Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[C:2]1(OCC=C)[CH:7]=CC=C[CH:3]=1.C(O[C:15]([CH:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:25])=[C:18]1[CH2:26][CH3:27])=[O:16])C>O1CCCC1.CCOCC>[CH2:26]([C:18]1[CH:17]([C:15](=[O:16])[CH2:7][CH:2]=[CH2:3])[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][C:19]=1[CH3:25])[CH3:27]
Reactant: C=CCOc1ccccc1
Reactant: CCOC(=O)C1C(CC)=C(C)CCC1(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A few crystals of diphenyl are added to a suspension, cooled to 5°-10° C and held under a nitrogen atmosphere, of 2.4 g (0.35 g-atoms) of finely cut lithium wire in 40 ml of absolute tetrahydrofuran. 2 ml of a solution of 9.4 g (70 mmol) of allyl phenyl ether in 10 ml of absolute ether are then added. After a greenish coloration sets in, the rest of the solution is added dropwise at -15° C. After completion of the addition, the mixture is stirred for 30 minutes at 0° C. The resulting allyl lithium solution is decanted off from excess lithium and transferred to a dropping funnel. This solution is added dropwise to a solution, cooled to -60° C and maintained under nitrogen, of 4.48 g (20 mmol) of 2-ethyl-3,6,6-trimethyl-2-cyclohexene-1-carboxylic acid ethyl ester in 40 ml of absolute ether. After completion of the addition, the mixture is left to warm to room temperature, poured on to ice-water and extracted with three portions of hexane. The combined hexane extracts are washed neutral with three portions of water, dried over sodium sulphate and evaporated. By fractional distillation of the residue there are obtained 3.75 g (85%) of 2-ethyl-3,6,6-trimethyl-1-[but-3-enoyl]-2-cyclohexene; boiling point 57°-58° C/0.04 mm Hg; nD20 = 1.4865.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:7].C(N(CC)CC)C.Cl.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50](Cl)=[O:51])=[CH:42][CH:41]=1.Cl>C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:50]([C:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:40]=[CH:41][CH:42]=2)=[O:51])[CH2:10][C@H:9]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7]
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccnc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1)c1ccnc2ccccc12
Reaction time: 15 h

Procedure:
A solution of 1.70 g (3.65 mmol) of (2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidine4-amine and 1.5 ml (10.96 mmol) of triethylamine in 3 ml of methylene chloride is added dropwise at 0° C. to a solution of 0.915 g (4.01 mmol) of quinoline4-carboxylic acid chloride hydrochloride [Nicolai E, Gungor T, Goyard J, Cure G, Fouquet A, Teulon J M, Delchambre C, Cloarec A, Eur. J. Med. Chem., 1992, 27, 977] in 10 ml of methylene chloride. After 15 hours, a further 228 mg (1.0 mmol) of quinoline-4-carboxylic acid chloride hydrochloride and a further 0.1 ml (1.0 mmol) of triethylamine are added and the mixture is stirred for 3 hours. 1 N hydrochloric acid is added to the mixture which is then extracted with ethyl acetate. The organic phase is washed with 1 N sodium hydroxide solution and with brine, dried over sodium sulfate and concentrated. The residue is crystallised from toluene and yields the title compound in the form of white crystals. M.p. 204-207° C. (phase transition 135-140° C.); TLC: ethyl acetate: Rf =0.48, FD-MS: M+ =619(621). ##STR17##
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1nccnc1Cl
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(c2nccnc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 3-cyano-2-chloropyrazine (0.45 g, 3.2 mmol) in methanol (10 mL) was added N-methylpiperazine (0.75 mL, 6.4 mmol) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate. The precipitate was filtered off and the filtrate was concentrated under reduce pressure. The residue was then purified by flash chromatography on silica gel (dichloromethane/methanol 95:5) to give the title compound as a yellow oil (0.59 g).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[C:8]#N)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=[O:26].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:26])([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C#N)ccn1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cc(C=O)ccn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 2-(2-hydroxypropan-2-yl)isonicotinonitrile (41.4 g, 0.255 mol) in toluene (500 mL) was added dropwise a solution of diisobutylaluminum hydride (1 mol/L in hexane, 765 mL, 0.765 mol) at −70° C. over a period of 1.5 h. The reaction mixture was stirred at −70° C. for 30 min. Methanol (30 mL) was added followed by a 20% aqueous solution of sodium tartrate (700 mL) while stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were washed with a 20% aqueous solution of sodium tartrate (700 mL). The organic phase was stirred with a 10% aqueous solution of sulfuric acid (800 mL) for 15 min. The organics were dried over sodium carbonate and sodium sulfate and concentrated under reduced pressure. A saturated aqueous solution of sodium bisulfate (400 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL×3). The aqueous layer was neutralized with aqueous sodium carbonate and extracted with ethyl acetate (200 mL×3). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (23 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([OH:21])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:21]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 0.54 g, 2.8 mmol) and 3-bromo-5-trifluoromethyl benzoic acid (0.81 g, 3.0 mmol) in DMF (7 mL) was added TBTU (0.96 g, 3.0 mmol) and DIPEA (1.41 g, 10.9 mmol). The reaction mixture was stirred under nitrogen overnight at RT and then partitioned between ethyl acetate and an aqueous NaHCO3 solution. The aqueous phase was extracted trice with ethyl acetate. The combined organic solutions were washed trice with water and then dried by a phase separator column. The solvent was removed by to evaporation and the product was purified by chromatography on silica gel (ethyl acetate-heptane 10% to 17%). There was obtained 0.86 g (68%) of 3-bromo-N-[(25)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide. 1H NMR (500 MHz, CDCl3): 2.1-3.8 (cm, 8H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.8-7.4 (cm, 6H), 7.8 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][C:26]1([CH3:36])[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([OH:35])[C:28]=2[O:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:34]3[C:28]4[O:27][C:26]([CH3:36])([CH3:25])[CH2:30][C:29]=4[CH:31]=[CH:32][CH:33]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)Cc2cccc(O)c2O1
Product: CC(NC(=O)c1coc(Oc2cccc3c2OC(C)(C)C3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 89.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 2,3-dihydro-2,2-dimethyl-7-benzofuranol (22 mg, 0.13 mmol) to give the title compound (50 mg, 94%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[CH3:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][CH3:19])[CH2:16][CH3:15]
Reactant: Cc1ccc(Br)c(I)c1
Reactant: CCC(=O)CC
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cc(C)ccc1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of 1-bromo-2-iodo-4-methylbenzene (28 g, 94 mmol) in THF (10 ml) at −10° C. under nitrogen was slowly added i-PrMgBr (47 ml, 94 mmol). The reaction mixture was stirred for 1 h at −10° C. Then the reaction mixture was cooled to −30° C., and pentan-3-one (8.1 g, 94 mmol) was added dropwise. The reaction mixture was stirred for 1 h at −30° C. under nitrogen and then warmed to rt and stirred for additional 2 h. Then the reaction mixture was quenched with 2N HCl solution and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:0 to 5:1) to give the desired compound (6.5 g, yield 26.9%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.52-7.50 (d, 1H), 7.43-7.40 (d, 1H), 6.95-6.92 (d, 1H), 2.48-2.40 (q, 2H), 2.31 (s, 3H), 1.86-1.78 (q, 2H), 0.77-0.71 (m, 6H). MS: m/z=257 and 259 [M+1]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]([O:34][CH3:35])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:23]3[CH:24]=[C:19]([F:18])[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]=3[O:34][CH3:35])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C/c1cc(F)cc(-c2cnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1OC
Temperature: 120 °C
Yield: 47.7 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg) and tripotassium phosphate (702 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (191 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D79) (311 mg) as a brown oil. MS (ES): C22H21ClFNO3S requires 433. found 434.1 (M+H+).
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][C:102]1[CH:110]=[CH:109][C:105]([C:106]([NH2:108])=[NH:107])=[CH:104][CH:103]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](=[O:71])[NH:100][CH2:101][C:102]4[CH:103]=[CH:104][C:105]([C:106]([NH2:108])=[NH:107])=[CH:109][CH:110]=4)[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: N=C(N)c1ccc(CN)cc1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccc(C(=N)N)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-aminomethyl-benzamidine. MS (ES+) m/e 771.56 (MH+)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([Br:41])=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[Br:41][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=3)[N:3]=2)=[C:38]2[C:33]=1[CH:34]=[CH:35][N:36]([CH3:40])[C:37]2=[O:39]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Cn1ccc2c(Br)ccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4ccn(C)c(=O)c34)n2)cc1)OCC
Yield: 62.8 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (166.9 mg, 0.3939 mmol) and 8-amino-5-bromo-2-methylisoquinolin-1(2H)-one (Compound 123A, 120 mg, 0.47 mmol). The crude material was adsorbed onto a pre-filled silica gel loading cartridge and purified using an ISCO Combiflash system eluting first with 0-100% EtOAc:CH2Cl2 and then 15% MeOH:EtOAc. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by trituration in CH2Cl2 and heptane to afford the title product (158.3 mg 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (br s, 1H), 9.90 (s, 1H), 8.82 (br s, 1H), 8.50 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58 (br d, J=5.6 Hz, 2H), 7.25 (dd, J=8.6, 2.3 Hz, 2H), 6.82 (d, J=7.6 Hz, 1H), 3.90-4.03 (m, 4H), 3.55 (s, 3H), 3.21 (d, J=21.2 Hz, 2H), 1.19 (t, J=6.9 Hz, 6H). MS (ES+): m/z 640.03/642.05 (96/100) [MH+]. HPLC: tR=3.90 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[C:32]([C:37]([NH:39][CH3:40])=[O:38])=[N:33][CH:34]=[CH:35][CH:36]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[C:32]([C:37](=[O:38])[NH:39][CH3:40])=[N:33][CH:34]=[CH:35][CH:36]=3)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CNC(=O)c1ncccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccnc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol) and 3-amino-N-methylpyridine-2-carboxamide (Compound 231C, 15.0 mg, 0.0992 mmol) were taken up in TFE (2.7 mL, 37 mmol) and treated with TFA (15.3 uL, 0.198 mmol). This mixture was irradiated on the CEM for 120 min at 100° C. R×n mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 20.8 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ1.19 (t, J=7.07 Hz, 6H), 2.81 (d, J=4.80 Hz, 3H), 3.28 (d, J=20.50 Hz, 2H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 6.90 (dt, J=8.15, 1.99 Hz, 1H), 7.05 (s, 1H), 7.33-7.51 (m, 2H), 8.21 (d, J=3.54 Hz, 1H), 8.41 (s, 1H), 9.08 (br. s., 1H), 9.11 (q, J=4.21 Hz, 1H), 12.45 (s, 1H). MS (ES+): m/z=569.10 (100) [M+1]. HPLC: tR=1.52 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(OCCCCN)cccc1[N+](=O)[O-]
Yield: 148.4 %

Procedure:
A solution of tert-butyl 4-(2-cyano-3-nitrophenoxy)butylcarbamate (Example 210e) (671 mg, 2 mmol) in DCM/TFA (1:1, 20 mL) was stirred at room temperature for 2 hrs. The solvent was removed under vacuum to give the title compound (698 mg, 100%). MS 236 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O:16]([C:18]#[N:19])[Na].FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:18](=[O:16])[NH2:19])[CH2:5][O:4]1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reactant: N#CO[Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 15 grams of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.0625 mols), 8.12 grams NaOCN (0.125 mols), and 75 ml methylene dichloride is stirred at 25°-35° C. while 14.3 grams trifluoroacetic acid is added dropwise. The mixture is stirred for 16 hours at 40° C. The product is filtered and the filter cake washed with methylene dichloride. The filtrate is washed with water and dried over Na2SO4 prior to vacuum-stripping. The reaction product is recrystallized from 1 part benzene to yield 2,2-bis(trifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 52°-54° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].C>C(C(C)=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Reaction time: 8 h

Procedure:
A mixture of m-nitrophenol (28 g, 0.2 mole), 2-chloroethanol (53.6 ml, 0.8 mole), and potassium carbonate (110.4 g, 0.8 mole) in 300 ml methyl ethyl ketone was kept at reflux temperature with stirring overnight. The solid was filtered and dissolved in water. The filtrate was concentrated and some solid was crystallized from 2-propanol/isopropyl ether. This light-brown solid was collected and weighed 22.78 g(62%). The mother liquor was concentrated and redissolved in toluene/ethyl acetate and extracted with the above aqueous solution. The aqueous layer was further extracted with fresh toluene/ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated to give a second crop of 6.46 g (17.6%). The second crop was dissolved in methanol, stirred with charcoal, filtered, evaporated, and crystallized from 2-propanol/isopropyl ether to give a pure sample. The sample was dried under vacuum at room temperature overnight, mp 85°-86° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:29](=O)[CH2:28][CH2:27]C1=O.C(Cl)CCl.C1(N)CC1>C(Cl)Cl>[CH:19]1([CH2:18][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]([OH:17])[C:14]([NH:24][CH:29]2[CH2:27][CH2:28]2)=[O:16])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(NC(CC1CCC1)C(O)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC(CC1CCC1)C(O)C(=O)NC1CC1)OCc1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (600 mg, 1.95 mmol) in DCM (20 mL) was added HOSu (337 mg, 2.93 mmol), EDC (562 mg, 2.93 mmol). After stiffing for 1 hour, cyclopropylamine (223 mg, 3.9 mmol) was added to the above mixture. The product was extracted with EtOAc. The combined organic layer was then washed with HCl (1N), water, NaHCO3, and brine and then concentrated in vacuo to afford benzyl 1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (530 mg). (M+1) 347.