Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:19][OH:20])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([O:20][CH2:19][C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:32])[CH3:31]
Reactant: C=CCCC(CO)(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCCC(COC(C)=O)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of the ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate (10.0 g, 35 mmol) and dimethylaminopyridine (4.48 g, 35 mmol) in dichloromethane (100 mL) was treated with acetic anhydride and stirred at room temperature overnight. The solution was concentrated and the resulting residue purified using a combiflash system (89 g column, eluting with 20-50% ethyl acetate in heptanes) to give ethyl 2-(acetoxymethyl)-2-(tert-butoxycarbonylamino)hex-5-enoate (10 g, 80%). 1H NMR (CDCl3) δ 5.78-5.68 (m, 1H), 5.55 (bs, 1H), 5.03-4.93 (m, 2H), 4.73 (d, J=11.0 Hz, 1H) 4.32 (d, J=11.0 Hz, 1H,), 4.20 (q, J=7.2 Hz, 2H), 2.36 (m, 1H), 2.07-2.05 (m, 1H), 2.02 (s, 3H), 1.89-1.75 (m, 2H), 1.43 (m, 9H), 1.27 (t, J=7.2 Hz, 3H). MS found for C16H27NO6 m/z[330(M+1)].
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1n[nH]c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 3-bromo-1H-indazole (0.20 g, 1.0 mmol), 4-methoxyphenylboronic acid (0.228 g, 1.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.228 g, 0.1 mmol) in ethylene glycol dimethyl ether (5 mL) and 2.0 M sodium carbonate solution (6 mL) under nitrogen was heated at 100° C. for 18 hours. It was quenched by water and extracted with chloroform. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.012 g, 5% yield): 1H NMR (CDCl3) δ 10.4 (br s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 7.46 (m, 2H), 7.22 (m, 1H), 7.06 (d, 2H), 3.89 (s, 3H); EI-MS (m/z) 224 [M]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[C:24]([F:36])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[C:24]([F:36])=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)ncc1F
Temperature: 125 °C
Yield: 8.4 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 2.5 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 488.2 (M+H)+, Rt 0.99 min.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([C:23]2[CH:24]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4′-phenylbenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.4 g, 17 mmol), aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g, 18 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the product as a white solid: mp 103-104° C.; 1H NMR (CDCl3) δ 7.88-7.84 (m, 2 H), 7.73-7.64 (m, 4 H), 7.52-7.40 (m, 5 H), 6.93-6.90 (m, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ 194.9, 152.9, 148.9, 144.5, 139.8, 136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7, 55.9, 55.9; Anal. Calcd for C21H18O3. Theoretical: C, 79.23; H, 5.70. Found: C, 78.91; H, 5.87.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][N:27]([CH3:29])[C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(4-dimethylaminophenyl)piperazine (2.01 g 6.58 mmol) in dichloromethane (20 ml) and the mixture stirred for 30 min at room temperature. The mixture was concentrated in vacuo and saturated aqueous potassium carbonate (100 ml) was cautiously added to the residue. The mixture was extracted with dichloromethane (3×100 ml), the extracts were washed with brine (50 ml), combined and dried (MgSO4). Concentration of the extracts gave 1-(4-dimethylaminophenyl)piperazine (1.14 g, 84%) as a cream solid; δH (DMSO-d6) 2.77 (6H, s, N(CH3)2), 2.79 (4H, m, 2×piperazinyl CH2), 2.86 (4H, m, 2×piperazinyl CH2), 2.86 (4H, m, 2×piperazinyl CH2), 6.68 (2H, m, ArH), and 6.82 (2H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(-c2ccc(C(C)O)cc2)cc1
Temperature: 100 °C

Procedure:
10 g of 4-hydroxy-4'-(1-hydroxyethyl)biphenyl (4) obtained in Example 3 was dissolved in 20 ml of acetic anhydride. A small amount of concentrated sulfuric acid was added to the solution. The mixture was heated to 100° C. to obtain 4-acetoxy-4'-(1-hydroxyethyl)biphenyl (2) quantitatively: ##STR56## The product was recrystallized from an acetone/hexane solvent mixture.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH2:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[NH:26])[CH2:20][CH3:21].C(N(CC)CC)C>C(#N)C>[C:13]1([C:4]2[N:3]=[C:2]3[N:26]=[C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH2:19][CH2:20][CH3:21])[NH:27][C:8](=[O:10])[C:7]3=[CH:6][N:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: CCCOc1ccccc1C(=N)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1-c1nc2nc(-c3ccccc3)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 3 reaction of ethyl 4-chloro-2-phenyl-5-pyrimidine carboxylate (1.05 g) with 2-propoxybenzamidine (from sodium, 0.10 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.40 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product which was recrystallised from methanol to yield the title compound, 0.52 g, m.p. 203°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[CH3:26])=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+].OO.CC[O:35]C(C)=O>CS(C)=O.CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:27][CH3:28])[CH:12]=[CH:11][C:10]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:19]([CH3:26])[CH:20]=1)(=[O:35])[NH2:25]
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C#N)cc1C
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
To a solution of ethyl 1-(4-chloro-2-methoxyphenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrole-3-carboxylate (5.0 g, 12.7 mmol) in DMSO (10 mL) was added aqueous NaOH solution (2 mol/L, 1.0 mL) and 30% aqueous solution of H2O2 (1.0 mL), the reaction mixture was stirred at room temperature for four hours. TLC (EtOAc: MeOH=10:1) indicated that the starting material was consumed. Saturated aqueous Na2SO3 solution was added to quench the reaction, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatograph to afford the titled compound as a yellow oil (1.2 g, yield: 23.1%). MS (ESI): m/z 413.1 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[S:1]1[C:5]([B:23]([OH:26])[OH:24])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cccs2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
In a flame-dried, 3-neck, 250 mL rbf, 2,2′-bithiophene (5.0 g, 30.1 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −78° C. (dry ice/acetone). A solution of n-BuLi in hexanes (2.5 M, 12.6 mL, 31.6 mmol) was added slowly over a period of ˜5 minutes. The reaction mixture was allowed to stir at −78° C. for 15 minutes, and then trimethyl borate (10.1 mL, 90 mmol) was added dropwise over a period of 5 minutes. The reaction was allowed to stir at −78° C. for 2 hours, then warm to RT and stir for a further 1 hour. The yellow reaction mixture was quenched by pouring it into a 10% HCl solution (250 mL). The mixture was extracted with ether (2×100 mL) and the combined organic portions were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting yellow solid was washed with water, filtered and air dried to afford (109) (6.15 g, 97%). The material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
6-Chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxamide (33 mg, 112 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (50 mg, 233 μmol) were combined in NMP (2 mL) and stirred at 140° C. for 48 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (50 mg, 233 μmol) was added and the reaction was stirred at 140° C. for 96 h, then cooled to room temperature and concentrated in vacuo. The residue obtained was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organics were combined and washed with brine. The solvent was removed in vacuo to give an orange foam. The foam was concentrated onto silica and purified by chromatography (4 g RediSep Gold, 0 to 5% of a mixture of MeOH containing 0.5% NH4OH in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-ethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (32.3 mg, 51.4 μmol, 46%) containing some dichloromethane impurity. This was used directly without further purification. MS (EI/CI) m/z: 372.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(OC2CCNCC2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.55 g, 21.39 mmol) and Et3N (5.92 mL, 42.8 mmol) in DCM (50 mL) was treated with methanesulfonyl chloride (2.48 mL, 32.09 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-70% EtOAc in cyclohexane) gave 2-chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (3.19 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.9 Hz, 1H), 7.28-7.16 (m, 2H), 4.58-4.49 (m, 1H), 3.44-3.28 (m, 4H), 2.83 (s, 3H), 2.13-1.92 (m, 4H). LCMS (m/z, Method A) ES+ 290.9 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(O)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (2.06 g, 15.1 mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 201°-204° C.; 1H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.82 (s, 1H), 6.93 (m, 2H), 7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, 1H).
Reaction SMILES: [C:1]([C@:8]([NH2:17])([CH2:13][CH2:14][CH2:15]O)[C:9]([O:11][CH3:12])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>>[C:1]([C@:8]([NH2:17])([CH2:13][CH2:14][CH2:15][Br:38])[C:9]([O:11][CH3:12])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@@](N)(CCCO)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)[C@@](N)(CCCBr)C(=O)OC(C)(C)C

Procedure:
The crude residue of methyl (S)2-BOC-amino-5-hydroxy-pentanoate is treated with triphenylphosphine and CBr4 to obtain a crude sample of methyl (S)2-BOC-amino-5-bromo-pentanoate.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]1[OH:17])=[N+:2]=[N-:3].[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19].[N:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[OH:17])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC1CCNCC1O

Procedure:
Compound 201B (44 mg, 0.18 mmol) was treated with a mixture of CH2Cl2 and TFA (1:1, 2 mL) for 30 min. The volatiles were removed under reduced pressure and the residue was azeotropically evaporated with heptane-CH2Cl2 three times to give a TFA salt of Compound 201C, which was used immediately in the next reaction without step further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.Cl[C:29]([O:31][CH3:32])=[O:30].CCCC(C)C>C(OCC)C>[CH3:32][O:31][C:29]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1)=[O:30]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCCC(C)C
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the technique of Example 113, starting from 3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one hydrochloride salt (170 mg, 0.43 mmol) and methyl chloroformate gave the desired product (114 mg) after trituration with diethyl ether and isohexane.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20](O)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20]([NH:10][C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:1][C:5]3=[N:6][CH:7]=2)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)Nc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-5-ylamine (example c), 0.5 mmol) and 4-methyl-isophthalic acid 1-tert-butyl ester from example 1-1 (0.5 mmol) in THF (5 ml) were added TBTU (0.5 mmol), HOBT (0.5 mmol) and Hunig's base (0.6 mmol) and stirred at RT for overnight. Solvent was concentrated, residue was diluted with EtOAc ( ), washed with 1(N) NaOH. Organics was concentrated to get 2.8 g of the crude title product. LC-MS: (m/z 352)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Na].[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCn1ccnc1

Procedure:
A 99.0 g amount of 2-(10-bromodecyl)-1H-isoindole-1,3(2H)-dione (prepared as described above) was dissolved in 300 ml of warm N,N-dimethylformamide with stirring. This solution was added to a stirred solution of 1H-imidazole, sodium salt (prepared by stirring a mixture of 20 g of imidazole and 14.0 g 50% sodium hydride in 500 ml of N,N-dimethylformamide at room temperature for 48 hours). The resulting mixture was heated on a steam bath for 14 hours, then taken to dryness in vacuo. The residue was partitioned between 500 ml of dichloromethane and 250 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and filter. The filtrate was evaporated in vacuo and gave 85.4 g of 2[10-(1H-imidazol-1-yl)decyl]-1H-isoindole-1,3(2H)dione as an oil which solidified on standing at room temperature.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.OC(C(F)(F)F)=O.[NH2:20][C@H:21]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:26][CH2:25]1)=[O:23].CCN(C(C)C)C(C)C.C([O:62][C:63](=O)[NH:64][CH2:65][CH2:66][CH2:67][NH2:68])(C)(C)C>>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@@H:21]([NH:20][C:63]([NH:64][CH2:65][CH2:66][CH2:67][NH2:68])=[O:62])[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH2:28][CH2:29]2)=[O:23])=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)NCCCN)CC1

Procedure:
Following the procedure of Example 51, N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl][(3-aminopropyl)amino]carboxamide, TFA salt was prepared from triphosgene (Avocado Chemical Company) (45 mg, 0.152 mmol), (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one TFA salt (200 mg, 0.36 mmol), DIEA (0.32 mL, 0.916 mmol), and tert-butyl-N-(3-aminopropyl)carbamate (Aldrich Chemical Company) (96 mg, 0.55 mmol). The Boc protecting group was removed by treating the compound with a soln of 50% TFA and CH2Cl2 (2 mL) for 2 h. The organic solvent was removed in vacuo to give the desired product. Preparative TLC purification with 60% Hexane, 35% CH2Cl2 and 5% 2N NH3 in MeOH afforded 90% pure compound. This was further purified by preparative HPLC (TFA buffer) to afford the title compound (TFA salt) as a white solid (10 mg). MS (ESI, pos. ion) m/z: 537 (M+H); MS (ESI, neg. ion) m/z: 535 (M−H). Calc'd for C24H33ClN6O4S: 536.20.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>ClCCl>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Aluminium chloride (2,49 g, 18,7 mmol) was added in 2 portions to a solution of 2-methoxynaphthalene (1,97 g, 12,5 mmol) in dichloromethane (15 mL) at 5° C. The red solution was cooled to -20° C. and the reaction vessel was evacuated to a pressure of 160 mbar. Ethyl pyruvate (2,17 g, 18,7 mmol) in dichloromethane (pre-cooled, 5 mL) was added over 5 minutes and the temperature was further reduced to -40° C. The reaction was allowed to proceed for 2 hours, at which time the system was opened to the atmosphere and poured on to ice. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed with a selectivity of 35% at 62% conversion of the starting material.