Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.[Li]CCCC.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:38][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.300 g, 0.624 mmol; Example 15, Step B) was placed in THF (10 mL) and cooled to −78° C. MeLi (1.17 mL, 1.87 mmol) was then added, and the reaction was stirred for 10 minutes. Excess THF (10 mL) was added to aid solubility. n-BuLi (0.525 mL, 1.31 mmol) was then added and stirred for an additional 10 minutes, followed by the addition of a hexachloroethane (0.296 g, 1.25 mmol) solution in THF (3 mL). The reaction was then stirred for an additional 10 minutes at 0° C., poured into water, and extracted into DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by reverse phase HPLC (50-75% ACN in water) to give the product (R)-tert-butyl 1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.100 g, 36.7% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:27]([CH2:30][CH3:31])[C:28]#[N:29]>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:31][CH2:30][CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(Br)C#N
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCC#N)c(=O)n2CCCC
Temperature: 80 °C
Yield: 83.4 %

Procedure:
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 0.0072 mol) in dry MeCN (20 ml) was added Cs2CO3 (4.68 g, 0.0144 mol) followed by bromobutyronitrile (1.38 g, 0.0094 mol). The mixture was heated at 80° C. for 18 h and then allowed to cool. The reaction mixture was evaporated and the crude product partitioned between EtOAc and HCl (2N). The organic phase was separated and washed with brine, dried (MgSO4) and evaporated to give the crude product. This was purified by silica SPE (50 g), eluting with cyclohexane:ethylacetate (2:1 to 1:1) to afford the title compound as a clear oil (2.1 g, 85%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[NH:35](C(OC(C)(C)C)=O)[C@H:36]([C:42]([O:44]C(C)(C)C)=[O:43])[CH2:37][CH2:38][C:39](=O)[OH:40].Cl.C(N(CC)CC)C.[Cl:64][C:65]1[CH:66]=[C:67]([NH2:75])[CH:68]=[C:69]([CH:74]=1)[C:70]([O:72]C)=[O:71]>ClCCl>[Cl:64][C:65]1[CH:66]=[C:67]([NH:75][C:39](=[O:40])[CH2:38][CH2:37][C@@H:36]([C:42]([OH:44])=[O:43])[NH2:35])[CH:68]=[C:69]([CH:74]=1)[C:70]([OH:72])=[O:71]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(N)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(C(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU, 38 mg (0.1 mmol), 14 mg (0.1 mmol) of HOAt, 30 mg (0.1 mmol) of Boc-Glu-OtBu hydrochloride, 0.014 ml (0.1 mmol) of triethylamine and 1 ml of dichloromethane were added to 30 mg (0.1 mmol) of methyl 5-chloro-3-aminobenzoate. The mixture was stirred at room temperature overnight.
Reaction SMILES: CN(C)C=O.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:12][C:10]1[N:11]=[C:7]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1csc(Oc2ccccc2)n1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
To 75 ml of N,N-dimethylformamide were added 3.00 g of 2,4-dibromothiazole, 1.74 g of phenol, and 3.44 g of potassium carbonate, and the mixture was stirred at 140° C. for 6 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture and two extractions were conducted with 100 ml of ethyl acetate. After being washed twice with 100 ml of water and once with 50 ml of saturated brine, the organic layer was dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=9:1) to give 2.86 g of an ether compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:24][C@H:25]1[O:27][CH2:26]1)(=O)=O>>[CH2:24]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:25]1[O:27][CH2:26]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1cccc2oc(-c3nnc(C(F)(F)F)o3)cc12
Product: FC(F)(F)c1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 27.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole (3.3 g) and (S)-glycidyl nosylate (3.7 g), the title compound (1.1 g) was obtained as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Br[CH2:34][C:35]#[N:36]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][C:35]#[N:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: N#CCBr
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13]([NH:34][C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@@H]2CCC(=O)C2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([C@@H](C[C@@H]2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3-oxo-cyclopentyl)-propionic acid (544 mg, 1.58 mmol), methylene chloride (7 mL), toluene (5 mL), and a catalytic amount of N,N-dimethylformamide (10 μL, 0.13 mmol) under nitrogen was treated with oxalyl chloride (1.4 mL, 16.3 mmol). The reaction was stirred for 1 h (gas evolution). At this time, the reaction was then partially evaporated in vacuo at 25° C. to remove excess oxalyl chloride. The residue was co-evaporated with toluene (2×4 mL) and concentrated in vacuo to about 4 mL. The resulting brown slurry was added via a cannula over 15 min to a mixture of 2-aminopyrazine (189 mg, 1.99 mmol), methylene chloride (4 mL), and pyridine (170 μL, 2.1 mmol) cooled to −10° C. The reaction was allowed to warm to 25° C., where it was stirred for 18 h. At this time, the reaction was quenched with water (700 μL) followed by a 1M aqueous citric acid solution (5 ml, 5 mmol). The reaction then was diluted with ethyl acetate (40 ml) and a 1M aqueous citric acid solution (20 mL), mixed well, and the phases were separated. The organic phase was washed with a 1M aqueous citric acid solution 3×5 mL). The combined aqueous phases were back-extracted with ethyl acetate (30 mL). The combined organic phases were washed with a 10% aqueous potassium bicarbonate solution 3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a crude product (506.6 mg, 76%) as a brown foam. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (442 mg, 66%) as a tan foam. HPLC (Zorbax XDB-C8 150×5 mm, 20-100% acetonitrile/water over 20 min, 20 min run, 220 nm, 1 cc/min Rt=7.7 min) indicated 95.3 area % purity, and HPLC (Chiralpak AD-RH, 150×5 mm, 5 ethanol/5 methanol/4 water, 60 min run, 220 nm, 0.5 cc/min, Rt of 2(R), 3(S)=25.2 min; 2(R), 3(R) =39.2 min) showed 90.5% de.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.7 g), the title compound (1.2 g) was obtained, melting point: 242° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8][CH:7]([O:9][S:10]([C:13]([F:39])([F:38])[C:14]([O:17][C:18]([F:37])([F:36])[C:19]([F:35])([F:34])[CH2:20][CH:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])([F:16])[F:15])(=[O:12])=[O:11])[CH2:6]1)=[O:4].C(O)(=O)C>C(OCC)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8][CH:7]([O:9][S:10]([C:13]([F:38])([F:39])[C:14]([O:17][C:18]([F:37])([F:36])[C:19]([F:35])([F:34])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])([F:16])[F:15])(=[O:12])=[O:11])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CC(I)CCCCCCCCC(=O)O)C1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCCCCCCCCCC(=O)O)C1

Procedure:
To the solution of 1-tert-butoxycarbonylamino-3-[2-(12-carboxy-1,1,2,2-tetrafluoro-4-iodododecyloxy)-1,1,2,2-tetrafluoroethanesulfonyloxy]-cyclobutane carboxylic acid methyl ester in diethyl ether was added an excess of zinc metal followed-by acetic acid. The mixture was heated at reflux for 1 hour. The mixture was cooled and the solvent decanted off taking care no zinc metal passed out of the reaction vessel. The solvent was removed at reduced pressure at ambient pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]2[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:7]=2[S:8][C:9]=1[CH3:10].CO.[OH-].[Na+]>O1CCCC1>[C:15]([C:13]1[CH:12]=[CH:11][C:7]2[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])[C:6]=2[CH:14]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo-[b]thiophene (0.52 g, 1.42 mmol), methanol (5 ml), tetrahydrofuran (5 ml) and 2 ml aqueous sodium hydroxide solution (7 ml) was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. Then, the mixture was acidified with 3N hydrochloric acid and the precipitate was extracted from hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was ffitered off, and the filtrate was concentrated under reduced pressure to give the objective compound (0.45 g, 90% by two steps) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:22])([CH3:21])[C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42].C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:22])([CH3:21])[C@H:10]([NH:20][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Yield: 74.1 %

Procedure:
(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropylamine (5.85 g, 16.9 mmol) was dissolved in 200 mL of anhydrous CH2Cl2 and the mixture was stirred under N2. To this solution were added triethylamine (4.70 mL, 33.8 mmol) and 4-chloro-3-nitroquinoline (3.51 g, 16.9 mmol). The reaction mixture soon became bright yellow. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure. The resulting yellow solid was partitioned between 200 mL H2O and 200 mL CH2Cl2. The layers were separated and the organic portion was washed with H2O and then brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting light brown oil was dissolved in about 200 mL of refluxing hexanes. A small amount of brown precipitate formed and was removed by filtration. The hexanes solution was concentrated to give a yellow solid. Chromatography (SiO2, 10% ethyl acetate/CH2Cl2) gave N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (6.51 g) as a yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1)=[O:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(C#N)=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)S1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
1.0 g (4.1 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 11 ml of THF and cooled in an ice bath. After adding 0.83 g (4.5 mmol) of trichloroacetyl chloride to the solution, 0.63 g (6.2 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 20 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-PrOH and stirred at room temperature for 15 min. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of a yellow solid, 165° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.39 (s, 3H), 6.23 (d, 1H), 6.86 (d, 1H), 7.19-7.4 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[C:24]([O:23][C:21]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc(CN(Cc2ccc(Cl)cc2Cl)C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
0.85 g (2.00 mmol) of 3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoic acid methyl ester was dissolved in 20 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was stirred for 5 h then poured into water. The resulting solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 3. The product was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][S:11](N)(=[O:13])=[O:12].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CS(N)(=O)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NS(C)(=O)=O
Yield: 127.4 %

Procedure:
5.1 ml of hexamethyldisilazane (24.5 mmoles) were added to a refluxing mixture of 3.0 g (31.6 mmoles) of methanesulfonamide, 20 mg (0.11 mmole) of saccharin and 15 ml of toluene while a stream of nitrogen passed over the reaction mixture to expel the ammonia evolved, which was absorbed in water and titrated with 1 N H2SO4. It was found that after refluxing for 20 minutes the calculated amount of ammonia was evolved. The solvent and excess hexamethyldisilazane were evaporated in vacuo and the solid residue was vacuum dried to obtain 5.22 g (99.5%) of N-trimethylsilylmethanesulfonamide melting at 69°-74.5° C. The experiment was repeated without the addition of saccharin and the calculated amount of ammonia was evolved in 35 minutes. Workup as described above yielded 5.25 g (100%) of N-trimethylsilylmethansulfonamide melting at 68°-72.5° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 72 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-tert-butylbenzenesulfonyl chloride under the conditions used in example 2 giving 72% of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH:47]1([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:54]2[CH2:55][CH2:56][N:51]([CH:47]3[CH2:50][CH2:49][CH2:48]3)[CH2:52][CH2:53]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1cccc(Br)c1)N1CCN(C2CCC2)CC1
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
In a 500 mL round bottom flask were added trans-3-(3-bromophenyl)acrylic acid (10.0 g, 44.0 mmol), HATU (20.1 g, 52.9 mmol), anhydrous DMF (130 mL) and DIPEA (18.4 mL, 0.11 mol). This mixture was left stirring for 30 min. 1-cyclobutylpiperazine hydrochloride (10.3 g, 48.5 mmol), DMF (20 mL) and DIPEA (20 mL, 0.11 mol) were added to another flask and the resulting mixture stirred until the solution was homogeneous. The solution containing the amine was added to the first solution dropwise and stirred overnight at RT. The DMF was concentrated in vacuo at 60° C. and the resulting semi-solid was dissolved with EtOAc (800 mL) and NaHCO3 sat. (300 mL). The aq. phase was separated and extracted with EtOAc (3×150 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash-chromatography (DCVC) eluting with Hexane/EtOAc/NH4OH 100:0:0 to 0:99:1 to afford 19 g 33A (>100% yield) as a beige solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.62-2.14 (m, 6H) 2.32-2.47 (m, 4H) 2.73-2.86 (m, 1H) 3.58-3.83 (m, 4H) 6.86 (d, J=15.5 Hz, 1H), 7.20-7.28 (m, 1H), 7.44 (dd, J=15.0, 7.9 Hz, 2H), 7.56 (d, J=15.4 Hz, 1H), 7.65 (t, J=1.7 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(=S)=S>[C:5]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
104.5 g (0.76 mol) of anhydrous aluminum chloride and 92.1 g (0.76 mol) of valeroylchloride were added to 350 ml of carbon disulfide chilled at 0° C. To the resulting mixture with chilling and stirring, 100 g (0.64 mol) of bromobenzene was added and the solution was stirred at room temperature for 24 hours. After completion of the reaction, the resulting mixture was added to 400 ml of cold 4N hydrochloric acid and the aluminum chloride complex was decomposed. Then the organic layer was extracted with chloroform and washed with water and the solvent was removed by distillation. The residue was distilled under reduced pressure to yield 95 g of 4-pentanoylbromobenzene having a b.p. 105° to 110° C./2 mmGn.