Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([C:19]([OH:21])=O)[CH2:18][CH:9]3[CH2:10][N:11]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[CH2:12][CH:8]3[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CC(C)=O.O>[CH:1]1([C:6]2([C:19]([N:35]=[N+:36]=[N-:37])=[O:21])[CH2:18][CH:9]3[CH2:10][N:11]([C:13](=[O:17])[N:14]([CH3:15])[CH3:16])[CH2:12][CH:8]3[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(C(=O)O)(C3CCCC3)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C(=O)N=[N+]=[N-])(C3CCCC3)CC2C1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
5-Cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, 6.95 mmol) was dissolved in 20 mL of acetone upon cooling by an ice-water bath, followed by addition of triethylamine (0.15 mL, 1.05 mmol) and a solution of 2 mL of ethyl chloroformate (0.1 mL, 1.05 mmol) in acetone at 0° C.˜−5° C. After the reaction mixture was stirred for 15 minutes, a solution of sodium azide (0.124 g, 1.9 mmol) in water was added dropwise. The reaction mixture was stirred for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated and the residue was diluted with 10 mL of water. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 16d (0.287 g, yield 95%) as a yellow oil which was directly used in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.C1C(=O)N([Br:34])C(=O)C1>C(#N)C>[Br:34][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.60 g, 15.0 mmol) in acetonitrile (50 mL) was added NBS (2.80 g, 15.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.40 g, 73%) as a light yellow solid. ESI-MS m/z calc. 452.3. found 454.5 (M+1)+; Retention time: 1.60 minutes (3 minute run).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:26])[C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:17][CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([N:12]([CH3:26])[C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH:16]=[CH:17][CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.3 %

Procedure:
To a solution of potassium thiocyanate (4.31 g, 44.4 mmol) in acetic acid (15 ml) was added a solution of N-[3-[(5-aminopyridin-2-yl)(methyl)amino]phenyl]-2,2,2-trifluoroacetamide (3.46 g, 11.1 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 20 min. To this solution was added dropwise a solution of bromine (1.95 g, 12.2 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (140 mL)/tetrahydrofuran (70 mL), and washed with aqueous sodium hydrogen carbonate solution (70 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (829 mg, 20%) as a violet powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NCC(F)(F)F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCC(F)(F)F)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.190 mmol) and 2,2,2-trifluoroethylamine (0.5 ml, 0.190 mmol) the title compound, was obtained as a white powder (70 mg, 0.116 mmol, 62.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.37-7.51 (m, 4H), 7.21-7.29 (m, 2H), 6.72 (d, J=5.2 Hz, 1H), 4.85 (q, J=8.9 Hz, 2H), 1.42 (s, 9H). MS (ESI): 602.9 [M+H]+.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.Cl.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:14])[C:9]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)O)CCCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
A solution of (S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoic acid (201.7 mg, 0.476 mmol), (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (138 mg, 0.572 mmol), WSC.HCl (137 mg, 0.714 mmol), DIPEA (0.125 ml, 0.714 mmol) and 1-hydroxy-7-azabenzotriazole (97 mg, 0.714 mmol) in DMF (2 ml) was allowed to stir at room temperature under nitrogen for 14 hours. The reaction was quenched with H2O. The products were extracted with EtOAc. The organic layer was washed with NH4Claq, 0.1 M HCl (twice) and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 0:100) to give (S)-benzyl 1-((S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoyl)pyrrolidine-2-carboxylate (243 mg); Retention time=1.74 minutes (condition B); MS (m+1)=611.2; 1H NMR (400 MHz, CD3CN, mixture of rotamers) δ ppm 0.91-1.06 (m, 3H) 1.33-1.42 (m, 6H) 1.55-2.09 (m, 6H) 2.25-2.42 (m, 2H) 2.57-2.93 (m, 2H) 3.06-3.59 (m, 2H) 3.75-3.91 (m, 2H) 4.14-4.61 (m, 2H) 4.68-5.09 (m, 3H) 6.40-6.52 (m, 1H) 7.00-7.45 (m, 14H).
Reaction SMILES: [OH:1][CH2:2]C(CO)OCN1C=C(C=C)C(=O)NC1=O.BrN1C(=O)CCC1=O.[OH:26][CH2:27][CH2:28][O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Br:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]>C(Cl)(Cl)Cl.CO>[OH:26][CH2:27][CH:28]([CH2:2][OH:1])[O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Br:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]
Reactant: [N-]=[N+]=NC(CBr)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC(CBr)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 31.4 %

Procedure:
Reaction of 9a with N-bromosuccinimide, using the procedure outlined for the preparation of 2a, and purification of the product by silica gel column chromatography using chloroform-methanol (92:8, v/v) as eluent provided 10a as a syrup (92 mg, 31.4%).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[CH2:41]([O:43][NH2:44])[CH3:42]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6](/[C:7](=[N:44]\[O:43][CH2:41][CH3:42])/[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:32][CH:33]=1
Reactant: CCON
Reactant: O=C(O)c1ccc(Oc2ccc(CN3CCC(C(=O)c4ccc(Br)cc4)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCO/N=C(\c1ccc(Br)cc1)C1CCN(Cc2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
To a solution of the compound prepared in Example 5(15) (912 mg) in ethanol (10 mL) were added pyridine (5 mL) and O-ethylhydroxyamine hydrochloride (340 mg) and the solution was refluxed for 3 hours. After finishing the reaction, the reaction solution was concentrated. Water and 2N hydrochloric acid were added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=25:1) and 4N hydrogen chloride/ethyl acetate solution was added to the obtained residue, which was concentrated to give the compound of the present invention (E-form: 409 mg, Z-form: 500 mg) having the following physical data.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC(c3ccccc3)CC2)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene (6.4 g) in ethyl alcohol (192 ml) and tetrahydrofuran (192 ml) was added 10% palladium on carbon (0.64 g), and hydrogen gas at atmosphere pressure for 6 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give 1-(4-aminophenyl)-4-phenylpiperidine (5.66 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20](O)=[O:21].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[CH2:33][CH3:34].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH2:33]([C:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:20]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=3[CH3:19])=[O:21])[CH:25]=2)[NH:29][N:28]=1)[CH3:34]
Reactant: CCc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(C(F)(F)F)cc3F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
The product of Example 21, Step 2 (50 mg, 0.158 mmol, 1.00 equiv), 5-amino-3-ethylindazole (25 mg, 0.158 mmol, 1.0 equiv), and EDC (36 mg, 0.189 mmol, 1.20 equiv) were suspended in 0.5 mL DMF. Et3N (0.026 mL, 0.189 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 25 mg (34%) of the title compound as an off white solid. MS (ES+) m/e 461 [M+H]+
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(O)=O.[O-:28][C:29]#[N:30].[Na+]>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:29]([NH2:30])=[O:28])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Yield: 48 %

Procedure:
According to the procedure of F. Kurzer, Org. Syn. Coll. Vol (IV) 49 (1963), mix 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine ((133 mg, 0.54 mmol) with HOAc (4 mL) and water (2 mL). Dissolve sodium cyanate (80 mg, 1.2 mmol) in water (1 mL) and add this solution to the amine derivative. Stir the reaction at room temperature for 2 h. and then pour into water (100 mL). Extract the title compound into EtOAc, dry (MgSO4) and concentrate to give 240 mg crude product. Purify on silica gel using EtOAc/hexane to give 150 mg (48%) product as a colorless oil. MS (ES) 341 (M+1), 339 (M−1). HPLC shows 96.6% purity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C[O-].[Na+]>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Reactant: C#CCO
Agent: C[O-]
Agent: [Na+]
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
10 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester, 30 of propargyl alcohol and 0.5 g of sodium methoxide are heated to reflux for 1/2 an hour The excess propargyl alcohol is thereupon slowly (5 hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether solution is dried with sodium sulfate and evaporated. The dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester obtained is purified over Kieselgel.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:11]>>[CH3:9][CH:4]1[C:5](=[O:8])[C:6]([O:7][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[C:2]([CH3:1])[O:3]1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: C=COCCCC
Product: CCCCOC(C)OC1=C(C)OC(C)C1=O
Yield: 38.7 %

Procedure:
2,5-Dimethyl-4-hydroxy-3(2H)-furanone (13.3 g, 0.1 mole) and butyl vinyl ether (20.0 g, 0.2 mole) are reacted as in Example 1 to give a 37.8% yield (8.83 g) of 2,5-dimethyl-4-[(1'-butoxy)ethoxy]-3(2H)-furanone, b.p. 68.8° C. (0.75 torr) IR (neat, film) 1200, 1625, 1700, 2865, 2930, 2958, 2978 cm-1, 1H NMR (CDCl3) δ0.95 (m, 3), 1.35 (d, J=5 Hz, 3), 1.38 (d, J=8 Hz, 3), 2.18 (S, 3), 3.70 (m, 2), 4.48 (q, J=7 Hz, 1) 5.31 (q, J=5 Hz, 1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:37]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccccc1Cl
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 46.9 (0.275 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 53.0 mg (39% of theory).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:5]=2[CH:6]=1
Reactant: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCNc2cc(Cl)ccc21
Temperature: 85 °C
Yield: 65 %

Procedure:
Add a mixture of crude 2-[tert-Butoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-4-chloro-benzoic acid methyl ester (141.5 g, ˜0.337 mol) in toluene to potassium t-butoxide (95%, 100 g, 0.847 mol) in anhydrous toluene (4.5 L) at 60° C. over 1 h. After heating of 24 h concentrate the mixture under vacuum. Partition the residue between ethyl acetate (1.5 L) and saturated KH2PO4 (1.5 L). Separate the aqueous layer and extract with ethyl acetate (2×0.5 L). Combine the organics and wash with water (2×0.5 L). Remove solvent under vacuum. Dissolve the residue in acetic acid (250 mL) and dilute with 5N HCl (1 L). After heating at 85° C. for 4 h, cool the mixture to room temperature. Basify (pH=10) with 5N sodium hydroxide (ca. 1.8 L) while cooling in an ice bath. Extract the organics with ethyl acetate (3×0.5 L) and wash with brine (0.75 L). Dry over sodium sulfate, filter and concentrate under vacuum. Pass the beige crude product through a pad of silica (8 cmD×3 cmH), eluting with DCM/hexanes (2/1, ca. 3.5 L). Concentrate the crude product under vacuum to give a yellow solid. Recrystallize from EtOAc/hexanes (1/4) to give the title compound (42.85 g, 65%) as an off white solid: H NMR (CDCl3, 300 MHz) δ 4.20 (m, 2H), 4.85 (t, J=4.2 Hz, 2H), 5.29 (t, J=4.2 Hz, 2H), 6.71 (bs, 1H), 8.79-8.82 (m, 2H), 9.68 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([CH3:6])[NH2:5].[Li+].CC([N-]C(C)C)C.CS(C[C:21]1[N:22]=[CH:23][C:24]2[N:25]([S:34]([CH3:37])(=[O:36])=[O:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)(=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C@:4]([C:21]1[N:22]=[CH:23][C:24]2[N:25]([S:34]([CH3:37])(=[O:35])=[O:36])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)([CH3:6])[NH2:5]
Reactant: CS(=O)(=O)Cc1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Reactant: COC(=O)[C@H](C)N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@](C)(N)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
The Schiffs' base (1.34 g, 7.0 mmol), derived from alanine methyl ester andbenzaldehyde was dissolved in THF (25 mL), and cooled to -76° C. To this was added a solution of LDA (11.6 mL of 10% in n-hexane) in THF (15 mL). After stirring for 30 minutes this solution was treated with 3-(methylsulfonylmethyl)-9-methylsulfonyl-β-carboline (25 Ml in THF) from Step 2, warmed to room temperature and stirred over night. The brown suspension was evaporated in vacuum, the residue dissolved in ethyl acetate and the solution was washed with water, combined with 100 mL 1N HCl and was stirred for 1 hour at room temperature. The organic layer was separated and the aqueous solution was treated with Na2CO3 to pH 8-9. This was extracted with ethyl acetate (2×100 mL), dried overNa2SO4 and the organic solvent was evaporated in vacuum. The residue was flash chromatographed on silica gel using 5% methanol/methylene chloride to yield 2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methyl ester (0.53 g, 21.2%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1.CN(C)C=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1cccnc1
Reaction time: 16 h
Yield: 48.4 %

Procedure:
(5R)-3-(3-Fluoro {6-[(5S)-5-(hydroxymethyl)-4,5,-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-4-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 200 mg, 0.46 mM), nicotinoylchloride hydrochloride (175 mg, 0.98 mM), 4-(dimethylamino)pyridine (DMAP, 20 mg, 0.17 mM) were placed in a flask. Anhydrous dimethylformamide (2 mL) and anhydrous pyridine (2 mL) were added and the suspension was stirred for 16 hours during which it became a clear solution. 500 mg silicagel was added and the solvents were evaporated. The residue was chromatographed on silicagel eluting with a gradient of methanol in dichloromethane (1–20%) to give title compound (120 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([NH:9][C:10](=[O:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5](O)=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[N:9][C:4]=2[C:3]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1c(O)ccc(Br)c1Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nc2c(Oc3ccccc3)c(Br)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A mixture of tert-butyl {2-[(3-bromo-6-hydroxy-2-phenoxyphenyl)amino]-2-oxoethyl}carbamate (0.298 g, 0.681 mmol), triphenylphosphine (0.393 g, 1.50 mmol), and freshly activated 4 A molecular sieves (2.72 g, 4 g/mmol) at 0° C. was treated with tetrahydrofuran (10.2 mL) and stirred at 0° C. for 1 h, followed by dropwise addition of diisopropyl azodicarboxylate (0.295 mL, 1.50 mmol) at this temperature. The resultant reaction mixture was warmed to RT and stirred at RT for 16 h, after which time the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to yield a crude residue that was purified by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) to give the desired product (207 mg, 72%) as a tan solid. LCMS calculated for C19H19BrN2O4Na (M+Na)+: m/z=441.0, 443.0. found: 441.0, 443.0.