Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=2)[C:29](I)=[C:28]1[C:38]([N:40]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:41][CH2:42][CH:43]=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:39])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:53]([O:52][C:50]([N:40]1[CH2:41][CH2:42][C:43](=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:28]=2[C:38]1=[O:39])=[O:51])([CH3:55])([CH3:56])[CH3:54]
Reactant: CCOC(=O)C=CCCN(C(=O)OC(C)(C)C)C(=O)c1c(I)c2cc(F)ccc2n1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C(=O)c2c1c1cc(F)ccc1n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of triphenylphosphine (3.36 g, 12.8 mmol), Pd(OAc)2 (1.44 g, 6.40 mmol) and Ag2CO3 (3.53 g, 12.8 mmol) in anhydrous THF (100 mL) is stirred at room temperature for 15 minutes. A solution of 2-[tert-butoxycarbonyl-(4-ethoxycarbonyl-but-3-enyl)-aminocarbonyl]-5-fluoro-3-iodo-indole-1-carboxylic acid tert-butyl ester (4.03 g, 6.40 mmol), prepared as in reference 15, in THF (10 mL) is added to the above prepared suspension. The mixture is heated at 60° C. for 16 hours. The inorganic precipitate is removed and the organic layer is concentrated. The residue is purified by silica gel column chromatography and eluted with EtOAc-Hexanes to give the 5-ethoxycarbonylmethylene-7-fluoro-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylic acid di-tert-butyl ester; 1H NMR (CDCl3) δ 1.34 (t, 3H, J=7.6 Hz), 1.57 (s, 9H), 1.60 (s, 9H), 3.46-3.52 (m, 2H), 4.13 (t, 2H, J=4.8 Hz), 4.24 (q, 2H, J=7.6 Hz), 6.30 (t, 1H, J=2.8 Hz), 7.21 (td, 1H, J1=2.8 Hz, J2=9.2 Hz), 7.42 (dd, 1H, J1=2.8 Hz, J2=8.8 Hz), 8.10 (dd, 1H, J1=4.0 Hz, J2=9.2 Hz); m/z [M++Na] 525.0.
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[CH:10]/[C@H:11]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19](C)[CH2:18][CH2:17][CH2:16][C@H:14]3O[C@H:13]3[CH2:12]2)[N:5]=1.[CH3:36]C1OC=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)CCCC(C)=CC2)\C)N=1>CO>[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:11]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[CH2:19][CH2:18][CH2:17][CH2:16][CH:14]=[CH:13][CH2:12]2)\[CH3:36])[N:5]=1
Reactant: CC1=CC[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Reactant: Cc1nc(/C=C/[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\CCCC[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: [Br-]
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCCC[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]D22−75.6 (c 1.0, MeOH); UV (MeOH) λmax nm (ε) 212 (17200), 248 (12500); IR (KBr) νmax 3434, 2974, 2932, 2859, 1735, 1686, 1252, 1046 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.96 (1H, s, H-19), 6.60 (1H, bs, H-17), 5.43 (1H, m, H-12), 5.40 (1H, m, H-13), 5.26 (1H, dd, J=9.6, 2.3 Hz, H-15), 4.41 (1H, ddd, J=11.4, 5.8, 2.5 Hz, H-3), 3.78 (1H, m, H-7), 3.70 (1H, bs, 3-OH), 3.46 (1H, d, J=0.9 Hz, 7-OH), 3.01 (1H, dq, J=0.5, 7.0 Hz, H-6), 2.69 (3H, s, H-21), 2.66 (1H, ddd, J=15.3, 9.6, 8.8 Hz, H-14a), 2.47 (1H, dd, J=14.5, 11.4 Hz, H-2a), 2.29 (1H, m, H-14b), 2.25 (1H, dd, J=14.5, 2.5 Hz, H-2b), 2.24 (1H, m, H-11a), 2.07 (3H, d, J=1.4 Hz, H-27), 1.96 (1H, m, H-11b), 1.51 (2H, m, H-8), 1.44 (2H, m, H-10), 1.37 (2H, m, H-9), 1.32 (3H, s, H-23), 1.17 (3H, d, J=7.0 Hz, H-24), 1.07 (3H, s, H-22); 13C NMR see Table 1; EIMS m/z 463 [M]+ (7), 276 (15), 171 (33), 168 (100), 164 (23), 151 (22), 111 (13); HREIMS m/z 463.2373 (calcd. for C25H37NO5S, 463.2392).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[O:17]=[C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:22])[N:16]1[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Under argon, a solution of 4-(2-hydroxy-ethyl)-benzonitrile [Helv. Chim. Acta 64 (1981) 1688-1703] (4.49 g, 30.5 mmol), phthalimide (4.94 g, 33.55 mmol), triphenylphosphine (8.8 g, 33.55 mmol) and dimethyl formamide (100 mL) was stirred at 0° C. for 20 minutes, then diethyl azodicarboxylate (7.59 mL, 48.8 mmol) was added dropwise at 0° C. The so obtained reaction mixture was stirred at room temperature overnight, then poured into ice-water (740 mL). The precipitated product was filtered off, washed with water and dried. The crude product was recrystallized from 2-propanol to yield 7.83 g (93%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)(O)[O-:16].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCCCc1ccc2nc(Br)sc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC(=O)c1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Step-3: To a solution of 2-bromo-6-butylbenzo[d]thiazole in acetic acid at 0° C. was added CrO3 in acetic acid. The reaction mixture was allowed to warm to RT and stirred over 2 days. The reaction was neutralized by aq. sodium bicarbonate and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated, The crude product was purified by preparative TLC to afford 1-(2-bromobenzo[d]thiazol-6-yl)butan-1-one. MS (ESI+) m/z 286.2 [M+2]+
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=2)=[CH:10][C:9]([F:37])=[CH:8][C:7]=1[N:38]1[CH2:49][CH2:48][N:47]2[C:40](=[CH:41][C:42]3[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=32)[C:39]1=[O:52])(=O)C.O.[Li+].[OH-]>C1COCC1>[F:37][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][O:33][CH2:34]5)[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:50])([CH3:51])[CH2:45][C:46]=43)[C:39]2=[O:52])[CH:8]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(F)cc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Yield: 53.5 %

Procedure:
To a solution of (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methyl acetate (200 mg, 0.28 mmol) in THF/iPA/H2O (6 mL/6 mL/2 mL) at room temperature was added LiOH (70 mg, 2.9 mmol) while stirring. This mixture was stirred for 0.5 h. Then, 20 mL H2O was added and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried with Na2SO4 and concentrated to give a yellow solid which was further purified by prep-HPLC to afford 304 as a white solid (100 mg, 53%). LCMS: [M+H]+ 668. 1H NMR (500 MHz, DMSO): δ 1.23 (s, 6H), 2.37-2.39 (m, 5H), 2.53-2.57 (m, 2H), 3.07 (s, 4H), 3.43-3.45 (m, 2H), 3.60 (s, 3H), 3.85-3.87 (m, 1H), 4.16-1.19 (m, 3H), 4.32 (d, J=6.0 Hz, 2H), 4.45-4.50 (m, 2H), 4.54-4.58 (m, 2H), 4.86 (s, 1H), 6.47-6.51 (m, 1H), 7.18-7.25 (m, 2H), 7.34-7.39 (m, 3H), 7.83-7.86 (m, 1H), 8.35-8.37 (m, 1H), 8.53-8.56 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]2)[CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[N:16]([CH2:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][CH2:10]2)=[O:23])[N:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3N)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3NC(=O)c3ccccc3)CC2)n1
Reaction time: 60 h
Yield: 100 %

Procedure:
The 1-[4-(2-amino-phenyl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.042 g, 0.136 mmol) is dissolved in 1.5 mL of CH2Cl2. To this is added diisopropylethyl amine (0.046 mL, 0.250 mmol) and benzoyl chloride (0.018 mL, 0.150). The mixture is stirred for 60 h. The reaction is quenched with 2 mL of saturated NH4Cl and extracted in the reaction vial with 2×2 mL of CH2Cl2. The organic phase is concentrated. The residue is purified using a SiO2 prep plate eluting with (75% EtOAc/hexanes) to give 58.1 mg of N-(2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-phenyl)-benzamide in 100% Yield. MS: MH+=418.2.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (197 mg, 0.766 mmol) and pyridine (0.074 mL, 0.919 mmol) in dichloromethane (5 mL) at room temperature was added cyanuric fluoride (0.078 mL, 0.919 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (40 mL) and washed with an ice-cold 0.5N aqueous solution of hydrochloric acid (20 mL). The aqueous layer was extracted with dichloromethane (20 mL), and the combined organic layers were washed with ice-cold water (20 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (199 mg, 0.768 mmol, 100% yield) as a pale yellow oil. The compound had an HPLC retention time=2.53 min. (methyl ester)-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:19])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN1CCNCC1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Product: CN1CCN(C(=O)CCCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC1

Procedure:
Compound 753 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 4-methyl-piperazine using the method described for compound 751. The title compound was isolated as a white powder (0.0508 g, 42% yield). HRMS (M+H) calcd for C22H29N4Cl2O4: 483.1566. found: 483.1581.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[CH:38]=5)[C:33]([CH3:46])=[CH:32][C:31]4=[O:47])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:48].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:48].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[CH:38]=5)[C:33]([CH3:46])=[CH:32][C:31]4=[O:47])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(-c3ccccc3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(-c3ccccc3)ccc12
Reaction time: 0.5 h

Procedure:
To 0.4 mL of methanol solution containing 47 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-2-oxo-7-phenylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.4 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 30 min. 0.8 mL of methanol and 0.8 mL of 4 mol/L hydrogen chloride/ethyl acetate solution were further added, stirred for 2 hours and allowed to stand at room temperature for 13 hours. Ethyl acetate was added, and the resulting solid was filtered to give 34 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-7-phenylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50].Cl[C:52]1[CH:53]=[C:54]([NH:67][C:68]2[CH:77]=[C:71]3[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]3[N:69]=2)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[N:57]=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.O>[CH3:13][C:14]1[C:19]([C:52]2[CH:53]=[C:54]([NH:67][C:68]3[CH:77]=[C:71]4[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]4[N:69]=3)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:63])([CH3:65])[CH3:64])[N:57]=2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(COCC[Si](C)(C)C)c3=O)cc2C1
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: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5 mL), water (1 mL) and sodium carbonate (143 mg, 1.35 mmol). After bubbling nitrogen through the resulting mixture for 30 min, 117c (240 mg, 0.451 mmol), 117e (185 mg, 0.451 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) were added, and the reaction mixture was heated at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and partitioned between water (25 mL) and methylene chloride (50 mL). The organic layer was separated, washed with brine (75 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to a dark oil, which was purified by flash chromatography to afford an 89% yield (315 mg) of 117f as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.88 (s, 1H), 7.66 (d, 1H, J=8.0 Hz), 7.45 (m, 3H), 7.39 (t, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.0 Hz), 7.24 (t, 2H, J=8.0 Hz), 6.12 (d, 1H, J=10.5 Hz), 6.05 (d, 1H, J=10.5 Hz), 5.69 (s, 1H), 5.63 (d, 1H, J=10.5 Hz), 5.52 (d, 1H, J=10.5 Hz), 4.09 (m, 2H), 3.88 (m, 2H), 3.75 (m, 2H), 3.68 (s, 3H), 3.59 (m, 2H), 3.26-3.17 (m, 4H), 2.61 (m, 2H), 2.29 (s, 3H), 0.98 (t, 2H, J=8.0 Hz), 0.85 (t, 2H, J=8.0 Hz), −0.01 (s, 9H), −0.07 (s, 9H); MS (ESI+) m/z 781.4 (M+H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=5[CH:29]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:28][N:24]1[C:23]2[CH:29]=[C:19]3[O:18][CH2:17][C:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[NH:8][C:9]4=[O:30])[C:20]3=[CH:21][C:22]=2[O:26][C:25]1=[O:27]
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (88%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ10.64 (br s, 1H), 7.30-7.22 (m, 1H), 7.09 (d, J=7.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.75 (s, 1H), 4.82 (d, J=9.3 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H), 3.30 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.2, 157.0, 154.5, 141.8, 136.2, 132.8, 132.4, 128.9, 123.8, 122.3, 122.0, 109.9, 104.9, 92.3, 79.8, 57.8, 28.2; MS (ES+) m/z 309.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:13]([S-:15])#[N:14].[K+].BrBr>CC(O)=O>[NH2:14][C:13]1[S:15][C:7]2[CH:6]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 (3.13 g, 1 mmol) in CH3COOH (15 ml) was cooled to −5° in iced bath. A mixture KSCN (6.36 g, 4.04 mmol) in CH3COOH (15 ml) added to the flask that contained 4 and CH3COOH at −5° in iced bath. A solution of bromine (0.80 ml) in CH3COOH (10 ml) is added dropwise to a stirred mixture of 4, KSCN and CH3COOH at −5° in iced bath. The reaction mixture is stirred for 1 h at room temperature. The mixture is extracted with ethyl acetate. The extracts are washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[NH:10]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: C1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 31 %

Procedure:
A mixture-of 1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 1D (168 g, 0.170 mole) and concentrated H2SO4 (500 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting dark brown solution ethanol (500 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (3 l). The white solid was filtered and washed with ethyl ether. The solid was then dissolved in H2O (500 ml) and the resulting solution washed with ethyl ether. Upon reducing the volume of the solution in vacuo to 200 ml, the pH was adjusted to 10-11 with 10N NaOH and the solvent was removed in vacuo. Ethanol (500 ml) was then added and removed in vacuo to dryness. The resulting tan oily solid was extracted with hot THF (2×500 ml) and filtered at room temperature. The filtrates were combined and the solvent removed in vacuo to give the crude product as a yellow crystalline solid which was then redissolved in CH3CN and filtered to remove insoluble impurities. Recrystallization from cold (-20° C.) CH3CN gave 11.3 g (31% yield) of the product as colorless needles: mp 108°-9° C.; 1H NMR (CDCl3) δ1.74 (br s, 5 H), 2.73 (s, 20 H); Exact mass (M+Li)+ : calcd, 222.2270; Found, 222.2269 (C10H25N5Li).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.288 g, 1.14 mmol) was treated with 1.0 M KOtBu in THF (1.10 mL, 1.10 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added as a solid, followed by the addition of DMF (3.3 mL), and the resultant mixture was stirred at ambient temperature for 40 hours. The crude reaction mixture was chromatographed on SiO2 eluting with a gradient of (2% NH4OH in isopropanol)/methylene chloride. The desired product was isolated as a pale yellow solid (196 mg). MS APCI (+) m/z 498.2 (M+1) detected.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]([NH2:16])=[S:15].II.[OH-].[Na+]>O>[CH:1]1([CH2:7][CH2:8][C:9]2[S:15][C:14]([NH2:16])=[N:13][C:10]=2[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(N)=S
Reactant: CC(=O)CCCC1CCCCC1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)sc1CCC1CCCCC1
Reaction time: 23 h
Yield: 36.8 %

Procedure:
A mixture of 22.2 g of 5-cyclohexyl-2-pentanone, 20.10 g of thiourea, and 33.48 g of iodine was stirred for 23 hours at a bath temperature of from 100° to 120° C. To the mixture was added 150 ml of water, followed by refluxing for 30 minutes. After cooling, an aqueous sodium hydroxide solution was added to neutralize. The mixture was extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography. Recrystallization from aqueous methanol yielded 10.9 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH3:16]>>[NH2:1][C:2]1[C:3]([C:8]([N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH3:16])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCOC
Reactant: Nc1cccnc1C(=O)O
Product: COCCN(C)C(=O)c1ncccc1N
Yield: 85 %

Procedure:
According to the procedure described in example 29, 3-aminopicolinic acid was reacted with 2-methoxy-N-methylethanamine to give the title compound (85%) as colourless viscous oil.