Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].C(O)(C)(C)C.[C:10]([O:14][OH:15])([CH3:13])([CH3:12])[CH3:11]>O>[C:2]([O:15][O:14][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C
Reactant: CC(C)(C)OO
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In accordance with the invention, isobutane oxidate comprised of both tertiary butyl alcohol and tertiary butyl hydroperoxide is reacted in the presence of a water soluble acid catalyst under conditions effective to form ditertiary butyl peroxide. The reaction mixture is phase separated in order to separately recover an aqueous phase containing tertiary butyl alcohol and the acid catalyst and an organic phase containing ditertiary butyl peroxide. The aqueous phase is distilled in order to recover tertiary butyl alcohol overhead and also to separate any water produced during the reaction or introduced in the reaction feed streams, and a concentrated aqueous acid stream is recovered and recycled to the peroxide-forming reaction. The organic phase containing product ditertiary butyl peroxide is then subjected to a series of separation steps including a water extraction step in order to recover product ditertiary butyl peroxide as well as such tertiary butyl alcohol as is contained in the organic phase.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
Under an argon atmosphere a solution of 1.08 g (7.05 mmol) 3,6-dichloro-pyridazin, 10 mL 2 M Na2CO3 solution and 80 mg (0.14 mmol) chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II) in 150 mL 1,4-dioxane is heated to 110° C. At this temperature a solution of 1.13 g (7.05 mmol) 4-chlorophenyl-boric acid in 50 mL 1,4-dioxane is added dropwise within 2 h and the reaction mixture is heated for another hour. After cooling it is combined with 100 mL water, extracted with 100 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 8:2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[CH:18]=1>C(#N)C>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[C:18]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 47.4 %

Procedure:
To a solution of 1.468 g of morpholine and 3.0 mL of diisopropylethylarnine in 80 mL of acetenitrile was added a solution of 5.019 g of 2,6-difluoro-4-nitrobenzene (trifiuoromethane) sulfonate in 10 mL of acetonitrile. The mixture was heated to reflux for 5 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel column (3 cm tall, 10 cm diam), eluting with 25% ethyl acetate/hexanes (v/v) and then 2% acetic acid/25% ethyl acetate/hexanes to give 1.95 g of an orange oil. This was washed with 5% ethyl acetate/hexanes, and the bright yellow solids air dried, mp 91°-92° C.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:24][CH3:25])=[CH:20][CH:21]=2)[C:16]1=O)[CH3:14]>>[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:24][CH3:25])=[CH:20][CH:21]=2)[C:16]1=[N:11][OH:12])[CH3:14]
Reactant: O/N=C1\CCOc2ccccc21
Reactant: CCC1Cc2ccc(OC)cc2C1=O
Product: CCC1Cc2ccc(OC)cc2C1=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 2-ethyl-6-methoxyindan-1-one and making non-critical variations provided the title compound as a oil: HRMS (FAB) calcd for C12H15NO2+H 206.1181, found 206.1175. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 69.90; H, 7.48; N, 6.64.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:19][S:16]([CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:33])[F:32])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:18])=[O:17]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OC(F)(F)F)n2)c1

Procedure:
Example 7 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [2-(trifluoromethoxy)phenyl]boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC:
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3([C:22](=[O:47])[NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][C:29]([C:33]6[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=6[C:41]6[N:45]=[C:44]([CH3:46])[O:43][N:42]=6)=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH2:21][O:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[C@@H:24]([NH:23][C:22]([C:18]2([NH2:17])[CH2:19][O:20][CH2:21]2)=[O:47])[CH2:25][CH2:26]3)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)no1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (3-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester (intermediate A-12) (2.94 g, 4.42 mmol) in MeCl2 (50.0 ml) was added piperidine (4.38 ml) and the mixture was stirred at room temperature for 15 h. The colorless solution was concentrated to dryness under high vacuum at RT. The remaining residue was purified by chromatography (silica gel; MeCl2/MeOH 100:0-95:5) and the title compound was obtained as light brown oil (1.09 g, 56%). MS: 443.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([O:29]C2CCCCO2)[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A 20 mL vial equipped with a magnetic stirbar was charged with 218 mg (0.42 mmol) of THP-ether 15 dissolved in 5 mL of methanol. To this was then added 350 mg (1.39 mmol) of pyridinium p-toluenesulfonate and the mixture was stirred at 25° C. over 8 h. The reaction was sampled by TLC (Rf of product was 0.5 in EtOAc) and worked up by concentration in vacuo to remove methanol. The residual products were taken up in ethyl acetate and filtered through 20 g of silica gel eluting with 300 mL of EtOAc. The filtrate was concentrated to yield 156 mg of products which were further purified by FCC through 25 g of silica gel, eluting with 1:1 EA-hexanes then 100% EA to yield 140 mg of product triol 16 as an oil; 1H NMR (CDCl3): 0.94 (t, J=7.2 Hz, 3H), 1.17 (d, J=6 Hz, 3H), 1.22-1.72 (m, 18H), 1.91 (m, 2H), 2.05-2.36 (m, 4H), 3.30 (br s, 1H), 3.78 (m, 1H), 4.02 (m, 5H), 4.5 (m, 2H), 5.50 (m, 2H). 13C NMR: 10.53, 21.52, 22.09, 23.74, 25.03, 26.83, 29.08, 29.49, 32.90, 34.42, 36.75, 38.52, 43.59, 53.53, 57.75, 60.98, 66.06, 67.50, 72.56, 74.98, 133.27, 135.79, 174.24.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:16]([OH:18])=[O:17])[N:4]=1.Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:16]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[N:4]=1
Reactant: CCOC(=O)CCl
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 0.08 h

Procedure:
0.4 g of a 55% suspension of sodium hydride in mineral oil are added to a suspension of 2.1 g of β-carbolin-3-carboxylic acid in 25 ml of dimethyl formamide, and after a period of 5 minutes, 1.2 ml of ethyl chloracetate are added. The mixture is refluxed for 4 hours and subsequently dimethyl formamide is evaporated in vacuo. After addition of 100 ml of water to the remainder, the mixture is extracted with chloroform to form 1 g of carbethoxymethyl β-carbolin-3-carboxylate having a melting point of 202°-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:23])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (4-methoxyphenyl)boronic acid (350 g, 2.30 mol, 1.00 equiv) in 1,4-dioxane (3500 mL), methyl 4-bromo-3-methylbenzoate (527 g, 2.30 mol, 1.00 equiv), Pd(PPh3)4 (79.8 g, 69.06 mmol, 0.03 equiv), Cs2CO3 (1501 g, 4.60 mol, 2.00 equiv), water (850 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then cooled and quenched by the addition of 3000 mL of water. The resulting solution was extracted with 2×2000 mL of ethyl acetate. The organic layers were combined, washed with 1×2000 mL of brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50-1:20). This resulted in 471.6 g (crude) of methyl 4-(4-methoxyphenyl)-3-methylbenzoate as a red solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([F:24])[C:15]=1[CH2:25][CH2:26][C:27]1[N:28]=[C:29]2[CH:35]=[CH:34][N:33]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=1.[Br:45]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:45][C:34]1[N:33]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=[C:27]([CH2:26][CH2:25][C:15]3[C:16]([F:24])=[C:17]([O:22][CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=3[F:13])[N:28]=[C:29]2[CH:35]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(OC)c(F)c(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(OC)c(F)c(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70456.4 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.150 mL, 1.07 mmol) in tetrahydrofuran (0.48 mL) at 78° C., n-butyllithium (2.5 M in hexanes, 0.428 mL, 1.07 mmol) was added dropwise. After a white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting solution was added to a stirred solution of 2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (400 mg, 0.871 mmol) in tetrahydrofuran (3 mL) at 78° C. After 10 minutes, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (0.283 g, 0.870 mmol) in tetrahydrofuran (2 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (330 g, 70%). LCMS calculated for C22H19BrF2N3O4S (M+H)+: m/z=538.0. Found: 538.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][S:12]([CH3:11])(=[O:14])=[O:13])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1

Procedure:
4-Aminobenzoic acid is reacted with methanesulfonyl chloride (Compound 19) to give N-(4-carboxyphenyl)methanesulfonamide. 2-Triethylsilyl-4-furaldehyde (Compound 18) is reacted with N-(4-carboxyphenyl)methanesulfonamide and lithium diisopropylamide. The resulting 4-[1-hydroxy-2-N-(4-carboxyphenyl)sulfonamido]-ethyl-2-triethylsilylfuran is esterified with dodecanoyl chloride in the presence of triethylamine. Oxidizing this ester with singlet oxygen, under conditions as in Example 1, gives the title furanone.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].Cl.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cnccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cnccc2Cl)n1
Temperature: 150 °C
Yield: 10.9 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 4-chloro-3-pyridinecarbonyl chloride hydrochloride (0.223 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.015 g (11% yield) of pure product: MS (ES) m/z 445 (M+).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[C:8]([NH:10][C@H:11]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([O:36]C)=[O:35])=[O:27])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:9])(=O)C.CO.[OH-].[Na+].Cl>C1COCC1>[CH2:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([OH:36])=[O:35])=[O:27])[NH:10][C:8](=[O:9])[C:7]1[CH:38]=[CH:39][CH:40]=[C:5]([OH:4])[CH:6]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCC[C@H](NC(=O)c1cccc(O)c1)C(=O)N[C@H]1CCC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a mixture of methyl (1R,2S)-2-({N2-(3-acetoxybenzoyl)-N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.35 g), methanol (3.0 ml), and THF (3.0 ml) was added a 1 M aqueous sodium hydroxide solution (1.9 ml) under ice-cooling, followed by stirring at room temperature over one night. Further, to the reaction mixture were added a 1 M aqueous sodium hydroxide solution (1.0 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, 1 M hydrochloric acid was added thereto under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and diisopropyl ether and ethyl acetate were added to the purified product obtained to give a solid. The solid was collected by filtration to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(3-hydroxybenzoyl)-L-ornithyl}amino)cyclopentanecarboxylic acid (0.12 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=[CH:5]2.C([Li])CCC.[Cl:28][CH2:29][C:30](N(OC)C)=[O:31]>O1CCCC1>[Cl:28][CH2:29][C:30]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:3]=1)=[O:31]
Reactant: CC(C)[Si](Oc1cccc2cc(Br)ccc12)(C(C)C)C(C)C
Reactant: CON(C)C(=O)CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc2cc(C(=O)CCl)ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (6-bromonaphthalen-1-yloxy)triisopropylsilane (10.4 g, 27.5 mmol) in tetrahydrofuran (180 mL) under argon at −78° C. was added n-butyllithium (2.5M in hexanes, 11.5 mL, 28.7 mmol). After stirring at this temperature for one hour, a solution of 2-chloro-N-methoxy-N-methyl acetamide (7.6 g, 55.2 mmol) in tetrahydrofuran (10 mL) was added to the reaction via cannula. The dry ice bath was removed and the reaction was allowed to warm to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash chromatography to yield 2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone (7.8 g, 75%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1cc(-c2c3c(nn2C2CCCC2)CCNCC3)ccc1Cl
Yield: 28.8 %

Procedure:
The title compound (31 mg) was prepared according to Example 180 using 146 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 168 mg of 3-chloro-4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21ClFN3, 333.14. found, m/z 334.4 [M+H]+, 336.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.31 (m, 2H), 7.22-7.18 (m, 1H), 4.37 (m, 1H), 3.31-3.28 (m, 2H), 3.07-3.03 (m, 2H), 2.67-2.64 (m, 2H), 2.11-1.78 (m, 6H), 1.56-1.47 (m, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[C:10]1[CH3:11]>CC(C)=O>[C:1]1([NH:8][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:15])=[O:16])[CH:2]=1
Reactant: Nc1cccc(N)c1
Reactant: CC1=CC(=O)OC1=O
Solvent: CC(C)=O
Product: C/C(=C/C(=O)Nc1cccc(NC(=O)/C=C(/C)C(=O)O)c1)C(=O)O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A 3-liter, 3-neck round bottom flask was charged with 54 g (0.5 mole) of m-phenylenediamine and 500 ml of reagent acetone and flushed with nitrogen. The flask was fitted with a reflux condenser, mechanical stirrer and thermocouple. A dropping funnel containing 112 g (1.0 mole) of citraconic anhydride in 500 ml of reagent acetone was attached and the solution added dropwise over about 1 1/2 hours with stirring as the temperature was allowed to rise to reflux the acetone. The reaction mixture was refluxed for an additional hour, cooled to room temperature and suction filtered to give 166 g of N,N'-(m-phenylene)bis citraconamic acid as shown by NMR analysis, as a tan mustard-colored solid melting at 152°-156° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][CH:41]4[CH2:43][CH2:42]4)[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:46][CH3:47].C(O)(C(F)(F)F)=O>>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]5[CH2:29][CH2:30][C@H:31]([N:34]6[CH2:39][CH2:38][N:37]([CH2:40][CH:41]7[CH2:43][CH2:42]7)[CH2:36][CH2:35]6)[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:46][CH3:47])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 1) (0.13 g, 0.43 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 1 (0.10 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→420% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative—1) to give 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 26%).