Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@@H](N)Cc2cccc(C)c2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-L-phenylalaninamide (0.6 g, 1.42 mmol) in CH2Cl2 (15 mL) is added 4-fluorophenylboronic acid (0.398 g, 2.85 mmol), cupric acetate (0.26 g, 1.4 mmol) and pyridine (0.23 mL, 2.85 mmol), and the dark blue solution is stirred overnight at room temp. The solution is then diluted with CH2Cl2 (35 mL), and washed with 1 N HCl (50 mL) and brine (50 mL), then dried (MgSO4), evaporated and chromatographed (silica, 30% EtOAc/hexane) to yield N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-(4-fluorophenyl)-L-phenylalaninamide, as a clear oil.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:13]>>[CH:1]1([NH:7][CH2:8][CH2:9][Cl:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNC1CCCCC1
Reactant: O=S(Cl)Cl
Product: ClCCNC1CCCCC1

Procedure:
2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-1-oxaspiro[4.5]decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:7]5[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=5)[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(N)=O)cc1

Procedure:
4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzamide was prepared from 4-carbamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:24](O)=O>C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC1CCNCC1)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=CO
Agent: C=O
Product: CN1CCC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 95 °C
Yield: 30.7 %

Procedure:
(1-piperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (4.07 g, 12.0 mmol) was dissolved in formic acid (20 mL) and 35% aqueous formaldehyde solution (20 mL). The reaction mixture was heated at 95° C. for 90 minutes, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto 1M aq Na2CO3 solution (200 mL), basified to pH10 with 1M aq KOH solution (30 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 97:2:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase column chromatography (gradient eluting with MeOH in water, 0-80%) to give (1-methylpiperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (1.30 g, 30.7%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](CN)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of cis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (2.55 g, 7.45 mmol) in CH2Cl2 (40 mL) was added 4 M hydrogen chloride in EtOAc (4 mL). The reaction mixture was stirred at ambient temperature for 5 hr and concentrated. The residue was dissolved in 1,4-dioxane (20 mL) and 10% aqueous sodium hydroxide (40 mL) and the resulting solution was cooled on an ice-bath. (Boc)2O (829 mg, 3.80 mmol) was added dropwise and the mixture was stirred at ambient temperature for 3 h. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered and concentrated, and purified by flash chromatography (silica gel, 9% MeOH in CHCl3) to give cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (255 mg, 14%) as a pale yellow oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:19][N:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: CNC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1

Procedure:
2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.2 g of N-methylcyclohexylamine are added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride, and to this mixture is added dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 5 ml of methylene chloride maintained at 10°-20° C. under external ice cooling and agitation, followed by additional 3.5-hour agitation at the same temperature. The precipitated crystals are filtered out and the filtrate is concentrated under reduced pressure and evaporated to dryness. The obtained residue is dissolved in 100 ml of methylene chloride and the organic layer is washed with a 5% aqueous solution of hydrochloric acid, a 5% aqueous solution of sodium carbonate and water in that order and then dried with anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is recrystallized from chloroform-ethanol to obtain 1.9 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril in the form of colorless needle-like crystals with melting point of 184.5°- 186° C.
Reaction SMILES: [K+].[Br-].CC1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1.[CH3:36][C:37]1[S:41][CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:46]2[O:64][C:62](=[O:63])[CH2:61][C@H:60]([OH:65])[C:59](C)([CH3:66])[C:57](=[O:58])[C@H:56]([CH3:68])[C@@H:55]([OH:69])[C@@H:54]([CH3:70])[CH2:53][CH2:52][CH2:51][C@H:49]3O[C@H:48]3[CH2:47]2)\[CH2:44]O)[N:38]=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC(C)=CC2)\C)N=1>CO>[CH3:36][C:37]1[S:41][CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:46]2[O:64][C:62](=[O:63])[CH2:61][C@H:60]([OH:65])[C@H:59]([CH3:66])[C:57](=[O:58])[C@H:56]([CH3:68])[C@@H:55]([OH:69])[C@@H:54]([CH3:70])[CH2:53][CH2:52][CH2:51][CH:49]=[CH:48][CH2:47]2)\[CH3:44])[N:38]=1
Reactant: Cc1nc(/C=C(\CO)[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]22D −11.6 (c 10.0, MeOH); UV (MeOH) λmax nm (ε) 212 (15500), 249 (12100); IR (KBr) νmax 3428, 2962, 2929, 2877, 2859, 1734, 1705, 1460, 1251, 9S2 cm−1; 1H NM (CDCl3, 300 MHz) δ 6.99 (1H, s, H-19), 6.66 (1H, bs, H-17),5.55 (1H, ddd, J=10.4, 9.2, 6.1 Hz, H-12), 5.38 (1H, ddd, J=10.4, 9.3, 6.2 147, H-13),5.22 (1H, dd, J=8.8, 2.8 Hz, H-15), 4.42 (1H, dddd, J=9.4, 5.6, 4.2, 4.1 Hz, H-3),3.93 (1H, d, J=5.6 Hz, 3-OH), 3.86 (1H, m, H-7), 3.15 (1H, bs, 7-OH), 3.12 (1H, dq, J=4.2, 7.0 Hz, H-4), 3.00 (1H, dq, J=6.9, 7.0 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, dddd, J=15.1, 9.3, 8.8, 0.8 Hz, H-14a), 2.58 (1H, dd, J=15.4, 9.4 Hz, H-2a), 2.38 (1H, dd, J=15.4, 4.1 Hz, H-2b), 2.31 (1H, ddd, 0.1=15.1, 6.2, 2.8 Hz, H-14b), 2.08 (3H, d, J=1.3 Hz, H-27), 2.15 (1H, m, H-11a), 2.04 (1H, m, H-11b), 1.71 (1H, m, H-8), 1.59 (1H, m, H-10a), 1.43 (1H, m, H-9a), 1.31 (114, m, H-9b), 1.26 (3H, d, J=7.0 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-23), 1.11 (1H, m, H-10b), 1.00 (3H, d, J=6.9 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 463 [M]+ (7), 324 (7), 306 (8), 290 (17), 168 (100), 164 (14), 139 (27); HREIMS m/z 463.2392 (calcd. for C25H37NO5S, 463.2392).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(p-fluoro) phenylalanine (1.3 g, 40.0 mmol) to 8.2 g (41.0 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (14.8 g, 86.5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][NH:56]1)=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][N:56]1[C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17])=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[CH:40][CH:39]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1sc(NC(=O)OC(C)(C)C)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reaction time: 1 h

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (1 eq) and TFFH (1 eq) were taken in 2 mL anhydrous THF and stirred for 10 min. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (50 mg) and DIEA (3 eq) were added to the reaction mixture and stirred for 1 hour. Reaction mixture was diluted with EtOAc (5 mL), washed with water and brine and dried over Na2SO4. The solvent was removed by rotavap and the residue was purified by silicagel column to give (S)-2-({(S)-7-(2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (42 mg). Treatment with HCl according to General Procedure C followed by NaHCO3 wash gave (S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (35 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:10]1([C:2]2[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ccccc2)c1
Yield: 129.7 %

Procedure:
This compound was prepared in a manner analogous to that of Example 4, Step B, using 10.0 grams (0.054 mole) of 3- bromophenyl-methanol, 7.2 grams (0.059 mole) of phenylboronic acid, 0.25 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), and 66 mL (0.135 mole) of aqueous 2M sodium carbonate in 50 mL of toluene. The crude product from this reaction was combined with a previous smaller run conducted on 4.6 grams (0.020 mole) of 3-bromophenylmethanol. The combination was subjected to column chromatography on silica gel. Elution was accomplished using 20:1 methylene chloride and ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.9 grams of 3-phenylphenylmethanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: C1CCNC1
Product: COC(=O)c1ccc(C(=O)N2CCCC2)nc1
Yield: 36 %

Procedure:
The title compound was synthesized as described for Intermediate example I-97 in 36% yield starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and pyrrolidine. Purification by column chromatography using a gradient of ethyl acetate in heptane; 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (d, 1 H), 8.47 (dd, 1 H), 7.84 (d, 1 H), 3.97 (s, 3 H), 3.61-3.68 (m, 4 H), 1.90-2.03 (m, 4 H); MS (ESI) m/z 235[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[Br:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18].[H-].[Na+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[C:21]([N:4]2[C:5]3[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=3[C:2]([CH3:1])=[CH:3]2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C#N)c(Br)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The title compound of Example 1 (9.8 g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this was added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55° C. for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z: (M+H)=358.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=O)[NH:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([N:25]=1)=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:15]=[N:16][C:17]=2[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12
Product: Clc1nnc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (845 mg) was stirred in phosphorus oxychloride (30 ml) at reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, yielding 2-benzyloxy-5-chloro-8-phenylpyrido[2,3-d]pyridazine as a pale yellow solid (950 mg). 1H NMR (400 MHz, DMSO) δ5.50 (2H, s), 7.35 (5H, m), 7.58 (3H, m), 7.65 (1H, d, J=9.0 Hz), 8.06 (2H, m), 8.60 (1H, d, J=9.0 Hz); MS (ES+) m/e 348, 350 [MH]+.
Reaction SMILES: Cl.C(O[C:5](=[NH:18])[CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:5](=[NH:18])[CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=N)Cn1c(C)ccc1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C)n1CC(=N)N1CCN(c2ccccc2F)CC1
Temperature: 55 °C
Yield: 85.4 %

Procedure:
A mixture of ethyl 1-(2-ethoxy-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate hydrochloride (950 mg, 3.46 mmol) and 1-(2-fluorophenyl)piperazine (1.87 g, 10.4 mmol) in ethanol (5 mL) was heated at 55° C. overnight. At this time, the reaction was concentrated in vacuo. Reverse phase column chromatography (0-100% acetonitrile/water) afforded ethyl 1-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate (1.1 g, 85.4%) as a white solid. LC-MS calcd. for C20H26N4O2 [(M+H)+] 373, obsd. 373.0.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 99 %

Procedure:
The title compound from Step B above (1.7 g, 6.72 mmoles) and triethylamine (1.1 g, 10.87 mmoles) were dissolved in CH2Cl2 (20 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (1.1 g, 9.6 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (2.32 g, 99%). FABMS (M+1)=332.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH2:40]([C@@H:47]([N:59]([CH3:76])[C:60](=[O:75])[C@H:61]([NH:73][CH3:74])[CH2:62][C:63]1[CH:72]=[CH:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[CH2:55][N:56]([CH3:58])[CH3:57])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl.CN(C)C=O.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:73]([C@@H:61]([C:60](=[O:75])[N:59]([C@H:47]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[CH2:55][N:56]([CH3:57])[CH3:58])=[O:49])[CH3:76])[CH2:62][C:63]1[CH:72]=[CH:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=1)[CH3:74])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (168 mg, 0.69 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)—N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (345 mg, 0.69 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml) and ethyldiisopropylamine were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (70 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 491 mg of {(3E)-4-[N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9](=[O:10])[CH2:11][CH:20]([OH:21])[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 23.6 %

Procedure:
A mixture of 1,1-bis(4-fluorophenyl)acetone (2.4 g) and ethyl glyoxylate (47% solution in toluene, 2.1 g) was stirred at 130° C. for 3 days. The reaction mixture was cooled to ambient temperature. The mixture was purified by silica gel column chromatography (n-hexane:EtOAc=4:1) to give ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (800 mg) as a brown oil.