Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.O[N:31]=[C:32]([O:34][CH2:35][CH3:36])[NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:26]3[O:27][N:33]=[C:32]([O:34][CH2:35][CH3:36])[N:31]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
226 mg (0.52 mmol) of the compound from Example 40A and 109 mg (1.05 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 2.0 ml of DMF and reacted with 298 mg (0.8 mmol) of HATU and 0.27 ml (203 mg, 1.6 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 5.0 ml of dioxane and admixed with about 1 g of 4 Å molecular sieve. The mixture was heated to reflux for 16 h, and the reaction mixture was purified by means of preparative HPLC. Yield: 86 mg (30% of theory)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O)=[O:4].[Sn](Cl)Cl>C(O)C.O.C(=O)(O)[O-].[Na+]>[NH2:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc(C(=O)OC)cc1N
Temperature: 70 °C
Yield: 56.1 %

Procedure:
A mixture of methyl 4-(methylamino)carbonyl-3-nitrobenzoate (3.84 g, 0.0185 mol) and tin (ii) chloride (15.3 g, 0.08 mol) in ethanol (80 mL) was heated at 70° C. for 1 h. The reaction mixture was diluted with water (150 mL) and sodium bicarbonate solution was added to it to bring the pH close to 8. The mixture was extracted with ethyl acetate and the organic layer washed with water and brine and dried over sodium sulphate. After filtration, the solution was concentrated and the residue was recrystallized from ethyl acetate-hexane to give 2.16 g (64%) of methyl 3-amino-4-(methylamino)carbonylbenzoate as tan needles, mp 167°-168° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cccc2cc[nH]c12

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-methylphenylboronic acid: ESMS m/e: 208 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[N:7][N:8]=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[N:7][N:8]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)N(CCSc1nnc(N)s1)C(C)C
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(CCSc1nnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole (2.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Tert-butylbenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.2 g of the aimed compound.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=C(S(C)(=O)=O)[N:12]=1.Cl>O1CCCC1.O>[NH:3]([C:1]1[N:12]=[C:11]([Cl:10])[CH:16]=[C:15]([O:17][CH3:18])[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: O=CNc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.5 %

Procedure:
1.8 g of formanilide was dissolved in 50 ml of tetrahydrofuran, and 0.4 g of sodium hydride from which the oily matter had been removed before hand with n-hexane was slowly added to the resulting solution at 10° to 20° C. while cooling with ice water. To the suspension thus obtained was added 3.3 g of 4-chloro-2-methanesulfonyl-6-methoxypyrimidine, and the mixture was stirred for 1 hour at room temperature. Then, 15 ml of 4N hydrochloric acid was added, and reaction was effected for 1 hour under reflux. The reaction liquid was poured in water, extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and then the ether was stripped by concentration. The residual crystals were recrystallized from n-hexane, and 4.0 g of 2-anilino-4-chloro-6-methoxypyrimidine was obtained (yield 87%). Melting point: 101°-103° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[O:5])C.N(C1C=CC=CC=1OC)=[C:15]=O.CNC>>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[N:3]([CH3:15])[CH3:1]
Reactant: CCNC(=O)Nc1ccccc1O
Reactant: COc1ccccc1N=C=O
Agent: CNC
Product: CN(C)C(=O)Nc1ccccc1O
Yield: 54 %

Procedure:
The subtitled compound was prepared using the procedure as described for Example 25 for N-ethyl-N′-(2-hydroxyphenyl)urea from 1-isocyanato-2-methoxybenzene and dimethylamine (2M solution in THF). Yield 54%.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([CH:12]1[CH2:17][CH:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[CH:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CC(Oc2ccncc2)CC(C(=O)NO)C1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield The titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](N3CCN(CCCS(C)(=O)=O)CC3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:57]1([CH2:63][C:64]([NH2:66])=[O:65])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>>[C:46]([NH:45][S:42]([C:40]1[C:39]([Cl:50])=[CH:38][C:37]([O:51][CH2:52][CH3:53])=[C:36]([C:10]2[N:11]([C:21]([N:60]3[CH2:61][CH2:62][N:57]([CH2:63][C:64]([NH2:66])=[O:65])[CH2:58][CH2:59]3)=[O:22])[C@@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C@@:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:54])[N:9]=2)[CH:41]=1)(=[O:43])=[O:44])([CH3:47])([CH3:48])[CH3:49]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 acetonitrile/ethanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N6O5SCl3 [(M+H)+] 777.2154, observed 777.2146.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[C:2]([CH3:4])=O.C(=O)(O)O.[OH:23][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH2:25][NH2:26].O>C1C=CC=CC=1>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH:24]([OH:23])[CH2:25][NH:26][CH:2]([CH3:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(COc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
A mixture of 4,5-dihydro-6-(4-acetonyloxyphenyl)3(2H)-pyridazinone (0.3 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine carbonate (0.26 g) in dry benzene (80 ml) was heated under reflux, with azeotropic removal of water, for 3 hr. The solvent was evaporated and the residue dissolved in methanol (80 ml) and treated with sodium cyanoborohydride (0.5 g). After 18 hr. the methanol was evaporated and the residue partitioned between ethylacetate and brine. The organic phase was washed with water, dried (MgSO4) and evaporated to a gum which was chromatographed on silica gel. Elution with methanol-chloroform (4:96) gave 6-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyloxy]-phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white crystalline solid, m.p.t. 140°-158° C., as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C@@H:46]([CH2:50][C:51]([OH:53])=[O:52])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C@H:46]([C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48])[CH2:50][C:51]([OH:53])=[O:52]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)[C@@H](N)CC(=O)O)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with (S)-2-(tert-butoxycarbonylamino)succinic acid give the title compound. LC/MS (M+H)+: 650. Ret. time: 1.12 min. (Condition G); analytical HPLC Ret. time: 6.33 min (Condition Q).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=O)=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15]([NH2:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CCCC(NC(=O)C(O)C1C=CC(O)=C(OC)C=1)CCC>>[CH2:15]([NH:22][C:7](=[O:9])[CH:6]([OH:10])[C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Reactant: CCCCCCCN
Agent: CCCC(CCC)NC(=O)C(O)c1ccc(O)c(OC)c1
Product: CCCCCCCNC(=O)C(O)c1ccc(O)c(OC)c1
Yield: 89 %

Procedure:
N-heptyl-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide was prepared from 4-hydroxy-3-methoxymandelic acid and n-heptylamine by the same procedure described for the preparation of N-(heptan-4-yl)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide. White crystals of the title compound (6.7 g, 89% yield) were obtained.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[OH:13])[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2].N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[Si:35]([O:13][C@@H:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)[C@H:7]1[C:6]([O:24][CH3:25])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Yield: 73.4 %

Procedure:
To a solution of (S)-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (3.5 g, 9.8 mmol), and imidazole (0.8 g, 11.8 mmol) in CH2Cl2 (50 mL) was added tert-butylchlorodimethylsilane (1.6 g, 10.4 mmol) and TEA (1.6 mL, 11.8 mmol) at room temperature. The mixture was stirred over the weekend. The mixture was diluted with DCM and washed with water, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (40-50% DCM-hexane) to provide the product as a white solid (3.4 g, 74%). LCMS (API-ES) m/z: 473 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](N)[CH2:14][NH2:15].[S]>>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH2:9][C:10]2[NH:15][CH2:14][CH2:13][N:11]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1CC#N
Reactant: NCCN
Agent: [S]
Product: Cc1cc(F)cc(C)c1CC1=NCCN1
Temperature: 200 °C

Procedure:
A mixture of 1.30 g (8 mmol) (4-fluoro-2,6-dimethyl-phenyl)-acetonitrile, 3.83 g (4.27 ml, 64 mmol) ethylene diamine and 0.128 g (4 mmol) sulfur in a pressurized glass tube was heated under microwave irradiation to 200° C. for 20 min. The cooled reaction mixture was poured onto water, extracted with methylene chloride, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification of the residue by flash-chromatography over silica gel with a ethyl acetate/methanol gradient containing 1% conc. ammonia provided 2-(4-fluoro-2,6-dimethyl-benzyl)-4,5-dihydro-1H-imidazole as light yellow solid: MS (EI): 206.1 ((M+.), 100%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C1C[O:28]CC1>>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wis.) in THF at −78° C. is added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction is stirred at −78° C. for 2 hours. To this is added via cannula a −78° C. solution of acid chloride A-1 (R=hexanoyl, 65 mmol) in THF and the mixture is stirred at −78° C. for 2 hours, then allowed to warm to rt and stirred overnight. The reaction is then quenched with aqueous saturated NH4Cl, extracted with EtOAc, dried and purified by silica gel chromatography (hexanes/EtOAc) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one (A-2).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:25]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:26][CH:2]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: N=C(N)c1ccccc1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(-c2ccccc2)n1
Yield: 92 %

Procedure:
As described for Example 57, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (1.0 g, 4 mmol) using benzamidine HCl instead of acetamidine HCl was converted to the title compound (992 mg, 92%) which was obtained as a white solid. MS: m/e=302.1 [M+H]+.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.Cl.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCN(CC)CC
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS, 2SR, 3RS)-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1M HCl in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3 :H2O(containing 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181°-182° C. (dec).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OC(C)C)(C)C>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:26])=[O:25])([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 5-aminopentylcarbamate 30a (20 g, 99 mmoles) and 2-nitrobenzene-1-sulfonyl chloride 30b (23 g, 1.05 eq) in DCM (200 mL) was added dropwise diisopropyl ethyl amine (19.2 g, 1.5 eq) at 0° C. After stirring at RT overnight, the RM was successively washed with an aqueous solution of citric acid, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 32.61 g (85% yield) of tert-butyl 5-(2-nitrophenylsulfonamido)pentylcarbamate 30c as a white solid; m/z 388 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:16]([CH2:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:17]([OH:19])=[O:18])[CH:11]=[CH:12][C:13]=1[S:14][CH3:15].[Mn]([O-])(=O)(=O)=[O:26].[K+].[OH2:31]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:16]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24]2)[C:17]([OH:19])=[O:18])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:15])(=[O:26])=[O:31]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a flask was placed sodium periodate (187 mg, 0.86 mmol) and water (1.5 mL). To this solution was then added dropwise (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-propionic acid (132 mg, 0.46 mmol) in methanol (3.5 mL). The reaction was then stirred at 25° C. for 1 h after which time there was a white precipitate forming. Thin layer chromatography indicated the reaction was not complete so another portion of sodium periodate (120 mg, 0.5 mmol) in water (1 mL) was added and stirred another 1 h, the reaction was then stored at 4° C. for 16 h. The reaction was then filtered through a plug of celite and was concentrated in vacuo and then azeotroped with acetonitrile. The residue was then dissolved in methanol (6 mL) and added slowly to a solution of potassium permanganate (85 mg, 0.51 mmol) in water (1.5 mL) and stirred at 25° C. for 1 h. After this time the reaction was concentrated in vacuo and the residue was dissolved in acetonitrile and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclobutyl-propionic acid (95 mg, 65%) as a colorless gum: [α]30589=−42.0° (c=0.20, methylene chloride); ES-HRMS m/e calcd for C14H17O4SCl (M+Na)+ 339.0428, observed 339.0427; 1H NMR (300 MHz, DMSO-d6) δ 1.49-2.16 (m, 9H, CH and 4×CH2), 3.36 (s, 3H, SO2CH3), 3.60 (t, J=7.3 Hz, 1H, ArCHCO), 7.54 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.67 (d, Jm=1.5 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 12.71 (s, 1H, CO2H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=Nc1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and aniline (0.27 g, 2.9 mmol) dissolved in methanol (5 ml) was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g). Elution with chloroform-methanol (100:1) gave the object compound, which was further crystallized from methanol-diethyl ether to give N-cyano-N'-phenyl-4-pyridinecarboximidamide (0.32 g, 1.4 mmol, yield: 54%) as colorless needles.