Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=O>C1(C)C=CC=CC=1>[CH3:19][C:12]1([CH3:18])[NH:10][CH2:7][CH2:8][NH:9][C:13]1=[O:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)NCCNC1=O

Procedure:
Potassium carbonate (390 grams) and ethylene diamine (1001 grams) are stirred with toluene (1.50 l). A solution of ethyl 2-bromoisobutyrate (500 grams) in toluene (750 ml) is added. The suspension is heated to reflux over night, and filtered. The filter cake is washed with toluene (500 ml). The combined filtrates (volume 4.0 l) are heated on a water bath and distilled at 0.3 atm. using a Claisen apparatus; first 1200 ml distillate is collected at 35° C. (the temperature in the mixture is 75° C.). More toluene is added (600 ml), and another 1200 ml distillate is collected at 76° C. (the temperature in the mixture is 80° C.). Toluene (750 ml) is added again, and 1100 ml of distillate is collected at 66° C. (temperature in the mixture 71° C.). The mixture is stirred on an ice bath and seeded, whereby the product precipitates. The product is isolated by filtration, washed with toluene, and dried over night in a vacuum oven at 50° C. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. NMR consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1C(F)(F)F
Yield: 54.9 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (116 mg, 55%). MS (ISP) 423.3 [(M+H)+]; mp 177° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[CH3:4])[CH3:2].[F:7][C:8]([F:14])([F:13])[S:9]([OH:12])(=[O:11])=[O:10]>>[F:7][C:8]([F:14])([F:13])[S:9]([O-:12])(=[O:11])=[O:10].[CH2:1]([NH+:3]([CH2:5][CH3:6])[CH3:4])[CH3:2]
Reactant: CCN(C)CC
Reactant: O=S(=O)(O)C(F)(F)F
Product: CC[NH+](C)CC
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Equimolar amounts of diethylmethylamine and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed diethylmethylamine and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][CH:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15]
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Solvent: CC#N
Product: CCCOC1CCN(CC(C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A 4 mL vial was charged with crude (S)-1-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g), 4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH3CN (2.5 mL). The mixture was shaken at 50° C. for 24 h and then purified by cation-exchange CC followed by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.051 g, 17%). 1H NMR (CD3OD) δ 7.85 (d, J=9.6 Hz), 7.70-7.63 (m, 2H), 7.60 (brt, J=7.8 Hz, 1H), 7.26 (brt, 7.6 Hz), 6.63 (d, J=9.6 Hz, 1H), 4.39-4.23 (m, 2H), 3.37 (t, J=6.6 Hz), 3.28-3.18 (m, 1H), 2.77-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.35 (dd, J=8.4, 12.0 Hz), 2.51-2.21 (m, 1H), 2.18 (dd, J=4.8, 12.0 Hz), 2.13-2.04 (m, 1H), 2.00-1.92 (m, 1H), 1.84-1.75 (m, 2H), 1.58-1.32 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CD3OD) δ 163.7, 140.2, 139.5, 130.8, 129.2, 12.5, 121.4, 120.4, 115.2, 75.3, 69.5, 63.6, 52.3, 51.5, 46.8, 31.4, 31.3, 30.0, 23.1, 16.1, 9.8.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH3:14])[C:11]=1[Cl:12].[CH3:15][C:16]1([CH3:32])[C:25]2[C:20](=[C:21]([CH3:29])[C:22]([C:26](Cl)=O)=[CH:23][CH:24]=2)[S:19](=[O:31])(=[O:30])[CH2:18][CH2:17]1.[OH-:33].[Na+]>CCCCCC.C(OCC)C.CO>[Cl:12][C:11]1[N:10]([CH2:13][CH3:14])[NH:9][C:8](=[C:7]=[O:33])[C:26]=1[C:22]1[C:21]([CH3:29])=[C:20]2[C:25]([C:16]([CH3:32])([CH3:15])[CH2:17][CH2:18][S:19]2(=[O:31])=[O:30])=[CH:24][CH:23]=1
Reactant: CCn1ncc(Br)c1Cl
Reactant: [OH-]
Reactant: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCC2(C)C
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: CCN1NC(=C=O)C(c2ccc3c(c2C)S(=O)(=O)CCC3(C)C)=C1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of protective gas and at 20 to 25° C., 2.6 ml (4.11 mmol) of n-butyllithium in hexane (1.6 molar) were rapidly added dropwise to 0.86 g (4.11 mmol) of 4-bromo-5-chloro-1-ethylpyrazole in 30 ml of diethyl ether. The mixture was stirred at room temperature for 15 minutes and the resulting suspension was then, at −70° C., added dropwise to a solution of 2.2 g (8.21 mmol) of 4,4,8-trimethyl-1,1-dioxothiochroman-7-carbonyl chloride in 30 ml of diethyl ether. The reaction mixture was subsequently warmed to room temperature and mixed with 11 ml of methanol and 26 ml of 2N aqueous sodium hydroxide solution. The organic phase was then separated off, dried and concentrated and the residue was chromatographed over silica gel (mobile phase: ethyl acetate/cyclohexane=3/2).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32](CC1C=CC=CC=1F)[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[F:50][C:51]1[CH:58]=[CH:57][CH:56]=[CH:55][C:52]=1[CH:53]=O.[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[NH:32][CH:33]1[CH:38]=[CH:37][C:36]([C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)=[O:40])=[CH:35][N:34]1[CH2:53][C:52]1[CH:55]=[CH:56][CH:57]=[CH:58][C:51]=1[F:50])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CC(C(=O)c2c[nH]c3ncccc23)=CN1Cc1ccccc1F
Temperature: 5 °C
Yield: 26 %

Procedure:
To 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.550 g, 1.37 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.65 mL) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −40° C., followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (579, prepared according to the protocol of Example 17, Scheme 19, Steps 1-3, replacing 4-chlorobenzaldehyde 40 with 2-fluoro-benzaldehyde in Step 1) in tetrahydrofuran (4.0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (580, 0.14 g, 26%). MS (ESI) [M+H+]+=447.0.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].O>C(#N)C>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[N:3]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17].[C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:6]2[CH:5]=[C:4]([F:9])[N:3]=[C:2]([F:1])[N:7]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: Fc1cc(F)nc(F)n1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2cc(F)nc(F)n2)CC1
Product: CC(=O)N1CCN(c2nc(F)cc(F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4,6-trifluoropyrimidine (2.0 g) and potassium carbonate (3.1 g) in acetonitrile (15 ml) was added a solution of 1-acetylpiperazine (1.9 g) in acetonitrile (5 ml) over 10 min under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow oil. The obtained pale-yellow oil was purified by silica gel column chromatography to give the title compound (1.8 g) and 1-acetyl-4-(2,6-difluoropyrimidin-4-yl)piperazine (1.7 g) both as a white solid.
Reaction SMILES: [ClH:1].C(NC[C:8]([C:10]1[CH:15]=[CH:14][C:13](O)=C(O)[CH:11]=1)=[O:9])(C)(C)C.[CH3:18][O-].[Na+].C1([O-])C=CC=CC=1.[Na+]>>[CH3:18][C:10]([CH3:11])([CH2:15][CH2:14][CH3:13])[C:8]([Cl:1])=[O:9]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCC(C)(C)C(=O)Cl

Procedure:
Proceeding in a manner similar to that described in Example 2A above, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was interacted with 18 g. of sodium methoxide, and the resulting sodium phenolate salt was interacted with 30 ml. of 2,2-dimethypentanoyl chloride to yield 17 g. of 3,4-bis(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 183°-185° C. (uncorr.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:9]1=[O:23].C(C1C=C(C=CC=1)N)#N.Cl.N[NH:45][C:46]([NH2:48])=[O:47].CN1CCOCC1>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:31])=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:48][C:46](=[O:47])[NH:45][N:19]=3)[CH:16]=2)[C:9]1=[O:23]
Reactant: NNC(N)=O
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3cccc(C#N)c3)C2=O)c(F)c1
Agent: Cl
Agent: N#Cc1cccc(N)c1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CO
Product: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3cccc(-c4n[nH]c(=O)[nH]4)c3)C2=O)c(F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A sample of 3-[1-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-2-oxo-piperidin-3-ylamino]-benzonitrile, prepared from the compound of Ex. 1, part A and 3-cyanoaniline according to the procedure of Ex. 1, Part B, was suspended in a 2:1 mixture of anhydrous MeOH and chloroform and cooled in a 0° C. ice-bath. HCl gas was then bubbled in the mixture for 30 minutes resulting in a clear solution. The reaction vessel was sealed and stored at 0° C. for 18 hours. The mixture was concentrated in vacuo and dried. The resulting residue was suspended in 1,4-dioxane. Semicarbazide hydrochloride (1.7 eq) was then added, followed by N-methylmorpholine (7.2 eq). The mixture was refluxed for 48 hours. The precipitate was filtered and washed with 1,4-dioxane, water, and ether. The solid was pumped dry to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 11.87 (s, 1H), 11.56 (s, 1H), 8.11(d, J=8.1 Hz, 1H), 7.75 (m, 2H), 7.47 (m, 2H), 7.37 (d, J=11.0 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.08 (br m, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.78 (br d, J=9.5 Hz, 1H), 4.28 (m, 1H), 3.73 (t, J=6.2 Hz, 2H), 2.90 (s, 3H), 2.30 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H); MS ESI (M+H) 522.4.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:7][CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].O>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:7])[OH:11])[OH:10])[OH:9]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Frozen flocculated cells are immersed in water or a glucose syrup. The cell mass is allowed to thaw and is gently crushed by mechanical means or stirring to give particles of approximately uniform size. This slurry is then subjected to vacuum conditions for approximately 30 minutes to remove occluded gases from the cell particles. A jacketed column of 1 inch diameter is partially filled with water or glucose syrup and the degassed slurry is then poured into the column. The packed column is heated to 60° C. and a 2 M solution of glucose having a pH of 8.0 and containing 0.004 M MgCl2.6H2O is passed through the column at flow rates which are regulated to give the degree of glucose conversion desired. Conversions ranging up to 50 percent are attainable by this process.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].I[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(N(CC)CC)C.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.[Cu]I>[C:19]([C:18]1[CH:22]=[CH:23][C:15]([C:2]#[C:1][C:3]2[C:4]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=3[S:6][CH:7]=2)=[CH:16][CH:17]=1)([OH:21])=[O:20]
Reactant: C#Cc1csc2cccc(OC)c12
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc2scc(C#Cc3ccc(C(=O)O)cc3)c12
Yield: 97.7 %

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.2 g) was dissolved in triethylamine (4mL). To the solution were added 4-iodobenzoic acid (0.29 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g) and copper (I) iodide (41 mg), and the mixture was heated for ref lux under an argon atmosphere overnight. The reaction mixture was poured into ethyl acetate-1 mol/L hydrochloric acid, and the insoluble material was removed by filtration. The organic layer was separated from the filtrate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2) to give 3-[2-(4-carboxyphenyl)ethynyl]-4-methoxybenzo[b]thiophene (0.32 g). This material was dissolved in N,N-dimethylformamide (10 mL). To the solution were added potassium carbonate (0.29 g) and benzyl bromide (0.16 mL), and the mixture was stirred at room temperature for three hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (0.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:62]=[N:61][C:45]2[NH:46][C:47](=[O:60])[CH2:48][N:49]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)[CH2:50][C:44]=2[CH:43]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:59][O:58][C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:49]2[CH2:50][C:44]3[CH:43]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:62]=[N:61][C:45]=3[NH:46][C:47](=[O:60])[CH2:48]2)=[CH:57][CH:56]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)OC(C)(C)C)cc3C2)cc1

Procedure:
tert-Butyl acrylate (972 μL, 6.64 mmol), diisopropylethylamine (612 μL, 3.47 mmol) and P(o-tolyl)3 (100 mg, 0.33 mmol) were successively added to a suspension of 7-bromo-4-(4-methoxybenzyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (600 mg, 1.66 mmol) in propionitrile (10 mL) and dimethylformamide (2 mL). The resulting mixture was then purged with argon prior to the addition of palladium acetate (40 mg, 0.16 mmol). The mixture was purged with argon a second time and refluxed overnight. The reaction mixture was then filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (30 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/ethyl acetate (7:3) as eluent. The title product was obtained as a yellow solid (112 mg, 16%).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:4][F:5].[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>O1CCCC1>[F:5][CH2:4][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[N+:27]([O-:29])=[O:28])[CH2:8][CH2:7]1)[CH2:2][F:1]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCN(C(CF)CF)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol (0.068 g) in tetrahydrofuran (1 mL) was added sodium hydride (0.056 g) and the reaction stirred for 30 minutes at room temperature. 4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was added in one portion and stirring was continued for 1 hour. The reaction was poured into water (20 mL) and extracted with dichloromethane. The pH of the aqueous layer was adjusted to pH˜8 and it was extracted with dichloromethane (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:63]([C:52]1[C:51]([NH:50][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:56][CH:55]=[CH:54][C:53]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:64])[NH2:65]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.4 g, 10 mmol) in DCM (40 mL) was added HATU (5.3 g, 14 mmol) and DIPEA (3.6 mL, 28 mmol) and the reaction mixture was stirred at room temperature for 1 h. 3-Aminobiphenyl-2-carboxamide (from Example 218) (1.5 g, 7.07 mmol) was added and the resulting mixture stirred for an additional 16 h. The reaction mixture was washed with water, the organic portion dried, filtered and concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (50% ethyl acetate in hexanes) to yield tert-butyl 4-(2-carbamoylbiphenyl-3-ylcarbamoyl)piperidine-1-carboxylate (1.0 g, 22% yield) as a white solid. LCMS Method T: retention time 1.71 min; [M+1]=423.0.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][F:37])=[CH:30][N:29]=1)[C:20]([O:22]C(C)(C)C)=[O:21])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][F:37])=[CH:30][N:29]=1)[C:20]([OH:22])=[O:21])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCC(Cc1ccc(OCCF)cn1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
To a solution of 56 mg of di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-{[5-(2-fluoroethoxy)pyridin-2-yl]methyl}hexanedioate (0.1 mmol) in anisol (0.7 mL) was added trifluoroacetic acid (1.5 mL), and the resulting mixture was stirred for 3 h at room temperature. Trifluoroacetic acid was removed under reduced pressure, water (approx. 2 mL) was added and separating anisol (which was expected to encumber preparative HPLC if present in large excess) was removed. The remaining aqueous solution of the crude product was directly loaded onto a preparative HPLC, method B, to give 14 mg of the target compound as white, hygroscopic lyophilisate (approx. 40% yield).
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>>[C:25]([S:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:28])[CH3:26].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: CC([O-])=S
Reactant: BrCCCCCCCCCCCC[c-]1cccc1
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Product: CC(=O)SCCCCCCCCCCCC[c-]1cccc1
Yield: 91.3 %

Procedure:
12-Ferrocenyldodecyl bromide 25 (2.0 g, 4.6 mmol) was treated with potassium thioacetate (0.70 g, 6.0 mmol) for 20 h as described for 27 to form yellow crystals (1.8 g, 93%): mp 45–47° C.; 1H NMR δ 1.27 (s, 18H), 1.55 (m, 2H), 2.32 (m, 2H), 2.33 (s, 3H), 2.87 (m, 2H), 4.05 (s, 2H), 4.07 (s, 2H), 4.11 (s, 5H); 13C NMR δ 29.5, 29.8, 30.2, 30.3, 30.3, 31.3, 31.8, 67.7, 68.8, 69.2, 90.4, 196.8; FAB-MS obsd 428.1851, calcd exact mass 428.1836; Anal. Calcd for C24H36FeOS: C, 67.28; H, 8.47; Found: C, 67.25; H, 8.51.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]=2[N:11]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH:26]2[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:25]2[O:24]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[C:8](=[O:21])[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][CH:26]5[CH2:29][CH2:30][NH:31][CH2:32][CH:25]5[O:24][C:23]4=[O:22])=[N:11][C:10]2=3)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Reactant: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)cc1
Product: COc1ccc(CN2C(=O)COc3ccc(N4CC5CCNCC5OC4=O)nc32)cc1
Yield: 95 %

Procedure:
Starting from 6-bromo-4-(4-methoxybenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (prepared as described in WO 2010/041194, 0.35 g, 1 mmol) and rac-(4aR*,8aR*)-tert-butyl 2-oxohexahydro-2H-pyrido[4,3-e][1,3]oxazine-7(3H)-carboxylate (Preparation A, 0.308 g, 1.2 mmol, 1.2 eq.), the title compound was obtained as an orange foam (0.255 g) using the procedures described in Preparation D, steps D.i and D.ii (Buchwald coupling: 95% yield, Boc deprotection: 63% yield).