Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[Na].Cl.[Cl:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:16]([SH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[ClH:7].[CH2:16]([S:23][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: ClCCN1CCCCC1
Reactant: CCCCCCCS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCSCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Generate sodium ethoxide by carefully adding sodium metal (1.4 g, 60 mmol) to absolute ethanol (50 mL). Add 1/2 of the sodium ethoxide (30 mL) to a solution of N-(2-chloroethyl)-piperidine hydrochloride (5.0 g, 27.2 mmol) in absolute ethanol. Add the other 1/2 of the sodium ethoxide (30 mL) to a solution of heptyl mercaptan (4.6 mL, 30 mmol) in absolute ethanol. Mix the two and stir at room temperature overnight. Concentrate in vacuo, partition between water and ethyl acetate and separate the organic phase. Extract the aqueous phase with ethyl acetate (2×50 mL), combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 6.34 g yellow oil. Dissolve the oil in ethyl ether, filter and treat with anhydrous hydrochloric acid. Collect the resulting white solid by vacuum filtration (5.6 g) and recrystallize (ethyl acetate/isopropanol) to yield 3.12 g of the title compound as white crystals; mp 169°-70° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 143 g 4-(2-aminoethyl)morpholine were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The mixture was extracted several times with methyl tert-butyl ether, and the combined organic phases were reduced to dryness in a rotary evaporator, yielding a dark liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:9]1[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccc(F)c(Br)c1
Product: N#Cc1ccc(F)c(-c2cc([N+](=O)[O-])ccc2F)c1
Yield: 99.9 %

Procedure:
3-Bromo-4-fluorobenzonitrile (2.00 g, 10 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.01 g, 15 mmol) following the procedure described in Example 14 part a), affording 6,2′-difluoro-5′-nitrobiphenyl-3-carbonitrile as a brown solid (2.60 g, 100%). δH (360 MHz, CDCl3) 7.38 (2H, q, J 8.8), 7.77-7.82 (2H, m), 8.33-8.38 (2H, m).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([S:47][CH2:48][C:49]3[N:50]=[C:51]([C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=4)[S:52][CH:53]=3)[N:42]=[C:41]([N:61]3[CH2:64][CH2:63][CH2:62]3)[C:40]=2[C:65]#[N:66])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70]>ClCCl>[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[F:67][C:68]([F:73])([F:72])[C:69]([OH:71])=[O:70].[NH2:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([S:47][CH2:48][C:49]3[N:50]=[C:51]([C:54]4[CH:55]=[CH:56][C:57]([Cl:60])=[CH:58][CH:59]=4)[S:52][CH:53]=3)[N:42]=[C:41]([N:61]3[CH2:62][CH2:63][CH2:64]3)[C:40]=2[C:65]#[N:66])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
180 mg (0.188 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate (Example 3A) were initially charged in 5 ml dichloromethane. 1.0 ml (12.98 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT for 30 min. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 153 mg (83% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([NH:28][C:29](=[O:31])[CH3:30])[CH2:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([NH:28][C:29](=[O:31])[CH3:30])[CH2:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCNC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cooled solution of N-[(R)-1-(t-butoxycarbonyl)-3-piperidylcarbonyl]-2 (S)-acetylamino-β-alanine benzyl ester (2.7 g) was added 4N HCl in ethyl acetate (25.5 ml). The mixture was stirred for 2.5 hours at an ambient temperature, then the solvent was decanted. The residue was washed with diethyl ether several times, and dried in vacuo to give N-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester hydrochloride (2.29 g) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[N:16]=[C:15]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCNCC1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Yield: 41.9 %

Procedure:
A mixture containing 6 g (0.025 mole) of 2-phenyl-4-chloroquinazoline, 3,53 g (0.035 mole) of 4-hydroxypiperidine and 100 ml of 95% ethyl alcohol was refluxed for 3 hrs. One gram of sodium hydroxide (in one ml of water) was added and the mixture was refluxed for an additional 2 hr period. The mixture was filtered and the filtrate was added to 300 ml of water. The white crystalline precipitate was separated and recrystallized with methanol and water to give 3.2 g of the title compound, m.p. 165°-167° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([N:26]=[N+:27]=[N-:28])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(N=[N+]=[N-])cc(-n2cnc3ccccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a solution of of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (EXAMPLE 306 Step B) (55.8 mg, 0.16 mmol) in DMF (1 mL) was added sodium azide (16 mg, 0.24 mmol) and the mixture was heated at 80° C. for 7 h. It was cooled and diluted with EtOAc, then the organic layer was washed with H2O followed by brine. The organic extract was dried over Na2SO4, and the crude material was purified by flash chromatography using 1:3 EtOAc:hexane to yield 48.8 mg of the title compound. Mass spectrum 357.1 (CI, M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Br)cc1
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (2.4 ml, 0.031 M) was added to a solution of 4-bromo-aniline (5.28 g, 0.031 M) and pyridine (2.5 ml, 0.031 M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a white solid (6.37 g).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:6]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:28])[F:29])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (27 mg, 0.054 mmol), acetone (4.4 μL, 0.060 mmol), and triethylamine (23.5 μL, 0.169 mmol) in methylene chloride (0.4 mL) was added sodium triacetoxyborohydride resin (47 mg, 0.11 mmol). The resulting mixture was stirred for 2 h at room temperature. The mixture was filtered and concentrated and dried in vacuo to give 22 mg of the crude the product which will be used without purification. LCMS calculated for C22H28ClF2N6O (M+H)+: m/z=465.2; Found: 465.1.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:36][C:33]2[S:34][CH:35]=[C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[N:32]=2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid (6) (100 mg, 0.28 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (41 mg, 0.23 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 42 mg (35%). 1H-NMR: 8.60 (d, J=4.0 Hz, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=7.5 Hz, 1H), 7.89 (dt, J=7.5, 7.5, 1.5 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.33 (dd, J=7.0, 5.0 Hz, 1H), 3.25 (s, 1H).
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>O.CO.[Zn]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([CH:5]=1)[NH2:12]
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of ammonium chloride (12.5 g, 0.2 mol) in water (30 ml) is added to a mixture of zinc dust (35.7 g, 0.5 mol) and 4-bromo-1-ethyl-2-nitrobenzene (18 g, 0.07 mol) in methanol (720 ml) and water (180 ml). The reaction mixture is refluxed for one hour, then cooled to room temperature and filtered through a plug of diatomaceous earth. The filtrate is concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo to yield 5-bromo-2-ethylaniline (14 g), used without further purification in the next step.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O-:19])=[O:18])[CH2:11][CH2:10]2.Cl[CH2:22]Cl>>[OH:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([CH2:16][C:17]([O:19][CH3:22])=[O:18])[CH2:11][CH2:10]2
Reactant: ClCCl
Reactant: COc1ccc2c(c1C)CCC2CC(=O)[O-]
Agent: BrB(Br)Br
Product: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (16.2 mL, 16.2 mmol) was added to an ice-cold solution methyl (R or S)-(5-methoxy-4-methyl-indan-1-yl)acetate (1.52 g, 6.49 mmol, from Step F) in dichloromethane (5 mL). The cooling bath was removed and the reaction mixture stirred at ambient temperature. After 1 hr, the reaction mixture was slowly transferred to an ice-cold solution of methanol (50 mL). Methanol was removed in vacuo, and the residue was partitioned between EtOAc and sat. NaH2PO4. The organic layer was washed with H2O, brine, and dried over MgSO4. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (5, 10% EtOAc/hexanes) on SiO2 to afford 1.22 g of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.78 (m, 1H), 2.16 (s, 3H), 2.35-2.44 (m, 2H), 2.71-2.79 (m, 2H), 2.86-2.90 (m, 1H), 3.54 (p, 1H, J=7.3 Hz), 3.72 (s, 3H), 4.83 (s, 1H), 6.61 (d, 1H, J=8.0 Hz), 6.85 (d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=O>>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][N:11]1[CH2:12][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=Cc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccccc3c2)C1

Procedure:
This compound was obtained via the reductive amination method described in 49.2, by reaction of (S)-3-tert-butyloxycarbonylaminopyrrolidine with 2-naphthaldehyde. The residue is purified on a column of silica (eluent: from 100/0 to 90/10 (v/v) dichloromethane/methanol).
Reaction SMILES: C([O:5][C:6](=[O:37])[C@H:7]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[NH:8][C:9]1[C:13]([N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:12][S:11](=[O:28])(=[O:27])[N:10]=1)(C)(C)C>C(O)=O>[CH2:15]([N:14]([C:13]1[C:9]([NH:8][C@H:7]([C:6]([OH:37])=[O:5])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[N:10][S:11](=[O:27])(=[O:28])[N:12]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 98.6 %

Procedure:
N-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester (100 mg, 0.19 mmol) was dissolved in formic acid and the mixture stirred at room temperature for 36 hrs. Excess formic acid was removed under reduced pressure to yield N-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine as a white solid (90 mg, 98%). Anal. Calc'd for C23H36N4O5S: C, 57.48; H, 7.55; N, 11.66. Found: C, 57.04; H, 7.23; N, 11.38.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 108 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (70) (1.84 g; 3.12 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. ESMS: MH+ 490.4
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH3:41])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCOC
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: COCCN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (367 mg, 0.72 mmol) and 2-methoxyethylmethyl amine (130 mg, 1.45 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[C:30](Cl)(=[O:32])[CH3:31].Cl>N1C=CC=CC=1>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[O:7]1
Reactant: CC(=O)Cl
Reactant: NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg, 0.038 mmol) obtained in Example 1-31 was dissolved in pyridine (380 μl). Thereafter, acetyl chloride (3.2 μl) was added to the obtained solution, and the obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 1 N hydrochloric acid was added to the reaction solution under cooling on ice, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain N-{2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl}acetamide (12.1 mg; yield: 71%) in the form of a colorless amorphous substance.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[CH2:7]1[O:10][CH:8]1[CH3:9]>C(O)(C)(C)C>[CH3:1][N:2]([CH2:7][CH:8]([OH:10])[CH3:9])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CC1CO1
Reactant: CNS(C)(=O)=O
Solvent: CC(C)(C)O
Product: CC(O)CN(C)S(C)(=O)=O

Procedure:
N-Methylmethanesulfonamide (21.8 grams; 0.2 mol), t-butylalcohol (50 ml) sodium hydride (0.5 grams; 50% in mineral oil), and propylene oxide (11.6 grams; 0.2 mol) were placed into a 3-necked glass reaction flask equipped with stopper, stirrer, thermometer, and reflux condenser. The mixture was heated at 50°-60° C. for three hours, cooled, and concentrated on a rotoevaporator. The concentrate was neutralized with concentrated hydrochloric acid (1 ml) and distilled under reduced pressure. Fractions 4 and 5 (13.2 grams; boiling point (140°-142° C./1.5 mm Hg) analyzed for the described product as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and DMF (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloroethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 hs. The reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound as a solid (7.84 g).