Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CC(F)(F)F
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CC(F)(F)F
Yield: 30.6 %

Procedure:
Proceeding as in Example 1, but substituting 3,3,3-trifluoropropanoic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 34, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3,3,3-trifluoropropanoyl)pyrrolidine-2-carboxamide (9.2 mg, 30.6%). 1H-NMR (400 MHz, DMSO-D6): σ 9.98 (s, 1H), 7.54 (m, 2H), 7.22 (m, 2H), 7.17 (m, 5H), 6.93 (m, 4H), 4.49 (m, 1H), 3.60 (m, 2H), 3.26 (m, 1H), 2.65 (m, 3H), 1.91 (m, 2H). MS (EI) for C27H24F4N2O3: 501.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1>CN(C=O)C>[OH:15][CH:14]([CH2:13][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:12]=2)[CH2:7][CH2:8][C:9]1=[O:17])[CH2:16][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1
Reactant: COc1ccc2c(n1)N(CC1CO1)C(=O)CC2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Yield: 37.9 %

Procedure:
A solution of 7-(methyloxy)-1-(2-oxiranylmethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (428 mg, 1.829 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (366 mg, 1.829 mmol) in DMF (2 ml) under argon was heated at 120° C. for 1 h. The mixture was then evaporated and chromatographed (0-10% methanol/DCM) to give the product as a yellow oil (301 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)(C)(C)C.C(#N)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])([O-:14])=[O:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Yield: 54.9 %

Procedure:
(a)(i) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (1.71 g) in t-butanol (30 ml) was added slowly to a solution of 1-nitro-2,2-bis methylthioethylene (1.66 g) in acetonitrile (20 ml) at room temperature. The solution was heated under reflux for 3 hours, evaporated to dryness and chromatographed on a column of silica gel with elution by anhydrous ether (250 ml) followed by acetone (500 ml). The acetone eluate was concentrated to low bulk to give 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene (1.58 g), m.p. 151°-153°. A sample recrystallised from acetonitrile had m.p. 152°-153°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (12.50 g, 34 mmol) in dry CH2Cl2 (150 mL) was added Et3N (13.74 g, 18.3 mL, 136 mmol, 4 eq) at −5-0° C. Then a solution of MsCl (7.75 g, 5.16 mL, 68 mmol, 2 eq) in dry CH2Cl2 (50 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Upon reaction completion water (100 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×80 mL), the combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (15 g), which was used in the next step without purification.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:21][OH:22]>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH3:21][O:22][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: -78 °C
Yield: 93.1 %

Procedure:
In a 22 L RBF, charge 4-Chlorosulfonyl-benzoyl chloride (990 g, 4.159 mole) in 8.3 L THF and cool to −78° C. In an addition funnel charge triethylamine (588 ml, 4.159 mole), methanol (168 ml, 4.159 mole), DMAP (5 g, 0.041 mole) and 4 L THF; add this solution dropwise to the reaction keeping the exotherm <−70° C. over 5 hours. After the addition is complete, stir the reaction in a cold bath overnight. Filter the reaction and rinse with 3×500 ml THF. Concentrate under vacuum the filtrate to give a yellow solid. Dissolve the solid in 7 L EtOAc and 7 L 1N HCl. Separate the organic layer and wash with 5 L brine. Dry the organics over Na2SO4, filter and concentrate under vacuum to give a white solid, 4-Chlorosulfonyl-benzoic acid methyl ester. Yield=93.1% (906 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][Br:28]>>[Br-:28].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH3:27])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Cc1ccccc1CBr
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 121 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 2-methylbenzyl bromide (45 μL, 0.34 mmol) as reactants. White solid. (Yield 73.9 mg, 75%).
Reaction SMILES: C1(N[C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=CC=2)=[O:16])C=CC=CC=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].N[C:39]1C=CC=CC=1>>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:37][C:8](=[O:29])[CH2:9][CH:10]([CH3:39])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[C:24]2[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccccc1
Reactant: Nc1ccccc1N
Reactant: Nc1ccccc1
Product: CC(CCCCC(=O)c1cccc2ccccc12)CC(=O)Nc1ccccc1N
Yield: 87 %

Procedure:
Following a procedure described in Example 35, but substituting acid 193 for acid 80 1,2-phenylenediamine for aniline, the compound 198 was obtained in 87% yield. 1H NMR: (300 MHz, CD3OD): 8.05-7.91 (m, 4H), 7.67-7.53 (m, 2H), 7.10-6.68 (m, 5H), 3.33-3.31 (m, 2H), 3.19 (dd, J=6.9, 7.4 Hz, 2H), 2.47-1.29 (m, 7H), 1.05 (d, J=6.6 Hz, 3H), 13C NMR (75 MHz, CD3OD): 20.1, 25.8, 27.7, 32.1, 37.7, 39.4, 44.87, 118.6, 119.5, 124.7, 127.1, 127.8, 128.3, 128.8, 129.5, 129.6, 130.7, 131.1, 134.1, 137.1, 174.6, 202.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1C=CC=CC=1.ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:21][CH:18]1[CH2:20][CH2:19]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-4-methyl-benzoic acid (Aldrich, 5 g, 23.25 mmol) in benzene (50 mL), dichloromethane (10 mL) and N,N-dimethylformamide (0.5 mL) was treated with oxalyl chloride (4 mL, 46.5 mmol). The reaction mixture was allowed to warm to ambient temperature over 3 h. The volatiles were then distilled off in vacuo, the residue was diluted with anhydrous dichloromethane (50 mL) under argon, cooled (ice bath) and treated with 4-(dimethylamino)pyridine (5.67 g, 46.5 mmol) followed by cyclopropyl amine (1.93 mL, 27.9 mmol). After 3 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried-over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product that was used as such for the next step (6.0 g,˜100%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH2:38])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][N+:17]([O-:21])=[CH:16][C:15]=1[Cl:22])=[O:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:38][S:55]([C:49]1[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:47]([O:46][CH3:45])[CH:48]=1)(=[O:57])=[O:56])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:15]([Cl:22])=[CH:16][N+:17]([O-:21])=[CH:18][C:19]=1[Cl:20])=[O:10])(=[O:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N[C@H](CCCOC(C)=O)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.2 %

Procedure:
To a solution of 4-((S)-2-((R)-5-acetoxy-2-aminopentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (205 mg, 0.354 mmol) dissolved in DCM (2.5 mL), pyridine (58 μl, 0.710 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (168 mg, 0.710 mmol) were added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated, to yield 284 mg of a yellow solid which was purified by preparative reverse-phase HPLC to yield 42 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:19]([O-:21])=[O:20])=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1CCCOC
Reactant: O=[N+]([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1CCCOC

Procedure:
4.00 g (15.9 mmol) of the above prepared [2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 5.0 ml of TFAA and added slowly and carefully via dropping funnel to a mixture of 5 ml of TFAA and 4 ml of conc. HNO3 (65%) kept at −10° C.; the reaction was then allowed to proceed for additional 30 Min. Careful quenching with ice, twofold extraction with AcOEt, washing with NaHCO3 and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=75/25) to deliver finally 3.00 g of the title compound as light brown oil, contaminated according to NMR with roughly 35% of the ortho-isomer which was separated after the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:5][CH:4]([CH2:6][OH:7])[CH:3]([C:8]([F:10])([F:9])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)C(C(F)(F)F)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To a solution of 4,4,4,4′,4′,4′-hexafluoro-dl-valinol (0.50 g, 2.37 mmol), triethylamine (0.43 mL, 3.08 mmol) and CH2Cl2 (17.5 mL) at 0° C. was added a previously dissolved mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (0.606 g, 2.37 mmol) in CH2Cl2 (5 mL). After 15 min, the ice bath was removed and the reaction allowed to warm up to 25° C. After 16 h, the reaction was then diluted with CH2Cl2 (20 mL) and poured into a separatory funnel containing a saturated NaHCO3 solution. The organic phase was separated, washed sequentially with 1N HCl solution, distilled water, brine, dried over MgSO4 and evaporated to afford the crude product which was purified using Biotage Flash™ chromatography, eluent: 3:1 hexanes-ethyl acetate, to afford the product as a solid (0.134 g, 13%). MS (−ESI) 428.9 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]=1[NH:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: CSc1nc(Cl)c(F)c(NCc2nccs2)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(=NN)c(F)c(NCc2nccs2)[nH]1
Temperature: 80 °C
Yield: 29.3 %

Procedure:
6-Chloro-5-fluoro-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.6773 g, 2.336 mmol) was dissolved in DMSO (7 mL) and hydrazine monohydrate (0.91 mL, 18.72 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone as an orange solid (0.1958 g, 29%). LCMS: (M+H)+=287.1.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)N/C(=C\c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound (8) mentioned in Reference Example 3, was heated at 120°-130° C. in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH2:13][CH:14]=[CH2:15].C1COCC1.[CH:22]1([Mg]Cl)[CH:26]=[CH:25][CH:24]=[CH:23]1.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:12][CH2:13][CH:14]=[CH2:15])=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: C=CCCC(=O)c1ccc2ccccc2c1
Reactant: Cl[Mg]C1C=CC=C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=C1C=CC=C1)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
First, 6-(2-naphthyl)-6-(3-butenyl)fulvene was prepared from cyclopentadienyl Grignard reagents as follows. A 1 L round bottomed flask was charged with 1-(2-naphthyl)-4-penten-1-one, 97% (21.73 g, 100 mmol), THF (100 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (150 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over ½ hour. The yellow solution was stirred for 2 hours in the ice bath. The yellow solution was then refluxed for 2.5 hours, during which time a red color developed. The solution was acidified by first adding 100 mLs of water, and then adding 100 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with pentane and concentration under vacuum afforded 20.25 g (73%) of the product 6-(2-naphthyl)-6-(3-butenyl)fulvene as a red oil, which was 93% pure. The major impurity was dicyclopentadiene.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[N:36][N:37]2[C:42]([O:44][CH3:45])=[O:43])=O>CN(C=O)C.O>[C:1]1([CH2:11][NH:12][C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][N:37]3[C:42]([O:44][CH3:45])=[O:43])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: NCc1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)n1ncc2c(NC(=O)NCc3cccc4ccccc34)cccc21
Reaction time: 0.5 h

Procedure:
1-Naphthylmethylamine (2.1 mmol) and diisopropylethylamine (2 mmol, 0.26 g) were combined in DMF (6 mL) and treated with methyl 4-({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}amino)-1H-indazole-1-carboxylate (6.6 g, 2 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was diluted with water (6 ml) and filtered. The filter cake was washed with water:acetonitrile (1:1) and dried to provide the title compound. 1H NMR (DMSO-d6) δ 4.02 (s, 3H); 4.81 (d, 2H); 6.85 (m, 1H); 7.42-7.64 (m, 5H); 7.67 (d, 1H); 7.87 (m, 2H); 7.97 (d, 1H); 8.15 (d, 1H); 8.38 (s, 1H); 8.99 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([CH:18]=[CH:19][CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([CH2:49][O:50]CC[Si](C)(C)C)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:31][N:32]([CH3:42])[S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:24][CH2:23]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:57]CCl>>[ClH:57].[CH2:8]([O:15][C:16]([CH:18]=[CH:19][CH2:20][NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]([CH2:49][OH:50])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:31][N:32]([CH3:42])[S:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:26][CH2:27]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(CC(CCN1CCC(NCC=CC(=O)OCc2ccccc2)CC1)(COCC[Si](C)(C)C)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(CO)(CCN1CCC(NCC=CC(=O)OCc2ccccc2)CC1)c1ccccc1)S(=O)(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution of N-(4-(4-(N-(benzyloxycarbonyl)allylamino)piperidin-1-yl)-2-(2-(trimethylsilyl)-ethoxymethyl)-2-phenylbutyl)-N-methylbenzenesulfonamide (34 mg, 0.048 mmol) in dichloromethane (1.5 mL). After stirring the solution 1 h at RT, the solvents were evaporated. The residue was dissolved in 20 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate followed by 10 mL of brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane, to give the free base corresponding to the title compound in quantitative yield. The enantiomers of the free base could be separated by preparative HPLC on a Chiracel OD column, eluting with 40% isopropanol in hexane. 1H NMR (400 MHz, CD3OD): δ 7.77 (d, 2H, J=7 Hz), 7.65 (t, 1H, J=7 Hz), 7.58 (t, 2H, J=7 Hz), 7.41-7.27 (m, 9H), 7.23 (t, 1H, J=7 Hz), 5.81 (ddt, 1H, J=17, 10, 5 Hz), 5.19-5.04 (m, 4H), 4.02 (d, 1H, J=11 Hz), 3.97-3.82 (m, 4H), 3.36 (d, 1H, J=14 Hz), 3.16-3.08 (m, 2H), 2.85 (db, 1H, J=11 Hz), 2.43-2.33 (m, 1H), 2.31-2.23 (m, 1H), 2.16-1.95 (m, 4H), 2.03 (s, 3H), 1.86-1.60 (m, 4H). Mass spectrum (ESI): m/z=606 (M+1, 100%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([N:1]=[N+:2]=[N-:3])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 125 °C
Yield: 56.8 %

Procedure:
Sodium azide (6.96 g, 0.107 mol) and ammonium chloride (2.13 g, 0.0399 mol) were added to a solution of 1-(tert-butoxy carbonyl)3-[(methylsulphonyl)oxy]piperidine (10 g, 0.0358 mol) in DMF (75 ml) and water (12.5 ml). The mixture was heated overnight at 125° C. under stirring, cooled and diluted with water and extracted with chloroform. The organic layer was washed with water, dried over Na2SO4 and concentrated to give 4.6 g of thin reddish brown oil. 1H NMR (CDCl3) δ: 2.80-4.30 (m, 5H), 1.60-2.20 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: c1nc[nH]n1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cncn4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and 1,2,4-triazole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.