Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)C1(Cl)C=CC=CN1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.58) (5.45 g, 15 mmol) and commercially available 2-chloropyridine boronic acid (2.48 g, 15.75 mmol) according to the general procedure IVb. Obtained as an off-white solid (3.82 g, 73%). MS (ISP) 349.2 [(M+H)+] and 351 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cnccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cnccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyrazin-2-ylmethyl ester (preparation described in WO 2002064574) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23]4)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CC(O)=O.[Pd]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][NH:24][CH2:23]4)[C@H:14]2[CH3:51])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl 5-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-1,3-dihydro-2H-isoindole-2-carboxylate (12 mg, 0.016 mmol) in AcOH (0.5 mL) was added a catalytic amount of Pd/C (10%). The mixture was stirred at room temperature under a H2 atmosphere for 2 h. The reaction mixture was filtered through Celite and the filtrate was adjusted to basic pH with sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=611.2; found=610.8 (M+H)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 7.87 (s, 1H); 7.70 (s, 2H); 7.42 (s, 0.5H); 7.33 (s, 0.5H); 7.14 (s, 0.5H); 7.13 (s, 0.5H); 7.04 (d, J=8.5 Hz, 0.5H); 7.00 (d, J=8.5 Hz, 0.5H); 6.70 (d, J=5.4 Hz, 0.5H); 6.67 (d, J=5.3 Hz, 0.5H); 5.57 (d, J=8.1 Hz, 0.5H); 5.39 (d, J=8.0 Hz, 0.5H); 4.85 (d, J=15.4 Hz, 0.5H); 4.81 (d, J=15.5 Hz, 0.5H); 4.33 (s, 4H); 4.08 (d, J=15.4 Hz, 0.5H); 3.83 (d, J=15.4 Hz, 0.5H); 3.78 (s, 3H); 3.86-3.75 (m, 1H); 3.26-3.18 (m, 1H); 2.61 (br s, 1H); 1.31-1.25 (m, 4H); 1.19 (d, J=6.9 Hz, 2H); 0.52 (d, J=6.5 Hz, 1.5H); 0.34 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH2:5]([C@H:2]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:3]1=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(Cl)C=O
Reactant: COC(=O)/C=C/C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(c2ccccc2)=C[C@@H]1C(=O)OC
Yield: 90 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-methyl 4-oxo-4-phenylbut-2-enoate using 0.5 mol % 1 as the catalyst in 90% yield as a single diastereomer (white solid). [α]r)20 (c 1.15, CHCl3)=+154.3; mp=108-111° C.; 1H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.40-7.37 (m, 3H), 5.89 (d, 1H, J=6.4 Hz), 3.73 (s, 3H), 3.57 (t, 1H, J=6.3 Hz), 2.76 (q, 1H, J=6.3 Hz), 2.04 (t, 1H, J=7.0 Hz), 1.47-1.26 (m, 18H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 171.0, 169.5, 152.4, 132.0, 129.8, 128.8, 125.0, 97.9, 52.7, 41.9, 40.7, 32.1, 29.8, 29.8, 29.6, 29.6, 27.4, 27.3, 22.9, 14.4; IR (thin film) ν 3062, 2916, 2846, 1758, 1722, 1464, 1339, 1176, 1115 cm−1; HRMS (ESI) calcd for C23H32O4 [M+Na]+ 395.2192, found 395.2192; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=7.2 min, tr (3R,4R)=10.3 min.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH2:37])=[NH:36])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](=O)([O:51]C(C)(C)C)[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32](/[C:35](/[NH2:37])=[N:36]\[C:45]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:51])=[CH:33][CH:34]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)N)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(/C(N)=N\C(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[amino(imino)-methyl]benzyl}-L-methioninamide (20 mg, 0.032 mmol) was dissolved in dimethylformamide (0.5 ml), to which triethylamine (0.018 ml, 0.13 mmol) and di-t-butyl carbonate (14 mg, 0.065 mnol) were then added and stirred for 16 hours. After addition of ethyl acetate to the reaction mixture, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-(benzylsulfonyl)-D-isoleucyl-N1-[4-((E)-amino-[[(t-butyloxy)carbonyl]imino]methyl)benzyl]-L-methioninamide (16 mg, 0.024 mmol; yield 76%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1CNC(=O)C1.[Br:19][Br-]Br>>[Br:19][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:12]
Reactant: CC(=O)c1ccc(C(C)C)cc1
Agent: O=C1CCCN1
Product: CC(C)c1ccc(C(=O)CBr)cc1

Procedure:
2-Bromo-1-(4-isopropyl-phenyl)-ethanone was prepared (0.95 g) following general procedure A using 1-(4-isopropyl-phenyl)-ethanone (0.66 mL, 3.92 mmol) and pyrrolidone hydrotribromide (2.1 g, 4.31 mmol).
Reaction SMILES: [C:1]1([C:7]#[C:8][Sn:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:19][CH2:20][CH3:21])[N:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 150 °C

Procedure:
Phenylethynyltri-n-butyltin (8.25 g, 21.1 mmol) and benzyl azide (2.3 mL, 18.4 mmol) were combined and heated to 150° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 526.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:22][CH2:21]1.B(OCCCC)(OCCCC)OCCCC.N1CCCCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:33]/[C:32]3[CH:35]=[CH:36][C:29]([O:28][CH2:27][CH2:26][N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)=[CH:30][CH:31]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: CC(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: CCCCOB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [B]=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(OCCN2CCOCC2)cc1)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 37.8 %

Procedure:
To 2.5 g of (E)-6-(1H-indol-6-yl)hex-5-ene-2,4-dione were added 44 mL of AcOEt and 1.07 g of boron oxide, and the mixture was stirred at 70° C. for 40 minutes. To this, 2.27 g of 4-(2-morpholinoethoxy)benzaldehyde and 7.07 mL of tributyl borate were successively added, and the mixture was stirred at the same temperature for 40 minutes. Then, 0.11 mL of piperidine was added, and the mixture was stirred at 70° C. for 1.5 hours and was allowed to cool back to room temperature. To the reaction mixture, 22 mL of a 20% K2CO3 aqueous solution and 20 mL of THF were added and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated, washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/acetone or CHCl3/methanol system) to give 1.62 g of the title compound (33% yield).
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1)#[CH:3]
Reactant: CC(C)(O)C#Cc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[5-(3-methyl-3-hydroxy-butyn-1-yl)-3-pyridyl]-4-tert-butoxycarbonyl-homopiperazine (0.40 g, 1.1 mmol), sodium hydride 60% (4.5 mg, 0.11 mmol) and toluene (10 ml) was stirred at 110° C. for 3 h. The crude mixture was purified by chromatography on silica gel with ethyl acetate:toluene, (3:1) gave the title compound. Yield 0.13 g, 39%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCOC(C)=O>CN1C(=O)CCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:8]=[C:9]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a slurry of 2-morpholino-4,6-dichloropyrimidine (prepared as in Method 22, 2.0 g, 8.54 mmol) in NMP (14 mL), triethylamine (1.43 mL, 10.25 mmol) was added. The heterogeneous mixture was stirred for 15 minutes, then treated with morpholine (0.75 mL, 8.54 mmol). Upon refluxing at 85° C. under argon for 2 hours, the solution was cooled, then added to EtOAc (160 mL). The organic solution was washed with 25 mL of NaHCO3(sat.) (2×), water (2×) and brine, dried over Na2SO4, filtered and concentrated. The crude material was dissolved in 200 mL EtOAc and filtered through a SiO2 pad, further eluting with EtOAc, yielding 2.2 g (93%) of 2,4-dimorpholino-6-chloropyrimidine as an off-white solid. LCMS (m/z): 285.0 (MH+), 1H NMR (CDCl3): δ 5.86 (s, 1H), 3.71-3.76 (m, 12H), 3.52-3.56 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1>>[ClH:2].[C:11]1([CH3:15])[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:10]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Cc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: Cc1cccc(-c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)c1
Yield: 70.5 %

Procedure:
Following General Procedure A2, 4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.048 g, 0.32 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.075 g, 99%) as a tan solid. MW=393.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.93 (s, 1H), 9.79 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.39-7.33 (m, 4H), 6.96 (s, 1H), 6.91 (s, 1H), 3.42 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 2.24 (quin, J=7.6 Hz, 2H); APCI MS m/z 358 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.NN.[CH3:10][O:11][C:12](=[O:31])[CH2:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:17]=1)[NH2:15].[O-:32][C:33]#[N:34].[Na+]>C1(C)C=CC=CC=1>[NH2:34][C:33]([NH:15][N:14]([CH2:13][C:12]([O:11][CH3:10])=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:17]=1)=[O:32]
Reactant: COC(=O)CN(N)c1cccc(OCc2ccc(F)cc2)c1
Reactant: N#C[O-]
Agent: NN
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cccc(OCc2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.75 ml, 35.8 mmol) was added at 25° to a stirred suspension of the hydrazine (Intermediate 79, 3.7 g, 12.2 mmol) and sodium cyanate (2.71 g, 41.75 mmol) in toluene (70 ml). The mixture was stirred at 25° for 1 h, during which time a white solid precipitated. 8% sodium bicarbonate (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were then washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to a yellow oil. Trituration with hexane/ether/ethyl acetate (1:1:4) gave the title compound (Intermediate 80) as a white crystalline solid (2.9 g; 68%) m.p. 119°-121°.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(#N)C.[F:20][C:21]1[CH:22]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:55][C:54]3[CH:56]=[CH:57][CH:58]=[CH:59][C:53]=3[NH:52]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](N3C(C)=CC(C)=N3)=[NH:43])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1>C(OCC)(=O)C>[F:27][C:25]1[CH:24]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:52][C:53]3[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=3[NH:55]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](=[NH:43])[N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:2][CH2:3]3)(=[O:39])=[O:40])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2cccc(C(=O)C(C(=O)c3cc(F)cc(F)c3)=C3Nc4ccccc4N3)c2)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 30.5 %

Procedure:
At 0° C., benzyl piperazine-1-carboxylate (1.37 g) was added to an acetonitrile (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-3,5-dimethyl-1H-pyrazole-1-carboximidamide (205 mg), and heated under reflux for 3 days. After cooling, ethyl acetate was added, then washed with aqueous saturated ammonium chloride solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/4) to obtain benzyl 4-[[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)methyl]piperazine-1-carboxylate (76 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and quinolin-6-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C21H21NO5 [M+H]+: 368.3.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)[N:3]=[CH:2]1.[ClH:18].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:42][CH:43]1[CH2:50][CH:49]2[N:51]([CH3:52])[CH:45]([CH2:46][CH2:47][CH2:48]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[ClH:18].[CH3:52][N:51]1[CH:45]2[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH:43]([NH:42][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:10][C:9]=13)=[O:17])[CH2:44]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3cscn3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cscn4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (60 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg, 0.48 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (68 mg, 0.30 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.10 mL, 0.73 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (51 mg, 56%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.14 (br s, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.76 (dd, J=8.0, 0.9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.70-4.61 (m, 1H), 3.35-3.28 (m, 2H), 2.75-2.66 (m, 2H), 2.68 (s, 3H), 2.40-2.30 (m, 1H), 2.24-2.12 (m, 2H), 1.97-1.85 (m, 2H), 1.70-1.61 (m, 1H), 1.50-1.41 (m, 2H); MS (ESI+) m/z 383 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7](C(OC)=O)[N:6]1[CH2:18][CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)=[O:4].Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]2[C:21](=[O:23])[NH:20][CH2:19][CH2:18][N:6]12)=[O:4]
Reactant: COC(=O)C1c2ccccc2C(C(=O)OC)N1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1c2ccccc2C2C(=O)NCCN21

Procedure:
A mixture of 1,3-dihydro-2-[2-[N-(1,1-dimethylethoxycarbonyl)amino]ethyl]-2H-isoindole-1,3-dicarboxylic acid dimethyl ester (1.5 g, described in Example 23), 25% hydrochloric acid (3 ml) and ethyl acetate (30 ml) is refluxed for 2 hr and evaporated. Water (20 ml) is added and the solution is extracted with chloroform. The chloroform extract is evaporated and the residue is chromatographed on silica gel using methanol-chloroform (1:49). The eluate is evaporated and the residue (0.45 g) is crystallized from dichloromethane-hexane to obtain the title compound, mp 165°-167° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[NH:6][CH:7]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+]>O.C1COCC1>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[N:6]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:7]=1
Reactant: Cc1nc(CO)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CO)nc2C)cc1
Yield: 30 %

Procedure:
4-Hydroxymethyl-2-methylimidazole (0.7 g, 6.25 mmol), prepared as in Example 180A, and p-toluenesulfonylchloride (1.2 g, 6.25 mmol) were suspended in 5 mL of distilled water and 3 mL of THF. Sodium hydroxide (1N) was added to maintain a pH of 9 over a period of 3 hours. The reaction mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried over magnesium sulfate, concentrated and crystallized from ethyl acetate, collected by vacuum filtration and dried to give 4-hydroxymethyl-2-methyl-1-p-toluenesulfonylimidazole (0.5 g, 35%) as a white solid; m.p. 140-143°; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 8.25 2H), 7.36 (d, J=8.25 Hz, 2H), 7.33 (s, 1H), 4.49 (s, 2H), 2.50 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.38, 140.96, 134.85, 130.51, 127.57, 116.05, 57.37, 21.84, 15.02; MS m/e calc'd: 266.0725, found: 266.0714.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:30][NH2:31].Cl>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([NH:31][CH3:30])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Agent: Cl
Product: CNC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and methylamine;hydrochloride as starting materials and isolated (5.9 mg, 16%); MS (ESI, m/z): 428.4 (M+H+).