Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[N:38][CH:39]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[O:23][CH2:33][C:34]2[CH:39]=[N:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=2)=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCC1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)nc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
0.3 mmol 1-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-cyclobutanecarboxylic acid ethyl ester (94 mg), 0.6 mmol cesium carbonate (196 mg) (0.75 mmol in case of non-benzylic halides, +1 eq. in case of hydrochlorides) and 0.03 mmol sodium iodide (4 mg) are stirred for 10 min in 3 ml dry DMF. 0.33 mmol 5-Chloromethyl-2-trifluoromethyl-pyridine (65 mg) (0.45 mmol in case of non-benzylic halides) is added and the mixture is stirred for 2 h at RT and then for 5 h at 80° C. The cooled mixture is filtered, the filter washed with 5 ml ethyl acetate, the filtrate diluted with 20 ml ethyl acetate and washed twice with 20 ml 5% brine. The organic phase is dried and evaporated to yield 140 mg of 1-{[1-(6-Tri-fluoromethyl-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclobutane-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:9]S(C(C)(C)C)=O)[CH3:8].[ClH:16]>CO>[ClH:16].[ClH:16].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH2:9])[CH3:8]
Reactant: CC(NS(=O)C(C)(C)C)c1nccn1C
Agent: Cl
Solvent: CO
Product: CC(N)c1nccn1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 mL round-bottomed flask, 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide (700 mg, 3.05 mmol) was combined with methanol at 0° C. to give a colorless solution. Hydrogen chloride (4.0 M in 1,4-dioxane, 10 ml, 40.0 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h then concentrated in vacuo to provide 1-(1-methyl-1H-imidazol-2-yl)-ethylamine dihydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 9.28 (bs, 1H), 7.67 (bs, 2H), 4.92 (bs, 1H), 3.93 (bd, 1H), 1.67 (bd, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:4]([NH:6][CH3:7])=[O:5])[CH3:2].[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34](Br)[CH:33]=1>>[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:33]=[C:34]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=2[CH2:8][N:3]([CH2:1][CH3:2])[C:4]([NH:6][CH3:7])=[O:5])[CH:35]=[C:36]([Cl:38])[CH:37]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NC
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NC

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 1-ethyl-3-methyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C@H:15]2[CH2:22][CH2:21][C:18]3([CH2:20][CH2:19]3)[O:17][CH2:16]2)(=O)=O)=CC=1.[NH2:31][CH3:32]>C(O)C>[CH2:20]1[C:18]2([CH2:21][CH2:22][C@H:15]([CH2:14][C@H:13]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][NH:31][CH3:32])[CH2:16][O:17]2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCC3(CC3)OC2)NC(=O)OC(C)(C)C)cc1
Reactant: CN
Solvent: CCO
Product: CNC[C@H](C[C@H]1CCC2(CC2)OC1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
The (S)-2-(tert-butoxycarbonylamino)-3-((R)-4-oxaspiro[2.5]oct-6-yl)propyl 4-methylbenzenesulfonate was dissolved in 100 mL of 33% NH2Me in ethanol. The mixture was heated to 50° C. for 3 hr. After this time LC/MS analysis shows formation of the desired amine. The solution was evaporated and the residue taken up in EtOAc, washed with 10% K2CO3, brine, dried over Na2SO4, filtered and evaporated. The tert-butyl (S)-1-((R)-4-oxaspiro[2.5]oct-6-yl)-3-(methylamino)propan-2-ylcarbamate was used directly in the next step with no further purification. MS ESI +ve m/z 301 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([N:14]2[CH2:15][CH2:16][C@@H:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13]2)[CH:23]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccc(CCCOC[C@@H]2CCNC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](COCCCc3ccccc3)C2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 3(R)-[(3-phenylpropoxy)methyl]pyrrolidine (220 mg, 1.00 mmol, 1.50 equiv.) and 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (240 mg, 0.67 mmol) in toluene (15 mL) were added sodium tert-butoxide (96 mg, 1.00 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 13.4 μmol, 0.02 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 23 mg, 40 μmol, 0.06 equiv.) under N2. The mixture was stirred for 4 h at 100° C. After concentration in vacuo, the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated under reduced pressure. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:1 to afford the product (300 mg, 90%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.68 (br s, 1H), 7.63 (br s, 1H), 7.37-7.19 (m, 5H), 6.43 (br s, 1H), 4.18-4.10 (m, 2H), 3.90 (br s, 1H), 3.49-3.29 (m, 9H), 3.13 (dd, 1H, J=9.0, 6.6 Hz), 2.74-2.61 (m, 3H), 2.20-2.12 (m, 1H), 2.06 (m, 2H), 1.99-1.82 (m, 5H). LC-MS (ESI) m/z 496 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnc(Cl)c1
Yield: 49 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-chloroisonicotinoyl chloride to afford the title compound (39 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.96 (d, 1H, Harom, J=8.0 Hz), 7.45 (t, 1H, Harom, J=8.0 Hz), 7.59 (t, 1H, Harom, J=2.0 Hz), 7.64 (d, 1H, Harom, J=8.0 Hz), 7.82 (d, 1H, HPy,6, J=6.0 Hz), 7.85 (d, 1H, Harom, J=5.0 Hz), 7.97 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=5.0 Hz), 10.66 (s, 1H, NHamide), 11.21 (s, 1H, NHPy3), 11.42 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C18H13N5O3Cl: 382.0707; found: 382.0702.
Reaction SMILES: C(C(C([O-])=O)(O)C(C(C)C)(O)C([O-])=[O:7])(C)C.C(OO)(C)(C)C.[C:23]([C:35]1[CH:36]=[C:37]([CH2:41]/[CH:42]=[CH:43]/[OH:44])[CH:38]=[CH:39][CH:40]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:23]([C:35]1[CH:36]=[C:37]([C@H:41]2[O:7][C@@H:42]2[CH2:43][OH:44])[CH:38]=[CH:39][CH:40]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCC#Cc1cccc(C/C=C/O)c1
Reactant: CC(C)C(O)(C(=O)[O-])C(O)(C(=O)[O-])C(C)C
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CCCCCCCCCCC#Cc1cccc([C@H]2O[C@@H]2CO)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 916.1 %

Procedure:
To a solution (-) diisopropyltartrate (524 mg) in dry dichloromethane (60 ml) and 4A molecular sieves (1 g) at -20° C. was added titanium(IV) isopropoxide (0.53 ml) followed by t-butylhydroperoxide (3.0M, isooctane) (20 ml). The reaction mixture was stirred for 20 mins at -20° C. and then a solution of trans-3-[3-(1-dodecynyl)phenyl]propene-1-ol (8.88 g) in dichloromethane (20 ml) was added slowly. The mixture was stirred for 1.5 hr and quenched with 25% aqueous sodium hydroxide (6 ml) followed by water (40 ml). The mixture was allowed to warm to room temperature, and was stirred for 30 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with ethyl acetate/Heptane/1:2). The appropriate fractions were collected and evaporated. The residue was crystallized from heptane to afford 6.5 g (69%) of product, mp 41°-42° C. [α]D25 +33.1° (c. 0.725, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@H:6]1[C@@H:12]([CH2:13][CH3:14])[O:11][CH:8](OC)[C@@H:7]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.[Sn](Cl)(Cl)(Cl)Cl.ClCCl.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:13]([C@H:12]1[O:11][C@H:8]2[C@H:7]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][C:22]=32)[C@H:6]1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[F:1])[CH3:14]
Reactant: CC[C@H]1OC(OC)[C@H](OCc2cccc(C)c2)[C@H]1OCc1ccccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H]1O[C@@H]2c3ccc(C)cc3CO[C@@H]2[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
0.62 g of methyl 5-deoxy-3-O-(2-fluorobenzyl)-5-C- methyl-2-O-(3-methylbenzyl)-D-xylofuranoside (a mixture of alpha and beta forms) obtained in 1) was dissolved in 10 ml of acetonitrile and 4.97 ml of tin tetrachloride (a 1.0 M dichloromethane solution) were added under cooling with ice. The resulting mixture was stirred at room temperature for 3 hours and then poured into a saturated aqueous sodium hydrogen carbonate solution with ice. The organic phase was thoroughly washed with water and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain an oily product. The crude product was purified by silica gel chromatography (developing solvent: n-hexane:ethyl acetate=5:1) and 0.39 g of the target compound was obtained. (Yield: 68.4%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[NH2:36]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:3]=[C:2]([NH:36][C:32]2[S:31][CH:35]=[CH:34][N:33]=2)[CH:7]=1
Reactant: Nc1nccs1
Reactant: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Br)cc(-c3ccc(F)cc3F)c2)cn1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Nc3nccs3)cc(-c3ccc(F)cc3F)c2)cn1
Yield: 11.7 %

Procedure:
The compound was prepared from 1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole (0.05 g, 0.107 mmol) using the procedure of Example 280 and thiazol-2-amine (0.01 g, 0.10 mmol, 1.0 eq.) to yield the title product in 11.7% yield (0.06 g). 1H NMR (400 MHz CD3OD): δ 9.45 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.86-7.83 (m, 2H), 7.74 (s, 1H), 7.67-7.65 (m, 1H), 7.45 (s, 1H), 7.28-7.27 (d, 1H), 7.16-7.11 (m, 2H), 6.89 (d, 1H), 3.95 (s, 3H) LC-MS (ESI): Calculated mass: 484.52; Observed mass: 485.2 [M+H]+ (rt: 1.01 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:21][CH2:22][CH2:23][O:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:20]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)cc(C)c1C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 2,3,5-trimethylphenol (3.0 g, 22.0 mmol), potassium carbonate (3.65 g, 26.4 mmol) and potassium iodide (0.55 g, 3.3 mmol) in N,N-dimethylformamide (50 mL) was added 2-chloroethyl ethyl ether (3.59 g, 33.3 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 24 hr. To the reaction mixture were added reagents (potassium carbonate, potassium iodide and 2-chloroethyl ethyl ether) in the same amount as mentioned above, and the mixture was further stirred at 70° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1-hexane/ethyl acetate=4/1) to give the title compound (4.1 g, yield 90%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3Cl)[CH:23]=2)=[O:21])[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:23]=2)=[O:21])[CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCc1cccnc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCc5cccnc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide by a procedure analogous to Example 1C. MS: 414 (MH+), HPLC Rf: 4.12 min.; HPLC purity: 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1.O>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:36][C:33]3[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Yield: 28.8 %

Procedure:
To a solution of compound 12 (84 mg, 0.30 mmol) in DMF (3 mL) at room temperature were added DIPEA (0.103 mL, 0.6 mmol) and 5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol). The reaction mixture was heated at 40° C. overnight. Water was added, and the yellow precipitate was collected by filtration and washed with water. The solid was purified by silica gel chromatography eluting with DCM/MeOH to give compound 1 (30 mg, 29%). 1HNMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.54 (s, 1H), 7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H), 8.08 (m, 2H), 8.74 (d, 1H), 10.66 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z: 348 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>C1COCC1>[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:13]([NH:12][C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])=[NH:14])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)N[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 60 mg (0.27 mmol) 3,5-diamino-6-chloro-N[(methylsulfanyl)methanimidoyl]-pyrazine-2-carboxamide (intermediate 3) and 60 mg (S)-3-amino-1-benzyl-piperidine in 2 ml THF is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure treated with excess HCl in methanol and evaporated again.
Reaction SMILES: C1(=O)NCCCCC1.[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])#[N:10]>>[NH2:10][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: N#CCCCCC(=O)O
Agent: O=C1CCCCCN1
Product: NCCCCCC(=O)O

Procedure:
ε-caprolactam is also prepared by reduction of 5-cyanovaleric acid or ester obtained above to 6-aminocaproic acid or ester, and then cyclisation of the 6-aminocaproic acid or ester to ε-caprolactam.
Reaction SMILES: [O:1]=[C:2]([N:8]([CH3:16])[CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5]CC)=O.Cl[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]=[CH:24][C:23]1=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH:9]1[N:8]([CH3:16])[C:2](=[O:1])[C:3]([OH:5])=[C:24]2[CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][C:20]1[CH:19]=[CH:18][C:31]([F:32])=[CH:30][CH:29]=1)[C:23]2=[O:28]
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)N(C)Cc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1c1ncccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of ethyl 2-oxo-2-[N-methyl-N-(pyrimidin-2-yl)methylamino]acetate from the previous step (1.43 g, 5.85 mmol) and 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. for 48 hours. The mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of enantiomers. The hydrogens at positions 4a and 5 were found to have a trans relationship to one another. The enantiomers were separated on a ChiralPak AD column with 1:1 EtOH:MeOH as the mobile phase. The first eluting enantiomer had a positive sign of rotation and the following properties: 1H NMR (400 MHz, CD3OD), δ8.76 (d, J=4.8 Hz, 2H), 7.41 (t, J=4.8 Hz, 1H), 7.23 (dd, J=8.5, 5.5 Hz, 2H), 7.01 (t, J=Hz, 2H), 4.81 (d, J=6.7 Hz, 1H), 4.57 (d, J=15 Hz, 1H), 4.47 (d, J=15 Hz, 1H), 3.63 (m, 1H), 3.2-3.4 (m, 2H), 2.91 (s, 3H), 2.11 (m, 1H), 0.96 (dq, Jd=4.5 Hz, Jq=13 Hz, 1H). ES MS M+1=383. The second eluting enantiomer had a negative sign of rotation and 1H NMR and MS properties identical to that of the first eluting enantiomer.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=C(OCC=CCO)c1ccccc1
Product: O=C(CCc1ccccc1)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl hydrocinnamate was prepared by the procedure of Example 1 from 19 gms. (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 17 gms (0.1 mole) of hydrocinnamoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].O[CH2:10][C@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>>[C:1]([O:4][CH2:5][C:6]([O:8][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:36])([F:35])[F:37])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1)=[O:7])(=[O:3])[CH3:2]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CC(=O)OCC(=O)O
Product: CC(=O)OCC(=O)OC[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using acetoxyacetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([C:15]1([CH2:29][CH3:30])[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].[NH4+].[Cl-].C1C[O:36]CC1>>[CH3:11][O:12][C:13]([C:15]1([CH2:29][CH3:30])[CH:19]([OH:36])[C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: CCC1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CCC1(C(=O)OC)CN(c2c(C)cccc2C)C(=O)C1O
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
LHMDS (1 M solution in THF, 6 mL, 6 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-3-ethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 1.1 g, 4 mmol) in THF (15 mL). The solution was stirred at −50° C. for 5 min then warmed to 0° C. and stirred for an additional 5 min. After cooling back to −50° C., (R,S)-camphorsulfonyloxaziridine (1.1 g, 4.8 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (30 mL) was added, and the solution was extracted with EtOAc (3×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30→70% EtOAc/hexanes) to give 1-(2,6-dimethyl-phenyl)-3-ethyl-4-hydroxy-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.1 g, quantitative yield). LC-MS: Rt (retention time): 1.89 min, MS: (ES) m/z 292.1 (M+H+).