl)Cl>[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:5](=[O:6])[CH2:4][CH2:3][C:2]([OH:1])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cccc(N)c1C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a partial suspension of dihydrofuran-2,5-dione (1.0 g, 10.0 mmol) in DCM (40 mL) was added a solution 2,3-dimethylaniline (1.21 g, 10.0 mmol) in DCM (40 mL). The reaction was stirred at room temperature for 3 h and filtered. The solid was washed with CH2Cl2 to afford the title compound (1.89 g, 85% yield). LCMS, [M+H]+=222.4.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([NH:9][CH:10]=[O:11])=[CH2:8]>C1(=O)C=CC(=O)C=C1.C[O-].[Na+]>[CH:7]([N:9]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:10]=[O:11])=[CH2:8]
Reactant: C=CC(=O)OC
Reactant: C=CNC=O
Agent: C[O-]
Agent: O=C1C=CC(=O)C=C1
Agent: [Na+]
Product: C=CN(C=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 91.9 %

Procedure:
To a 1000 mL three-neck round bottom flask equipped with a cold water condenser and stirrer was added 215 grams (2.5 moles) of methyl acrylate, 195 grams (2.75 moles) of N-vinylformamide, and 0.1 gram of benzoquinone. The mixture was stirred at ambient temperature for two minutes and 1.5 grams sodium methoxide was added in one portion. The mixture was stirred for approximately 2 hours at ambient temperature and allowed to stand overnight. The reaction mixture was distilled under vacuum and 361 grams of product (92% yield) boiling at 75° C. (0.8 mm Hg) was collected for analysis. 1H NMR analysis confirmed the identity of the 3-N-vinylformamido adduct.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][O:21][CH3:22])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[O-][CH2:31]C.[Na+]>C(O)C.CO>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][O:21][CH2:22][CH3:31])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-6-yl)ethanol was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinolin-6-yl)ethanol of Example 12, except that sodium ethoxide in ethanol solution was used instead of sodium methoxide in methanol solution. LCMS-ESI+ (m/z): 428.2, 430.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 13.3 %

Procedure:
Ethyl-2,2-dimethyl-7-bromoheptanoate (7.0 g, 0.026 mol) was treated with 4-chlorobenzenesulphonamide (9.9 g, 0.052 mol) and potassium carbonate (21.5 g, 0.016 mol) by the method described in Example 5(ii) to give the title compound (1.3 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[N:21]=[CH:20][C:19]=1[C:33](Cl)=[O:34]>O1CCCC1>[Br:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([NH:1][C:33]([C:19]2[CH:20]=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[C:18]=2[CH3:17])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: Cc1nc(Br)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Br)ccc1NC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-bromo-6-picoline (701 mg) and triethylamine (1.57 ml) in tetrahydrofuran (20 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (1.34 g) described in Reference Example 180 under ice-cooling, and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and saturated sodium bicarbonate water was added thereto. The insoluble matter was collected by filtration, washed with water, and then dried in vacuo to give the titled compound as a pale yellow solid (1.66 g). MS (ESI) m/z: 440 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:19][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@@H:25]([CH3:26])[NH2:27])=[CH:19][CH:18]=1)[CH3:9]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [(1R)-2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 47, 251.1 mg) was dissolved in dichloromethane (2 mL) to give a pale orange solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes the solvent was evaporated under vacuum affording a yellow oil which was charged on a 5 g SCX cartridge and flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (170.0 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][NH2:15]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([NH:15][CH2:14][CH2:13][NH2:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:15][CH2:14][CH2:13][NH2:16])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCN
Solvent: C1COCCO1
Product: NCCNc1cc(Cl)cc(NCCN)c1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
0.35 mole (79 g) of 2,4,6-trichloronitrobenzene is added to 280 ml of ethylenediamine diluted with 140 ml of dioxan, the temperature being maintained at 10° C. The mixture is heated for 2 hours at 50° C. The product expected precipitates on standing overnight at ambient temperature. After draining and re-impasting in water, the product is recrystallized from isopropanol in order to remove an insoluble product by filtering in the heated state. After drying under reduced pressure in the presence of phosphorous pentoxide, it melts at 113° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C(#N)C.[CH2:10]([O:12][C:13](Cl)=[O:14])[CH3:11]>C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: Cn1ccnc1
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nccn1C
Temperature: -20 °C
Yield: 59.9 %

Procedure:
N-methylimidazole (16) (320 g, 3.9 mol) was combined with 2 liters of acetonitrile and 1 liter of triethylamine in a flask equipped with a mechanical stirrer and the solution was cooled to −20° C. Ethylcloroformate (1000 g, 9.2 mol) was added with stirring, keeping the temperature between −20° C. and −25° C. The reaction was allowed to slowly warm to room temperature and stir for 36 hours. Precipitated triethylamine hydrochloride was removed by filtration and the solution was concentrated in vacuo at 65° C. The resulting oil was purified by distillation under reduced pressure (2 torr, 102° C.) to provide (17) as a white solid (360 g, 82% yield). TLC (7:2 benzene/ethyl acetate) Rf 0.2; 1H NMR (DMSO-d6) δ 7.44 (d, 1H, J=2.8 Hz), 7.04 (d, 1H, J=2.8 Hz), 4.26 (q, 2H, J=3.5 Hz) 3.91 (s, 3H), 1.26 (t, 3H, J=3.5 Hz); 13C NMR (DMSO-d6) δ 159.3, 129.1, 127.7, 61.0, 36.0, 14.5; IR (KBr) 3403, 3111, 2983, 1713, 1480, 1422, 1262, 1134, 1052, 922, 782, 666; FABMS m/e 155.083 (M+H 155.083 calc. for C7H11N2O).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 74 %

Procedure:
A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) and N-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/brine. The dried (MgSO4) organic layer was concentrated and the remaining oil was purified by chromatography on silica gel using CHCl3/MeOH (95:5) as eluent to give 10.7 g (75%) of the title compound as an oil that crystallized upon standing: mp 34-36° C. Anal. (C9H13CIN4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (780 mg, 2.4 mmol) was dissolved in N,N-dimethylformamide (15 mL) and to this was added potassium hydrogen carbonate (260 mg, 2.6 mmol) followed by benzyl bromide (281 μL, 2.4 mmol) and stirring continued at ambient temperature for 6 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2×60 mL). The organic extracts were washed with water (2×20 mL), brine, dried over sodium sulfate and filtered through a layer of silica gel. The filtrate was concentrated in vacuo and the residue crystallized from 100% hexane to give (4-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (500 mg, 50%).