Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([C:19]([CH2:21][C:22](OCC)=[O:23])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)=[CH:21][C:22](=[O:23])[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: O=c1cc(-c2cccc3ccccc23)c2ccc(O)cc2o1
Temperature: 0 °C

Procedure:
A solution of resorcinol (4.84 g., 0.041 moles) and ethyl 1-naphthoylacetate (10 g., 0.041 moles) in ethanol (50 ml.) was saturated with hydrogen chloride at room temperature (cooling with ice/water) and left to stand in s stoppered flask for 24 hours. The solution was filtered to give the required coumarin as an orange solid (7.8 g., 66%, m.p. 292°-295° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[C@H:47]([OH:48])[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[C:59](O)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCCC1>[C:59]([O:48][C@H:47]1[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43][C@H:42]1[NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
To a solution of triphenylphosphine (5.83 g, 22.24 mmol) in tetrahydrofuran (THF) (60 mL) was added DIAD (4.38 mL, 22.24 mmol) and the mixture was stirred in an ice-water bath for 15 min and then allowed to warm to rt. To the suspension was added a suspension of trans-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (6.495 g, 18.54 mmol) in tetrahydrofuran (THF) (75 mL) followed by benzoic acid (2.72 g, 22.24 mmol). The reaction mixture cleared to a yellow solution and was stirred for 2 h. LCMS analysis showed product formation, however the SM peak was obscured by by-product so it was difficult to confirm reaction had gone to completion. The reaction was left to stir overnight (20 h). The reaction mixture was concentrated under vacuum. The residue was purified by silica chromotagraphy. The residue was loaded in DCM on a 340 g silica cartridge and purified using a 0-40% EtOAc/cyclohexane gradient. The appropriate fractions were combined and the evaporated in vacuo to give the crude product cis-benzyl 4-(benzoyloxy)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (8.11 g, 17.84 mmol, 96% yield) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[P:8]([OH:11])([OH:10])[OH:9].P(Cl)(Cl)Cl>CCCCCCCC>[CH2:3]([CH2:2][NH2:1])[CH2:4][C:5]([P:8]([OH:11])([OH:10])=[O:9])([P:8]([OH:11])([OH:10])=[O:9])[OH:7]
Reactant: OP(O)O
Reactant: NCCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: CCCCCCCC
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 43.1 %

Procedure:
4-Aminobutyric acid (50 gm), phosphorous acid (140 gm) and n-octane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (240 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and ethanol (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered and washed with ethanol and dried under vacuum to yield 52.0 gm product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:22]([O-])([OH:24])=[O:23].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(C(=O)Cc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A heterogeneous mixture of 2-(3,4-dichloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ethanone (8.33 g, 25.6 mmol) in acetic anhydride (65 ml) was added dropwise to a cooled (0° C.) solution of 65% nitric acid (140 ml) and acetic anhydride (21.3 ml). The resulting mixture was stirred at 0° C. for 2 h. Water was added dropwise and the resulting heterogeneous mixture was allowed to stir and warm-up slowly. The crude was then filtered and the beige solid was washed several times with distilled water and dried under HV (6.98 g, 74%).
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9]OC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].CN1CN=C(S)S1.Cl.NC1C(=O)N2C(C(O)=O)=C(CSC3SC(C)=NN=3)CS[C@H]12.[CH3:53][N:54]1[C:58]([SH:59])=[N:57][N:56]=[N:55]1>O.CC(C)=O>[NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][S:59][C:58]3[N:54]([CH3:53])[N:55]=[N:56][N:57]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CN1CN=C(S)S1
Agent: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 10.5 h

Procedure:
To a stirred suspension of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid (13.5 g., 0.05 mole) in water (100 ml.) and acetone (50 ml.) was added a solution of sodium bicarbonate (9.45 g., 0.113 mole) in water (50 ml.). When a homogeneous solution was obtained, 2-methyl-1,2,4-thiadiazole-5-thiol(10 g., 0.075 mole) was added and the mixture heated at 40°-50° under nitrogen while the pH was adjusted to 7.6 by the addition of a solution of 3N HCl. The pH was maintained at 7.6 and the course of the reaction was followed by removing 0.3 ml. aliquots, adjusting the pH to 3 with 1NHCl, filtering the precipitate, washing it with acetone and then ether and examining it by infra red for the disappearance of the carbonyl absorption. The reaction was complete after 10.5 hours and the whole reaction was worked in the same way as described above for the aliquots. There was thus obtained 7-amino-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid. In a similar manner, but using an equivalent amount of 1-methyl-1H-tetrazole-5-thiol in place of 2-methyl-1,2,4-thiadiazole- 5-thiol, but making the initial adjustment of pH to 7.6 with sodium bicarbonate, and carrying out the reaction for 5 hours under reflux, there was obtained 7-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[CH:37]=[N:38][CH:39]=[N:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:33]=[C:34](/[C:36]3[CH:37]=[N:38][CH:39]=[N:40][CH:41]=3)\[CH3:35])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1cncnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cncnc1
Temperature: 85 °C

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in DMF (3 mL), potassium phosphate (212 mg, 1 mmol), copper(I) iodide (9 mg, 0.05 mmol) and L-proline (11 mg, 0.1 mmol) was added. 5-(1-Bromoprop-1-en-2-yl)pyrimidine (98 mg, 0.5 mmol) was dissolved in DMF (2 mL) and added dropwise. Nitrogen was purged for 2 min. and the reaction mixture was heated at 85° C. overnight (prolonged heating was required in some cases). DMF was evaporated under reduced pressure and water was added to the residue obtained. Compound was extracted with EtOAc (3×25 mL), the organic layer was washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. Yield: 7 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.18 (s, 1H), 9.08 (s, 2H), 7.35 (s, 1H), 7.24 (s, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 4.78 (m, 1H), 3.30 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:27][C:28]([C:30]2[N:34]3[CH:35]=[CH:36][C:37]([CH2:39][CH:40]=O)=[CH:38][C:33]3=[N:32][CH:31]=2)=[O:29])[N:20]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[N:19]=1)[CH3:17]>C(Cl)Cl.C(O)(=O)C>[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:27][C:28]([C:30]2[N:34]3[CH:35]=[CH:36][C:37]([CH2:39][CH2:40][N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)=[CH:38][C:33]3=[N:32][CH:31]=2)=[O:29])[N:20]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[N:19]=1)[CH3:17]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Reactant: FC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC(F)C5)ccn34)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-fluoroazetidine hydrochloride (61 mg, 0.55 mmol) in DCM (2 mL) was treated at ambient temperature with Hunig's base (0.10 mL, 0.57 mmol). To the hazy solution was added N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (prepared according to (Example 127, Steps A-B; 50 mg, 0.11 mmol) (prepared according to the procedure for Example 127) and the (10 equivalents) was added, followed by 2 drops of glacial acetic acid, and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative thin-layer chromatography on silica, with a 10% MeOH-DCM mixture as eluent to afford the desired product (10 mg) as a white solid. MS (ES+APCI) m/z=512 (M+H) detected.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:38]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:50]2[CH:51]=[CH:52][C:47]([B:38]3[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]3)=[CH:48][CH:49]=2)=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Placed (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((perfluorobutyl)sulfonyl)oxy)phenyl)propanoate (800 mg, 1.385 mmol), 1,4-benzenediboronic acid bis(pinacol) ester (1372 mg, 4.16 mmol), palladium acetate (16 mg, 0.071 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (57 mg, 0.139 mmol), and tribasic potassium phosphate (882 mg, 4.16 mmol) under nitrogen in nitrogen flushed toluene (2.0 mL) and water (0.1 mL). The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature and poured into saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 50 g silica gel cartridge eluted with 0-10% methanol in DCM over 20 column volumes. The product fractions were collected and concentrated under reduced pressure. Further purification of the resultant white solid was performed by chromatography using a Biotage™ 25 g silica gel cartridge eluted with 0-20% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined, concentrated under reduced pressure, redissolved in MeCN and water, frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C27H36BNO6 481.26, observed m/e: 482.33 (M+H)+ (Rt 2.65/4 min).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1([C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]=[CH:21][C:20](=[O:23])[O:19]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:18]3([C:24]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:22]=[CH:21][C:20](=[O:23])[O:19]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@H]1CONC1=O
Reactant: O=C1C=CC(Cl)(C(=O)OC(c2ccccc2)c2ccccc2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)C=CC(=O)O2)C1=O
Yield: 71.8 %

Procedure:
In 2.5 ml of dichloromethane suspension of 35 mg of (4S)-4-phenylacetamido-3-isoxazolidinone and 50 mg of diphenylmethyl 2-chloro-5-oxo-2,5-dihydro-2-furancarboxylate obtained in Example 49 was added under ice-cooling and stirring, 0.025 ml of triethylamine. The reaction solution was stirred at room temperature for 30 minutes, which was diluted with ethyl acetate, followed by washed with water and drying (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 56 mg of the subject Compound (51) as colorless crystals. Recryslallization from dichloromethaneethylether afforded colorless prisms, m.p. 168°-169° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]2[CH:17]=1.Cl.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1
Reactant: Clc1ccc(-c2cn3ccccc3n2)c(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Yield: 26.3 %

Procedure:
To 4.5 g (17.1 mmol) of the above 2-(2,4-dichlorophenyl)-imidazo[1,2-a]pyridine in a Paar bottle, 100 ml of ethanol, 1.5 ml of concentrated hydrochloric acid, and 0.4 g of platinum oxide were added. This mixture was placed on a Paar hydrogenator at 45 psi of hydrogen at room temperature for 15 minutes. Thin layer chromatography revealed that the reaction was complete. The mixture was filtered through celite and washed with 300 ml of ethyl acetate. To the filtrate, excess saturated aqueous sodium bicarbonate was slowly added. The ethyl acetate layer was separated, washed with saturated brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo gave a solid residue to which n-butyl chloride was added. The solid was filtered, washed with n-butyl chloride, and dried to give 1.2 g of the title compound (m.p. 134-136° C.). The filtrate was also concentrated in vacuo to give a sludge which on silica gel chromatography (5:1 followed by 3:1 followed in turn by 1:1 hexane/ethyl acetate) afforded another 2.1 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:13][CH3:14])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C#Cc1ccccc1OC
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccccc1OC)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 80 %

Procedure:
The title compound was synthesized from (2-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 80% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.45 (m, 1H), 7.28-6.95 (m, 4H), 6.85-6.60 (m, 4H), 6.49 (m, 2H), 6.25 (s, 1H), 4.39 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 3.68 (s, 2H), 3.58 (s, 1H), 3.80 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 1.89 (m, 2H), 1.50 (s, 9H), 1.25 (t, 3H, J=6.8 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+H); found 498.4.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:15][CH2:14][CH2:13][N:12]([CH3:32])[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2].CCOCC>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][C:25]([OH:27])=[O:26])[CH2:15][CH2:14][CH2:13][N:12]([CH3:32])[CH2:11][CH2:10]1)([OH:3])=[O:2]
Reactant: CN1CCCN(CC(=O)OC(C)(C)C)CCN(C)CCCN(CC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCCN(CC(=O)O)CCN(C)CCCN(CC(=O)O)CC1
Yield: 99.2 %

Procedure:
Compound (33) (1.46 g, 3.19 mmol) was dissolved in a mixture of CF3CO2H (TFA) and CH2Cl2 (1:1 (v/v), 50 ml). The resultant mixture was stirred at an ambient temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (34) (1.09 g, 99% yield). HRMS (FAB) calculated for C16H33N4O4: 345.2502 [(M+H)+], measured value: 345.2506 [(M+H)+].
Reaction SMILES: [Si](OO[CH2:10][C@H:11]1O[C@@H:14]([N:16]2[CH:23]=[C:22](CBr)[C:20](=O)[NH:19][C:17]2=O)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[Cu].[Cu:27]([I:29])[I:28].[F:30][C:31]([F:42])([F:41])[C:32]([NH:34][CH2:35][CH2:36][O:37][CH2:38][C:39]#[CH:40])=[O:33].CCCCCCC=CCCC.[Si](OOC[C@H]1O[C@@H](N2C=C(CC#CCOCCNC(=O)C(F)(F)F)C(=O)NC2=O)CC1)(C(C)(C)C)(C)C.[C-]#[C-]>>[Cu:27]([I:29])[I:28].[F:30][C:31]([F:41])([F:42])[C:32]([NH:34][CH2:35][CH2:36][O:37][CH2:38][C:39]#[CH:40])=[O:33].[CH2:12]1[CH2:13][CH2:14][N:16]2[C:17](=[N:19][CH2:20][CH2:22][CH2:23]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CBr)c(=O)[nH]c2=O)O1
Agent: I[Cu]I
Agent: [Cu]
Agent: C#CCOCCNC(=O)C(F)(F)F
Product: C1CCC2=NCCCN2CC1

Procedure:
Next, 5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′-dideoxyuridine (3) can be coupled with an alkyne, in this case 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, to form the 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4). It will be readily appreciated by one of skill in the art that the coupling of an alkyl halide with an alkyne can be carried out by a number of methods known in the art. Without being limiting in any way, one example of such a method known in the art is the so-called Castro-Stephens coupling, see for example, White, J. D., et. al. J. Am. Chem. Soc., 123(23), 5407-5413 (2001) and Stephens, R. D., et. al. J. Org. Chem., 28, 3313 (1963). For example, as shown in Scheme 1,5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′ dideoxyuridine (3) can be contacted with a mixture comprising a copper reagent, for example copper iodide (CuI), an alkyne, for example 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and a base, for example 1,8-diazobicyloclo[5.4.0]undec-7-ene (DBU), to form 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4), where an acetylide anion is formed in the mixture comprising CuI, 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and DBU.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>C(OCC)C.C(=O)=O.CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h
Yield: 112.6 %

Procedure:
N-Boc-4-piperidone (Boc-29.155) (200 mg, 11.0 mmol) was dissolved in 5 ml of anhydrous ethyl ether, cooled in dry ice/acetone bath. 2-Tolylmagnesium bromide (550 μl, 2M in ethyl ether, 1.1 mmol) was added dropwise over 5 min. White precipitate was formed. After 5 h, remove the dry ice/acetone bath and rise to room temperature gradually. After 2 h, cooled in ice bath, 8 ml of saturated NH4Cl and 2 ml of H2O were added. The organic phase was separated and aqueous phase was extracted with 4×10 ml of Et2O. Combined with organic phase and washed with 8 ml of H2O and 10 ml of brine, dried over MgSO4. Concentrated and dried to obtain 361 mg of colorless oil. Separated by silica gel to obtain 4f (229.7 mg, 79% yield) as colorless oil. 1H NMR (CDCl3, 200 MHz) δ 1.47 (s, 9H), 1.93 (m, 4H), 2.60 (s, 3H), 3.27 (t, 2H, J=13.0 Hz), 3.96 (d, 2H, J=12.2 Hz), 7.15 (m, 3H), 7.35 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CC(C)([O-])C.[Na+].C1(C)C(C)=CC=CC=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[C:36]1([NH:35][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Nc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(Nc2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 7.5 h
Yield: 74.8 %

Procedure:
After putting 19 g (60 mmol) of 3-bromo-9-phenylcarbazole, 340 mg (0.6 mmol) of bis(dibenzylideneacetone)palladium(0), 1.6 g (3.0 mmol) of 1,1-bis(diphenylphosphino)ferrocene, and 13 g (180 mmol) of sodium tert-butoxide into a three-neck flask and replacing the air in the flask with nitrogen, 110 mL of anhydrous xylene and 7.0 g (75 mmol) of aniline were added. This was stirred for 7.5 hours while heating at 90° C. in a nitrogen atmosphere. After the reaction, about 500 mL of hot toluene was added to the suspension and the mixture was filtered through florisil, alumina, and Celite®. The obtained filtrate was concentrated and hexane-ethyl acetate was added thereto, and then the mixture was irradiated with ultrasonic waves. The obtained suspension was filtered and the residue was dried, thereby obtaining 15 g (yield: 75%) of 3-(N-phenylamino)-9-phenylcarbazole (abbr.: PCA) as a cream-colored powder.