Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Cn1cncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cncn2C)CCN(C)C1
Temperature: 120 °C
Yield: 8.5 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (166 mg, 0.74 mmol), 5-bromo-1-methyl-1H-imidazole (100 mg, 0.62 mmol), dichlorobistriphenyl phosphinepalladium (II) (13 mg, 0.018 mmol) and TBAF.3H2O (586 mg, 1.86 mmol) was heated at 80° C. (observed exothermic temperature was 120° C.) for 5 min by microwave. After completion of reaction (monitored by TLC&LCMS), the mixture was poured into water (20 mL) and saturated bicarbonate was added. The mixture was extracted with EtOAc (3×20 mL), the organic layer was washed with water (2×20 mL), dried over sodium sulfate and concentrated under vacuum to obtain 16 mg of 2,8-dimethyl-5-(3-methyl-3H-imidazol-4-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 7.56 (s, 1H), 7.38 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 2.92 (m, 4H), 2.60 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[CH:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH:23]=[O:24])[CH:26]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(C=O)c2)cc1OC
Yield: 90.6 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol), and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:18])[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[C:41]3[CH:40]=[N:39][CH:38]=[N:37][C:36]=3[N:35](S(C3C=CC(C)=CC=3)(=O)=O)[CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>O1CCOCC1.O>[C:19]1([C:4]2[N:3]=[C:2]([C:33]3[C:41]4[CH:40]=[N:39][CH:38]=[N:37][C:36]=4[NH:35][CH:34]=3)[N:7]=[C:6]([NH:8][CH:9]([CH3:18])[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cncnc32)cc1
Reactant: CC(Nc1cc(-c2ccccc2)nc(Cl)n1)C(=O)NCC(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Nc1cc(-c2ccccc2)nc(-c2c[nH]c3ncncc23)n1)C(=O)NCC(F)(F)F
Temperature: 60 °C

Procedure:
As shown in FIG. 3—step i, a mixture of phenylboronic acid (1.22 g), 2,4,6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(0) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80° C. overnight. After cooling to rt, addition of water (30 mL), extraction with dichloromethane (3×20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in FIG. 3—step ii, compound 1012 (0.34 g) was mixed with (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80° C. overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-N-(2,2,2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in FIG. 3—step iii, compound 1013 (29 mg), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1,4-dioxane (2 mL) at 80° C. overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 60° C. for 1 h, water (20 mL) was added. Extraction with dichloromethane (3×), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide (compound 18).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.[Cu](I)I>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isatin (0.12 g, 0.81 mmol) in anhydrous DMF (30 mL) was cooled in an ice-bath under nitrogen and treated with sodium hydride (21 mg, 1.1 equivalents). The reaction was stirred in ice for 0.5 hours and then warmed to room temperature. This solution was then treated with 4-(3-bromophenyl)phenol benzyl ether (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818–5827), (0.16 g, 0.47 mmol) followed by copper iodide (0.32 g, 1.68 mmol). The reaction was heated in an oil-bath at 140° C. After ˜16 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (˜75 mL) and filtered. The filtrate was concentrated under reduced pressure to afford a sticky, brown solid which was purified by preparative TLC on silica gel using 25% ethyl acetate in hexanes as the developing solvent. Rf (product)=0.38. Yield=47 mg (25%); MALDI-TOF MS 407.02 obs. (405.5 calc.); 1H-NMR (CDCl3) 5.12 (s, 2H), 6.95 (d, 1H, J=8 Hz), 7.06 (d, 2H, J=8.8 Hz), 7.18 (t, 1H, J=7.5 Hz), 7.33–7.47 (m, 7H), 7.53 (d, 2H, J=8.8 Hz), 7.57–7.60 (m, 2H), 7.71 (d, 1H, J=7.5 Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:46])[F:47])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 83 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at room temperature overnight. Dilute the mixture with 5 mL of Methanol and add sodium borohydride (0.8 mmol). Stir the suspension at room temperature for 30 min then dilute with water (20 mL) and ethyl acetate (20 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×20 mL). Separate the organics, dry over sodium sulfate, and filter. Remove the solvent under vacuum to afford (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate crude (0.2 g, MS (ES+): 557 (M+H)). Without further purification, add acetyl chloride (0.8 mmol) and pyridine (0.8 mmol) to a solution of (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in dichloromethane. After stirring for 2 h remove solvent under vacuum and chromatograph over silica gel using ethyl acetate/hexane (5-40%) to elute. This affords the title compound as an oil (0.2 g, 83%) which foams under vacuum: MS (ES−): 597 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[N:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([C:31]2([C:34]#[N:35])[CH2:33][CH2:32]2)=[O:30])[CH2:24]1)(=[O:3])[NH2:2].C[CH2:37][N:38](C(C)C)[CH:39](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C>[C:34]([C:31]1([C:29]([N:25]2[CH2:26][C@H:27]([CH3:28])[C@H:23]([NH:22][C:5]3[C:6]4[N:7]([CH:10]=[C:11]([C:13]5[CH:18]=[N:17][C:16]([C:19](=[O:21])[N:38]([CH3:39])[CH3:37])=[CH:15][CH:14]=5)[CH:12]=4)[N:8]=[CH:9][C:4]=3[C:1]([NH2:2])=[O:3])[CH2:24]2)=[O:30])[CH2:32][CH2:33]1)#[N:35]
Reactant: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)O)nc3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)N(C)C)nc3)cc12
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To solution of 5-(3-carbamoyl-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazin-6-yl)picolinic acid (15 mg, 0.026 mmol), DIPEA (0.018 mL, 0.102 mmol) and BOP (16.94 mg, 0.038 mmol) in DMF (0.3 mL) was added a 2 M solution of dimethylamine in THF (0.026 mL, 0.051 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated to remove the THF and was purified by preparative LC/MS with the following conditions: column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 7.2 mg of the title compound. LCMS (method H) retention time=1.78 min. (MH+501.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 9.06 (dd, J=7.9, 1.5 Hz, 1H), 8.40-8.29 (m, 2H), 8.22 (dd, J=11.1, 1.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.47-7.34 (m, 1H), 5.28-5.04 (m, 1H), 4.58-4.42 (m, 2H), 4.13-3.87 (m, 2H), 3.64-3.52 (m, 1H), 3.34-3.26 (m, 6H), 3.09-2.89 (m, 1H), 2.01-1.83 (m, 1H), 1.80-1.59 (m, 3H), 1.51-1.35 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[CH:12]\[C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH:27]([F:28])[F:29])=[CH:21][CH:20]=2)[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(OC(F)F)c(=O)[nH]2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(OC(F)F)c(=O)[nH]2)cc1

Procedure:
An (R,S) mixture of the title compound was obtained by performing substantially the same reaction as in Examples 4-207 and 4-208(2) except for using 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(difluoromethoxy)pyridin-2(1H)-one obtained in Example 4-165. This was preparatively isolated by a chiral HPLC column (CHIRALCEL OD-H, hexane:ethanol=50:50 v/v, 40° C., 7.0 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (20 mg) and the other diastereomer (B) of the title compound as a colorless powder (24 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34][CH3:35])[O:27]2)=[C:19]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.C(O)(=O)C.[C:49]1(=O)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([NH:15][CH2:16][C:17]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@H:26]3[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34][CH3:35])[O:27]3)=[C:19]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
Sodium triacetoxyborohydride (154 mg, 0.72 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (200 mg, 0.48 mmol) (preparation 48), acetic acid (30 mg, 0.48 mmol) and cyclohexanone (45 mg, 0.46 mmol). The reaction mixture was stirred for 24 hr at room temperature and the solvent then removed under reduced pressure. The residue was then azeotroped with dichloromethane before purification by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (93:7:0.3) to give the title compound (110 mg) as a viscous oil. MS: 497 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([NH2:14])=[O:13])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)[C@@H](O)CC(N)=O

Procedure:
Meanwhile, a mixture of 137 mg. (0.5 mmole) of (3S,4S)-4-t-butoxycarbonylamino-3-hydroxy-6-methylheptanoic acid amide and 5 ml. of 6N hydrochoric acid in dioxane was stirred under a nitrogen atmosphere for 20 minutes and then evaporated under reduced pressure to dryness. The residue was dissolved in 2 ml. of dimethylformamide and 0.05 g. of N-methylmorpholine was then added to form a solution of (3S,4S)-4-amino-3-hydroxy-6-methylheptanamide.
Reaction SMILES: C(O)C.NC1CC2NC3C=CC(C#N)=CC=3C=2C1.[NH:19]1[C:23](=[O:24])[CH2:22][CH2:21][C@@H:20]1[C:25]([OH:27])=[O:26]>O>[NH:19]1[C:23](=[O:24])[CH2:22][CH2:21][C@H:20]1[C:25]([OH:27])=[O:26]
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: N#Cc1ccc2[nH]c3c(c2c1)CC(N)C3
Solvent: CCO
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)N1
Temperature: 62.5 °C
Yield: 92779.8 %

Procedure:
In a 2 L flask equipped with mechanical stirrer and condenser, add ethanol (945 ml) and (±)-2-amino-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (40 g, 0.203 mmol). Stir the mixture and heat to 60-65° C. until complete solution is achieved. Add D-pyroglutamic acid (28.4 g, 0.192 mmol) and water (55 ml). Heat the mixture to reflux for 20 min. Cool to 40-45° C. over 90 min. Stir at 40-45° C. for one hour, and then cool to 24° C. over 2 h. Stir at this temperature for two additional hours. Isolate a crystalline solid by filtration and wash with a mixture of EtOH/water (95:5) (3×50 mL). Dry the solid in vacuo at 50° C. overnight to give 23 g pyroglutamic acid salt.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+].[N-]=[N+]=[N-].[Li+]>CN(C)C=O>[N:29]([CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 85 °C
Yield: 90.2 %

Procedure:
A mixture of 5-ethyl-5'-O-tosyl-2'-deoxyuridine (550 mg, 1.34 mmole) and sodium azide (480 mg, 7.4 mmole) or lithium azide (400 mg) in dry dimethylformamide (10 ml) is heated at 85° C. for 2 hr. Tlc indicates all the starting material has reacted. The solvent is evaporated in vacuo to dryness, and the remaining material is triturated with ice-cold water, filtered to collect the product, and dried over P2O5 to give a white solid (340 mg, 90%), m.p. 174°-177° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccoc1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccoc3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was used. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (9) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 3-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Upon usual work-up and purification by flash silica gel chromatography provided 0.110 g (76%) of compound 204 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=6.00 Hz, 2H), 7.11 (d, J=6.00 Hz, 2H), 6.94 (d, J=6.3 Hz, 2H), 6.89 (s, 1H), 6.67 (d, J=6.3 Hz, 2H), 2.19 (br s, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H). LCMS (ESI): m/z 359 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[CH:16](O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[C:30]([C:36]([O:38][CH3:39])=[O:37])#[C:31][C:32]([O:34][CH3:35])=[O:33].CO>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:16]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:2])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]=2[C:36]([O:38][CH3:39])=[O:37])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O
Reaction time: 8 h
Yield: 68.1 %

Procedure:
49.5 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are dissolved in 5 ml of toluene. 14.2 g of dimethyl acetylenedicarboxylate and 19 mg of p-toluenesulfonic acid monohydrate are added to the solution, and the mixture is refluxed for 3 hours. After cooling the reaction mixture, 200 ml of methanol are added thereto, and the mixture is allowed to stand at -30° C. overnight. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 33.1 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene as colorless prisms.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=O.Cl.[C:33](=[NH:37])([NH2:36])[CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:28]1([C:6]2[C:5]([C:3]3[NH:36][C:33]([CH2:34][CH3:35])=[N:37][CH:2]=3)=[CH:26][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:27])[CH:7]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: CCC(=N)N
Reactant: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ncc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 235.2, 100 mg, 0.210 mmol, 1.00 equiv) in CH3CN (5 mL). Propionimidamide hydrochloride (22.8 mg, 1.00 equiv) and potassium carbonate (86.6 mg, 0.63 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 80° C., then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 20 mL of water. The mixture was extracted with 2×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (˜100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 7 min, up to 100.0% in 3 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 43 mg (44%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d with fine structure, J=7.8 Hz, 2H), 7.56-7.53 (m, 4H), 7.30 and 7.20 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 3.84-3.70 (m, 1H), 3.70-3.53 (m, 1H), 3.33-3.19 (m, 1H partially obscured by methanol solvent peak), 3.13-2.92 (m, 4H), 2.48 & 2.38 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.29-2.11 (m, 4H), 2.11-1.93 (m, 2H), 1.93-1.72 (m, 3H), 1.72-1.53 (m, 1H), 1.45 (t, 3H).