Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([OH:30])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:56]([C:59]1[CH:81]=[CH:80][C:62]([CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C@H:70]([OH:79])[C:71]([N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)=[O:72])=[O:66])=[CH:61][CH:60]=1)([O-:58])=[O:57]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([N:76]2[CH2:75][CH2:74][N:73]([C:71](=[O:72])[C@@H:70]([OH:79])[CH2:69][CH2:68][NH:67][C:65]([O:64][CH2:63][C:62]3[CH:80]=[CH:81][C:59]([N+:56]([O-:58])=[O:57])=[CH:60][CH:61]=3)=[O:66])[CH2:78][CH2:77]2)=[O:30])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(S[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: O=C(NCC[C@H](O)C(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC[C@H](O)C(=O)N1CCN(C(=O)[C@@H]2C[C@H](SC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A 1.04 g portion of (2S,4S)-4-benzoylthio-1-(p-nitrobenzyloxycarbonyl)proline was dissolved in 20 ml of tetrahydrofuran, and, with cooling on an ice bath, 0.55 g of N-hydroxybenzotriazole and 1.49 g of dicyclohexylcarbodiimide were added to the solution, followed by 1 hour of reaction with stirring at room temperature. To the solution were added 0.88 g of 1-((2S)-4-(p-nitrobenzyloxycarbonyl)amino-2-hydroxybutyryl)piperazine and 0.49 g of triethylamine, followed by 1 hour of reaction at room temperature. After concentration of the solvent, the residue was mixed with ethyl acetate to remove insoluble material, washed with sodium bicarbonate aqueous solution, citric acid aqueous solution and sodium chloride aqueous solution in that order and then dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography to yield 1.80 g of (2S,4S)-4-benzoylthio-1-(p-nitrobenzyloxycarbonyl) -2-((1-((2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyryl)piperazine-4-yl)carbonyl)pyrrolidine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
2 g of 4-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidine, 2.67 g of N-(3-aminopropyl)-N′-methylpiperazine and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.22 g of N-[3-(4-methyl-piperazin-1-yl)propyl]-4-nitro-1-aminobenzene (9) were obtained.
Reaction SMILES: [S:1]([N:11]=[S:12]1[CH2:17][CH2:16][CH2:15][S:14](=[O:19])(=[O:18])[CH2:13]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Mn]([O-])(=O)(=O)=[O:21].[K+]>C(OC(=O)C)(=O)C>[S:1]([N:11]=[S:12]1(=[O:21])[CH2:17][CH2:16][CH2:15][S:14](=[O:18])(=[O:19])[CH2:13]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N=S2CCCS(=O)(=O)C2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)N=S2(=O)CCCS(=O)(=O)C2)cc1

Procedure:
A method as defined in claim 59 which includes the additional step of reacting said 1-tosylimino-1,3-dithiane-3,3-dioxide with potassium permanganate in acetic acid-acetic anhydride solution at about 20° to 30° C to yield the corresponding 1-tosylimino-1,3-dithiane-1,3,3-trioxide.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[N+](C1C=CC([O:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:34]1[CH:33]=[CH:32][C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:22])[CH2:30][CH2:29]2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C)[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Yield: 34.5 %

Procedure:
NaH (60% dispersion in mineral oil; 0.45 g, 11.3 mmol) was suspended in anhydrous THF (20 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 0.50 g, 3.47 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 10 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 1.50 g, 4.34 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 (40 mL) and the THF was removed in vacuo. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (5×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.42 g, 35%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH2:10])=[N:7][CH:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][CH:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ncc(Cc2ccccc2Cl)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccccc2Cl)o1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 37 %

Procedure:
5-(2-Chloro-benzyl)-oxazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (22 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (15 mg, 0.037 mmol, 37%). ESI-MS m/z calc. 396.1. found; 396.6 (M+1)+ Retention time 3.17 minutes.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].[BH4-].[Na+].Cl.N>C(O)C.CC(C)=O.C(OCC)(=O)C.O>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]2[CH:32]=[CH:31][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:35][CH:34]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(CC(C)(C)N)cc1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.18 g (6.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1.1 g (5.8 mmol) of 2-(4-isopropylphenyl)-1,1-dimethylethylamine are stirred in 40 mL ethanol at 50° C.-80° C. for one hour. After cooling to ambient temperature, 0.24 g (6.3 mmol) sodium borohydride is added. The mixture is stirred for one hour, diluted with 5 mL acetone, and stirred for a further 30 minutes. The reaction mixture is acidified with hydrochloric acid, combined with 100 mL water and 80 mL ethyl acetate, and made alkaline with ammonia. The organic phase is separated off, dried with sodium sulfate, and freed from solvent. The residue is dissolved in 20 mL ethyl acetate and 10 mL water, acidified with concentrated hydrochloric acid and diluted with diethyl ether. After the addition of a crystallization aid, the solid precipitate is suction filtered and washed. White solid. Yield: 1.7 g (52%, hydrochloride); melting point: 220° C.-222° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][N:27]=4)O)=[C:16]([CH3:36])[CH:15]=2)=[N:10]1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:16]([CH3:36])[CH:15]=2)=[N:10]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCc1cc2cccnc2[nH]1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
Triethylsilane (5 ml) was added to a stirred solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-7-azaindole (520 mg, 1.33 mmol) in 20 ml of trifluoroacetic acid at 20° C. under nitrogen. The mixture was stirred at 20° C. for 10 min and then stirred at 70°-75° C. for 16 h. To the mixture was added water, and basified with an aqueous sodium bicarbonate solution (to pH=8) followed by extraction with methylene chloride (3×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (7.5 cm column, ethyl acetate/hexane, 1/5-8/1). The mixture was recrystallized to afford 349 mg (74%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-7-azaindole, as a white solid, m.p.147°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([OH:16])=O)=[CH:7][CH:6]=2.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:16])=[CH:7][CH:6]=2
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)O
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)CO

Procedure:
(3-Bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid (23 g) from Example 1, Stage 1 above, 2-amino-2-methyl-1-propanol (8.06 ml), 1-hydroxy-7-azabenzotriazole (HOAT) (11.44 g), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (16.12 g) and triethylamine (14.63 ml) in dry DMF (175 ml) were stirred at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and poured into 200 ml sat. NaHCO3. The two phases were separated and the aqueous layer was extracted three times with ethyl acetate (3×200 ml). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 7:13) to give 2-(3-bromo-quinolin-6-yloxy)-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methylsulfanyl-acetamide as a white solid (16.94 g). 1H NMR (DMSO) δ ppm: 8.82 (1H, d); 8.57 (1H, d); 7.99 (1H, d); 7.58 (1H, dd); 7.52 (1H, s); 7.44 (1H, d); 5.94 (1H, s); 4.99 (1H, t); 3.48-3.37 (2H, m); 2.15 (3H, s); 1.28 (3H, s); 1.26 (3H, s).
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].CS(O)(=O)=O.N(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cccnc1Cl
Agent: CC(C)(C)ON=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Product: FC(F)(F)COc1cccnc1Cl
Yield: 67.3 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (5.4 g, 42 mmol), 2,2,2-trifluoroethanol (50 g, 500 mmol), and methanesulfonic acid (4.1 g, 43 mmol). The solution is heated to the range 55° C. to 60° C. and then t-butyl nitrite (5.3 g of a 90% solution,46 mmol) is added drop-wise to the vessel while maintaining the temperature at 60° C. to 65° C. After nitrogen evolution ceases, the solution is cooled, neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (11.1 g) with an actual yield of 67.3%.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C@H:3]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][CH2:24][CH2:25][OH:26])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:42]>ClCCl>[ClH:42].[ClH:42].[NH2:32][C@H:29]1[CH2:30][CH2:31][N:27]([C@H:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[C:16]([O:23][CH2:24][CH2:25][OH:26])[CH:17]=[CH:18][CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:40])([F:41])[F:1])[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cccc(OCCO)c5n4)n3c2)C(F)(F)F)C1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cccc(OCCO)c5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 228.4 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(8-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.40 g, 0.70 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 7.0 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The resulting solid was collected by vacuum filtration to give the title compound (0.38 g, 99%). LCMS APCI (+) m/z 473 (M+H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH:11]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:30][S:27]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][NH:7][CH3:6])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)(=[O:29])=[O:28]
Reactant: CN(CCC(c1ccccc1)c1ccc2c(ccn2S(C)(=O)=O)c1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(c1ccccc1)c1ccc2c(ccn2S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
To a 0° C. solution of [3-(1-Methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-carbamic acid tert-butyl ester LXXVI (56 mg, 0.127 mmol) in DCM (3 ml) was added triethylsilane (300 μl) and TFA (1.5 ml). The resulting mixture was stirred at 0° C. for 5 minutes and at room temperature for 40 minutes. The mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording [3-(1-Methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine LXXVIII as a white solid (31 mg, 71% yield). The amine LXXVIII (31 mg, 71% yield) was dissolved in Et2O (3 ml) and HCl (1M in Et2O, 95 μl) was added. The precipitate was filtered, washed with Et2O and dried in vacuo to afford the hydrochloride as a white powder (33 mg, 96% yield). MS (M+H)=343
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C(OCI)OC1CCCC1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 80.5 %

Procedure:
In the same manner as in Example 81, 167 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 128 mg of cyclopentyloxycarbonyloxymethyl iodide.
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.FC(F)(F)C(O)=O.ICI.[OH:22][C:23]1([CH2:36][C:37]([CH3:39])=[CH2:38])[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[OH:22][C:23]1([CH2:36][C:37]2([CH3:1])[CH2:39][CH2:38]2)[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:27][CH2:28]1
Reactant: CC[Zn]CC
Reactant: C=C(C)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCCCCC
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 0.25 h

Procedure:
To CH2Cl2 (20 mL) at 0° C. was added 1M solution of diethylzinc in hexane (11.75 mL, 11.75 mmol), followed by dropwise addition of a solution of trifluoroacetic acid (0.6 mL, 7.83 mmol) in CH2Cl2 (8 mL). After stirring for 15 min, a solution of diiodomethane (0.65 mL, 7.83 mmol) in CH2Cl2 (8 mL) was added. The mixture was stirred for 15 min and a clear solution resulted. tert-Butyl 4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate (12B) (1 g, 3.92 mmol) was added and the mixture was stirred at room temperature overnight. After quenching with 0.1 M aqueous HCl (50 mL), the CH2Cl2 layer was separated, washed with brine, dried (Na2SO4) and concentrated to give the crude product, which was used directly for the next step without purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:46])[C@H:43]([CH3:45])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])[CH3:45])[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](C)C(=O)OC(C)(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-alanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.19 (3H, m), 2.95 (2H, t, J=12.0 Hz), 2.60 (2H, m), 1.78 (4H, m), 1.50 (9H, m), 1.27 (3H, d, J=6.9 Hz), 1.23 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity 98%, m/z 435 [M+H]+
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25].C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:7]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C#N)cc2)CCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2.5 g, supplier Atlantic Scitech) and DIPEA (5.45 ml, 31.2 mmol) in dry dichloromethane (DCM) (60 ml) at 0° C. under argon was added 4-cyanobenzenesulfonyl chloride (2.64 g, 13.11 mmol) and the resulting clear solution stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (100 mL) was added, the layers separated, then the organic layers washed with 2M aqueous HCl (100 mL) and passed through a hydrophobic frit. The solution in DCM was cooled to 0° C., then TFA (8.87 ml, 115 mmol) was added. The resulting very pale yellow solution was allowed to warm to room temperature over 1 h, then stirred for 18 h. Aqueous 2M NaOH (100 mL) was added cautiously with cooling (0° C.) and layers were separated. The organic layer was extracted with 1M aqueous HCl (3×30 mL). With cooling (0° C.), the combined acidic aqueous layers were adjusted to pH 7 by addition of solid NaOH, and then extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a white solid (2.35 g).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[I:12]Cl.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:8]([I:12])=[C:6]([CH:5]=1)[NH2:7]
Reactant: ClI
Reactant: Nc1cccc(OC(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(OC(F)F)ccc1I
Yield: 51.2 %

Procedure:
A solution of 3-[(difluoromethyl)oxy]aniline (3.16 g), iodine monochloride (3.9 g) and sodium acetate (6.5 g) in acetic acid (30 ml) was stirred for 1 hour, then partitioned between saturated sodium bicarbonate solution and ether. The ether layer was separated, washed consecutively with sodium thiosulphate solution and brine. The solvent was removed and the residue was loaded onto a silica gel and chromatographed on silica gel eluted with hexane/ethyl acetate 0-20% to give the title compound as a red oil (2.9 g). Mass Spectrum 286 M+H+
Reaction SMILES: [N:1]1([C:6]2[CH:17]=[CH:16][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>ClCCl>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A solution of 2.3 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine (Example 2) in 50 ml of dichloromethane containing 2 ml of pyridine is treated with 2.0 g of 4-methoxybenzoyl chloride. The reaction mixture is allowed to stand at room temperature for 18 hours, and is then heated at reflux for one hour. The volatiles are removed in vacuo. The residue is partitioned between 100 ml of dichloromethane and 100 ml of water. The dichloromethane layer is dried over Na2SO4, and then heated to gentle boiling. Hexane is then added to turbidity and the mixture cooled at -10° C. A tacky precipitate results and crystals develop in the supernatant solvent. These are collected, washed with hexane, and dried in vacuo at room temperature; m.p. 125°-126° C.; yield, 0.4 g.