Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C([O-])(=O)C1C=CC=CC=1.[Li+].[OH-].[OH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([CH:25]([CH3:27])[CH3:26])[C@@H:20]1[CH3:28]>O>[OH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([CH:25]([CH3:27])[CH3:26])[C@H:20]1[CH3:28]
Reactant: CC(C)N1C(=O)O[C@H](CO)[C@H]1C
Agent: O=C([O-])c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1C(=O)O[C@H](CO)[C@@H]1C

Procedure:
A THF (87 ml) solution of 4.80 grams of (S)(S)-oxazolidinone from Step G was stirred at 22° C. and treated with 87 ml of 1N LiOH in H2O. After 2.5 hours at 22° C. the THF was removed by rotary evaporation and the product extracted with CH2Cl2. The combined organic portions were washed with saturated aqueous Na2CO3, H2O, and brine, dried (Na2SO4) and concentrated to essentially pure product as a white foam; yield 2.93 g (95%). ##STR25## Similarly prepared is the 5(S)-hydroxymethyl-4(R)-methyl-3-(1-methylethyl)oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (47 mg, 35%).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccccc2)nc2n1C=Cc1ccccc1C2

Procedure:
To a solution of 20 parts of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one in 300 volume parts of dimethylformamide is added 5.5 parts of a sodium hydride (55%) dispersion in mineral oil under stirring. To the mixture is added 13 volume parts of benzyl bromide dropwise. After stirring for 1 hour, the crystals are collected by filtration to give 2-benzyl-2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from ethanol gives colorless plates melting at 133° - 134° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[C:15]([Cl:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[C:15]([Cl:27])=[CH:14][C:10]=1[C:11]([NH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1
Reactant: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)O)cc2Cl)CC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)Nc3cccnc3)cc2Cl)CC1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of 2-(benzyloxy)-5-chloro-4-(4-methylpiperazine-1-carbonyl)benzoic acid (may be prepared as described in D 76) (108 mg, 0.278 mmol) in N,N-dimethylformamide (DMF) (5 mL) was added DIPEA (0.97 ml, 0.555 mmol), 3-aminopyridine (39.2 mg, 0.417 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (45 mg, 0333 mmol) and EDC (96 mg, 0.5 mmol). The solution was stirred overnight. The solvent was removed in vacuo and the residue was purified by MDAP (tartan, High pH, 25 minute run) to give a white solid (33 mg, 9% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.C(O)CCC.[OH-].[Na+].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1>O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
2-(2-hydroxy-3,5-di-t-amylphenyl)benzotriazole-N-oxide 23.2 g was added to a mixture of n-butanol 60 g, water 12 g and 97% sodium hydroxide 16.5 g, and 9-fluorenone 2.0 g was further added to the resultant mixture. The resultant mixture was heated to 80° C., and was further stirred at 80°~85° C. for 2.5 hours, thus the reduction reaction being completed. The reaction liquor was treated in the same manner as in Example 17 to recover butanol, and 1.8 g of 9-fluorenone catalyst was recovered as a fraction at 120°~130° C. under vacuum of 2~3 mmHg. After recovering the catalyst, the remaining material was washed with methanol to produce the desired product, i.e. 20.5 g of 2-(2-hydroxy-3,5-di-t-amylphenyl)benzotriazole having a melting point of 79°~80° C. at the yield of 92.8%.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)([CH3:25])[C:20](OCC)=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[BH4-].[Na+].O>C(O)C.O1CCCC1>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)([CH3:25])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)c1cnc(C)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ncc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 110 mg of ethyl 2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-(2-methyl-1,3-thiazol-5-yl)propanoate in 3.3 ml of ethanol and 0.66 ml of tetrahydrofuran were added 40 mg of sodium borohydride at 0° C., followed by stirring at room temperature for 16 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1O.C[Si](C)(C)N[Si](C)(C)C.[Na].I[CH:20]1[CH2:23][O:22][CH2:21]1.[CH:24]([OH:27])(C)[CH3:25]>CCO.[Ni](I)I>[O:22]1[CH2:23][CH:20]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:27])[CH3:25])=[CH:3][CH:4]=2)[CH2:21]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CC(C)O
Reactant: IC1COC1
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(C2COC2)cc1
Temperature: 80 °C

Procedure:
(4-Acetamidophenyeboronic acid {670 mg, 3.7 mmol), Nickel (II) iodide (35 mg, 0.11 mmol), trans-2-aminocyclohexanol (17 mg, 0.11 mmol), and Sodium hexamethyldisilazane (690 mg, 3.7 mmol) were weighed into a microwave reaction vial. A septum was placed over the top, nitrogen was purged and Isopropyl alcohol (5.7 ml, 75 mmol) was added. The vial was purged with nitrogen for 10 minutes and 3-iodooxetane (344 mg, 1.87 mmol) was added in 0.75 ml isopropyl alcohol. The septum was replaced with a microwave vial cap and the mixture was heated in a microwave reactor (microwave conditions: CEM Discovery Explorer microwave reactor; Ramp time: 10 min; 80° C. for 30 min; power: 300 W). The crude reaction mixture was diluted with 8 ml EtOH and the suspension was filtered through a pad of solka Floc®. The pad was washed with 35 ml EtOH and the filtrate was concentrated. The crude material was purified by flash chromatography (SiO2, eluting with 40-60% EtOAc/CH2Cl2) to give the desired product as an oil (200 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14](CC[Si](C)(C)C)[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25]CC2C=CC=CC=2)[CH:6]=1.C([O:35][C:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]=[C:44]=[O:45])C.N1C2C(=CC=CC=2)C=NC=1>>[OH:25][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:1]2[C:36](=[O:35])[C:37]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:43][C:44]2=[O:45])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[NH:14][S:15]1(=[O:16])=[O:17]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: CCOC(=O)c1ccccc1N=C=O
Agent: c1ccc2ncncc2c1
Product: O=C1CN(c2ccc(CCCn3c(=O)[nH]c4ccccc4c3=O)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[4-(3-aminopropyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 2-isocyanatobenzoic acid ethyl ester analogous to Example 214. Cyclization to the quinazoline occurs during the TMS-ethyl deprotection step. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (dq, J=7.71, 7.54 Hz, 2 H) 2.51-2.56 (m, 2 H) 3.92 (d, J=7.33 Hz, 2 H) 4.00 (s, 2 H) 6.63 (dd, J=8.08, 2.02 Hz, 1 H) 6.70 (d, J=2.02 Hz, 1 H) 7.17 (d, J=7.83 Hz, 2 H) 7.26 (d, J=8.08 Hz, 1 H) 7.61 (dd, J=15.41, 1.26 Hz, 1 H) 7.91 (dd, J=8.34, 1.52 Hz, 1 H) 8.93 (br. s., 1 H) 11.36 (br. s., 1 H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-:9].[Li+].[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:11]/[C:12]([O:13][CH2:14][CH3:15])=[O:9])=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=Cc1ccncc1
Reactant: CCOCC
Agent: [Li+]
Product: CCOC(=O)/C=C/c1ccncc1

Procedure:
To a solution of 4-pyridinecarboxaldehyde (67 ml, 700 mmol) and triethyl phosphonacetate (152 ml, 770 mmol) in THE (200 ml) at room temperature was added lithium hydroxide (32.4 g, 770 mmol). After 18 hours ether (500 ml) was added and the solution was washed with sodium hydrogen carbonate, brine and concentrated to give a white solid. Yield 102.1 g (83%). NMR: 8.62 (d, 2H), 7.60 (d, 1H), 7.35 (d, 2H), 6.59 (d, 1H), 4.30 (q, 2H), 1.35 (t, 3H); m/z 178.3.
Reaction SMILES: FC(F)(F)[O:3][C:4]1C=CC(N2C=NC(C3C=CC(C(CC)CC(N=[N+]=[N-])=O)=CC=3)=N2)=C[CH:5]=1.[N:32]([CH2:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[N:46]=2)=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[C:33]=[O:34].[F:61][C:62]1[CH:67]=[CH:66][C:65]([NH:68][C:69]([NH2:71])=[S:70])=[C:64]([CH:72]([CH3:74])[CH3:73])[CH:63]=1>>[F:61][C:62]1[CH:67]=[CH:66][C:65]([N:68]2[C:4](=[O:3])[CH2:5][S:70]/[C:69]/2=[N:71]\[C:33]([NH:32][CH2:35][CH:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]3[N:49]=[CH:48][N:47]([C:50]4[CH:51]=[CH:52][C:53]([O:56][C:57]([F:59])([F:58])[F:60])=[CH:54][CH:55]=4)[N:46]=3)=[CH:43][CH:44]=2)[CH2:37][CH3:38])=[O:34])=[C:64]([CH:72]([CH3:74])[CH3:73])[CH:63]=1
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Reactant: CCC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCC(CN=C=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCC(CNC(=O)/N=C1\SCC(=O)N1c1ccc(F)cc1C(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3-yl)phenyl)pentanoyl azide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C42a) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as a brown foam (0.072 g, 30%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Hg]Cl>[C:6]([NH:8][C:9](=[NH:21])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 129.9 %

Procedure:
To a solution of amine 228 (126 mg, 0.42 mmol), N, N′- bis-tert-butoxycarbonylthiourea (127 mg, 0.46 mmol), and triethylamine (123 μL, 0.88 mmol) in DMF (4 mL) at 0° C. was added HgCl2 (125 mg, 0.46 mmol). The mixture was stirred at 0° C.for 30 min and at room temperature for 1.5 h. The reaction was diluted with ethyl acetate and filtered through celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried (MgSO4), filtered and the solvent was evaporated. The crude product was purified on silica gel (2/1, 1/1-hexane/ethyl acetate) to afford bis-Boc-guanidine 251 (155 mg, 69%) as a solid: 1H NMR (CDCl3) δ 11.40 (s, 1H), 8.66 (d, 1H, J=7.9), 6.8 (s, 1H), 6.22 (d, 1H, J=8.9), 4.43 -4.34 (m, 1H), 4.19-4.08 (m, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.35 (m, 1H), 2.79 (dd, 1H, J=5.4, 17.7), 2.47-2.36 (m, 1H), 1.92 (s, 3H), 1.50, 1.49 (2s, 18H), 0.89 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1Cl.[CH3:18][C:19]1([CH3:29])[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:21]=2[O:20]1>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[O:28][C:27]1[C:21]2[O:20][C:19]([CH3:29])([CH3:18])[CH2:23][C:22]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(Oc3ccc([N+](=O)[O-])cc3Cl)c2O1
Temperature: 110 °C
Yield: 95.8 %

Procedure:
To a mixture containing 32.63 g (0.236 mole) of anhydrous potassium carbonate and 30.41 g (0.158 mole) of 3,4-dichloro-1-nitrobenzene in 250 ml of dry DMF at room temperature and under an atmosphere of nitrogen was added 30.88 g (0.188 mole) of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran. The reaction mixture was then placed in an oil bath and heated to 110° C. for 20 hours The reaction mixture was cooled to room temperature. The DMF was removed under vacuum. The residue was dissolved in 1.5 L of 1:1 ethylacetate:ether and 300 ml of water. The layers were separated. The organic layer was washed twice with 5% NaOH, twice with H2O and once with a saturated aqueous NaCl solution. After drying over anhydrous Na2SO4, removal of the solvents afforded 48.42 g of a light tan solid. This was recrystallized from hexane:ethyl acetate to afford 44.19 g of white crystals mp 132°-133° C. NMR (CDCl3): δ1.42 (s, 6H), 3.05 (s, 2H), 6.5-7.2 (m, 4H), 7.95 (doft, J=9, 2 Hz, 1H), 8.28 (d, J=2 Hz, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:37])[C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:38])[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[OH:38][CH:13]1[CH:14]([NH:18][C:19]([C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:37])[CH2:15][CH2:16][CH2:17][NH:11][CH2:12]1
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Yield: 97.6 %

Procedure:
To a solution of 4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78b (1.6 g) in methanol:ethyl acetate (50 mL: 100 mL) was added 10% Pd/C. The reaction was stirred under a balloon of hydrogen for 2 hours whereupon it was filtered and concentrated to provide the title compound (1.16 g): MS(EI) 387 (M+H+).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[C:10](Cl)(=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][N:37]=1)[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([NH:27][C:25](=[O:26])[C:24]1[CH:35]=[CH:36][N:37]=[C:22]([NH:21][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)NCc2ccccc2)ccn1
Yield: 42 %

Procedure:
Following the procedure as describe in preparation of Example 5, making variations as required to replace benzoyl chloride with hydrocinnamoyl chloride, to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-phenylpropanamido)-isonicotinamide was obtained in 42% yield: mp 177-179° C.; 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 9.26 (s, 1H), 8.46-8.36 (m, 2H), 7.54-7.14 (m, 11H), 4.43 (s, 2H), 2.86-2.68 (m, 4H); MS (ES+) m/z 360.6 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:6][O:5]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC1COC(C)(C)O1
Reaction time: 72 h
Yield: 56.5 %

Procedure:
To NaH (1.85 g, 60% dispersed in mineral oil) under argon was added anhydrous N,N-dimethylformamide (DMF, 30 mL) at RT. Solketal (2.20 g, 16.7 mmol) in 10 mL anhydrous DMF was then added dropwise with constant stirring. 1-Bromohexadecane (5.10 g, 16.7 mmol), dissolved in anhydrous DMF (20 mL) was then added to the reaction mixture dropwise and stirred for 72 hours. The reaction was quenched by adding about 5 mL of methanol. It was then poured into cold ice water (100 mL) and extracted with hexane (100 mL, 3×). The solvent was removed under reduced pressure and the residue chromatographed on silica gel using hexane-dichloromethane to obtain 1a (3.363 g, 57% yield); 1H NMR (in CDCl3): δ in ppm 0.83-0.86 (3H, t, J=6.5 Hz), 1.22 (26H, m), 1.33 (3H, s), 1.39 (3H, s), 1.52-1.55 (2H, m), 3.37-3.48 (4H, m), 3.68-3.71 (1H, t, J=6.5 Hz), 4.01-4.03 (1H, t, J=6.5 Hz), 4.20-4.25 (1H, quintet, J=6.0 Hz); 13C NMR (in CDCl3): δ in ppm 14.3, 22.9, 25.6, 26.2, 27.0, 29.6, 29.7, 29.8, 29.9, 32.1, 67.1, 72.0, 72.1, 74.9, 109.5.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Brc1cccc2c1cnn2C1CCCCO1
Yield: 82 %

Procedure:
A solution of 4-bromo-1H-indazole (1.82 g, 9.24 mmol), 3,4-dihydro-2H-pyran (1.55 g, 18.48 mmol) and toluene-4-sulfonic acid (0.26 g, 1.39 mmol) in anhydrous tetrahydrofuran (40 mL) was heated at 80° C. overnight under nitrogen. The solvent was removed under reduced pressure and the residue was purified on silica gel column (3% ethyl acetate in petroleum ether) to give the title compound (2.13 g, 81% yield) as a yellow solid. MS (ESI): m/z 280.9 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]([O-:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(OCC)C(=O)[O-]
Reactant: Nc1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OCC)C(=O)Nc1ccc(Br)cc1
Yield: 20 %

Procedure:
Mono-ethyl ethoxymalonate (1.44 grams, 0.01 mole), prepared in Example LXVIII Part A, 4-bromoaniline (1.41 grams, 0.01 mole) and 1,3-dicyclohexylcarbodiimide (1.68 grams, 0.01 mole) were reacted in a manner similar to that described in Example LVII to give 0.39 gram (0.002 mole) of ethyl 3-[(4-bromophenyl)amino]-2-ethoxy-3-oxopropanoate having a melting point of 59°C.-64° C. An analytical sample recrystallized from hexane-ethyl acetate had a melting point of 62° C.-64° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]([O:14]CC)=O)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1.O1CCCC1C(Cl)=O.N[N:26]1C(C(OCC)=O)=C(C2CCCO2)[N:28]=[C:27]1C>>[CH3:1][C:2]1[N:3]2[C:4]([C:12](=[O:14])[NH:28][CH:27]=[N:26]2)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1
Reactant: CCOC(=O)c1[nH]c(C)nc1C1CCCO1
Reactant: CCOC(=O)c1c(C2CCCO2)nc(C)n1N
Agent: O=C(Cl)C1CCCO1
Product: Cc1nc(C2CCCO2)c2c(=O)[nH]cnn12
Temperature: 25 °C

Procedure:
Ethyl 2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C52) [prepared in an analogous manner to C63 in Preparation P2, by employing tetrahydrofuran-2-carbonyl chloride as starting material] (0.4 mol) was converted to ethyl 1-amino-2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C53) using the general method for synthesis of C64 in Preparation P2. In this case, due to enhanced water-solubility, extraction was carried out with a mixture of ethyl acetate and tetrahydrofuran. The isolated material was judged by proton NMR analysis to be a 3:1 mixture of C53 and its regioisomer ethyl 1-amino-2-methyl-5-(tetrahydrofuran-2-yl)-1H-imidazole-4-carboxylate. The mixture was subjected to reaction with formamide and formamidine acetate, as described for the synthesis of P2 in Preparation P2. After the reaction was cooled to room temperature, it was partitioned between water and a mixture of ethyl acetate and tetrahydrofuran. The extracts were concentrated in vacuo, dissolved in a small volume of ethyl acetate, and the product was extracted into aqueous potassium carbonate solution. Adjustment of the aqueous layer to a mildly acidic pH resulted in precipitation of the product. Additional product was obtained by evaporating the aqueous layer to dryness, triturating the residue with methanol and filtering. The filtrate was treated with a small amount of water, and the methanol was removed in vacuo. Additional product precipitated from the aqueous residue. Combined yield: 13.5 g, 61 mmol, 15%. LCMS m/z 221.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.81 (s, 1H), 5.33 (dd, J=6.8, 6.8 Hz, 1H), 3.87-3.93 (m, 1H), 3.70-3.76 (m, 1H), 2.46 (s, 3H), 2.04-2.18 (m, 3H), 1.85-1.96 (m, 1H).