Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH:20]=[O:21])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1csc2ccc(F)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 5-fluoro-3-methyl-benzo[b]thiophene (4.83 g, 29.1 mmol) in THF (50 mL) at −30° C. under N2 was added n-butyllithium (20.0 mL of a 1.6 M solution in hexanes, 32.0 mmol) dropwise. The resulting orange solution was stirred for 1 h and then DMF (3.4 mL, 43.7 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.55 g, 97%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.80 (dd, J=9.0, 4.8 Hz, 1H), 7.53 (dd, J=9.3, 2.6 Hz, 1H), 7.31-7.24 (m, 1H), 2.76 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:32])=[CH:29][N:28]=2)=[CH:25][CH:26]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)nc4)ccc3o2)C1

Procedure:
Combine rac-N2-Methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 6-(4-fluoro-phenyl)-nicotinic acid (0.043 g, 0.198 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution in vacuo. Dilute with CH2Cl2, wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue to silica gel flash column chromatography (4 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as an impure mixture. Re-subject the mixture to silica gel flash column chromatography (3×4 g columns, 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white oil (0.030 g, 51%). mass spectrum (m/e): 460.0 (M+1), 458.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.0, 2.4 Hz, 1H), 8.03-7.97 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.20-7.11 (m, 3H), 3.58-3.46 (m, 2H), 3.16 (s, 3H), 2.72-2.56 (m, 3H), 2.55-2.48 (m, 1H), 2.38-2.32 (m, 1H), 2.33 (s, 3H), 2.04-1.95 (m, 1H), 1.57-1.48 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1cccc(N)c1
Yield: 66 %

Procedure:
A mixture of ethyl 3-nitrophenoxyacetate (10 g) in ethanol (200 ml), iron powder (10 g) and concentrated hydrochloric acid (4.8 ml) was heated at reflux for 5 hours. The solid residue was removed by filtration whilst the mixture was hot, and was washed with warm ethanol. The solvent was evaporated and the residue partitioned between sodium bicarbonate solution and methylene chloride. The aqueous layer was separated and extracted with fresh methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated. The residue was eluted through silica using a 5:3 mixture of hexane and ethyl acetate as eluent to give ethyl 3-aminophenoxyacetate as an orange oil in 66% yield;
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)#[CH:13]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:16]=1
Reactant: Brc1cncc2ccccc12
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(C#Cc2cncc3ccccc23)cc1
Reaction time: 4 h
Yield: 58.7 %

Procedure:
According to Scheme 29 Step 1: The title compound was prepared from 4-bromoisoquinoline (1 eq, 5.30 mmol, 1.10 g) and 1-ethynyl-4-methoxybenzene (1 eq, 5.30 mmol, 0.70 g) according to the procedure described for Example 13 Step 1. Reaction conditions: 70° C. for 4 hours. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 90/10 to 80/20) to afford 4-(2-(4-methoxyphenyl)ethynyl)isoquinoline (3.11 mmol, 0.81 g, 59%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([OH:11])[CH2:8][CH2:7]2.ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2
Reactant: OC1CCc2cccc(Br)c21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 37.9 g (177 mmol) of 7-bromoindan-1-ol in 3500 ml of dichloromethane 194 g (900 mmol) of pyridinium chlorochromate was added. The resulting mixture was stirred at room temperature for 5 h, then passed through a silica gel pad (500 ml), and the elute was evaporated to dryness. Yield 27.6 g (74%) of a white crystalline solid. Anal. Calc for C9H7BrO: C, 51.22; H, 3.34. Found: C, 51.35; H, 3.41. 1H NMR (CDCl3): δ 7.51 (m, 1H, 6-H); 7.36-7.42 (m, 2H, 4,5-H); 3.09 (m, 2H, 3,3′-H); 2.73 (m, 2H, 2,2′-H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].CCCCCC>O1CCCC1>[CH2:3]([O:5][C:6]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:13])[CH3:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)=C(OCC)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To a dispersion of 3.1 g of NaH in 20 mL of tetrahydrofuran (THF) at room temperature was added 20 mL of diethylmethylmalonate, at an addition rate of 0.5 mL/minute. The mixture was kept below 30° by the use of a water/ice bath. After complete addition of the diethylmethylmalonate, the mixture was stirred for 30 minutes, then cooled to 0° and 13.5 mL of chlorotrimethylsilane was added. After 40 minutes, 10 mL of hexane was added and the mixture was stirred overnight, filtered under argon, and distilled A forerun (40°-58°, 0.32 mm) was discarded, the product distilling at 62°-64°, 0.40 mm. NMR. (CD3CN, TMS) indicates that the product is a 75/25 mixture of E/Z isomers of ECPS; major isomer: 0.303 (s, 9H, SiMe3); 1.255 (t, J=b 7 Hz, 6H, OCH2CH3); 1.754 (s, 3H, vinyl CH3); 3.988-4.250 (m, all OCH2 for both isomers. Minor isomer: 0.308 (s, 9H, SiMe3); 1.264 (t, J=7H, 6H, OCH2CH3); 1.727 (s, 3H, vinyl CH3 1.754); 3.988-4.250 (m, all OCH2 for both isomers). Anal. calc. for C11H22SiO4 : C 53.67; H 8.94. Found C 53.33; H 8.76.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15]O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.C1COCC1>N1C=CC=CC=1>[Cl:19][CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=S(Cl)Cl
Reactant: OCC1c2ccccc2Oc2ccccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: ClCC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To a mixture of 4.0 g of 9-xanthenemethanol and 3.0 mL of freshly distilled thionyl chloride in 30 mL of freshly distilled THF was added dropwise 1.7 mL of pyridine over a period of 15 minutes. The mixture was heated in an oil bath at 50° C. for 12 hours, cooled to room temperature, and washed with half sat'd brine (30 mL), sat'd NaHCO3 (30 mL) and water (2×30 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give 4.16 g (95.7%) of the crude 9-chloromethylxanthene as an off-white solid. Recrystallization from CH3OH--CH2Cl2 (4:1) gave 3.53g (81.35%) of the pure 9-chloromethylxanthene as white needles, m.p. 104.5°-106° C.; 1H NMR (CDCl3 ):δ 3.67 (d, 2H, CH2), 4.32 (t, 1H, CH), 7.04-7.46 (m, 8H, aryl).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Oc1ccccc1
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of phenyl chloroformate (5.64 g) in dichloromethane (70 ml) was added a solution of 4-aminopyridine (2.84 g) and triethylamine (5.02 ml) in dichloromethane (100 ml) dropwise under cooling on an ice-water bath. After stirring for 1 hour, the solvents were removed under reduced pressure. A residue was diluted with dichloromethane (200 ml) and water (200 ml). An organic phase was separated and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. The reaction mixture was diluted with diisopropyl ether and the precipitates were filtered. After rinse with diethyl ether, O-phenyl N-(4-pyridyl)carbamate (5.07 g) was obtained.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1)C.[H-].C([Al+]CC(C)C)C(C)C.C(O)(C)C.O>C1(C)C=CC=CC=1.ClCCl>[Br:15][C:11]1[N:10]=[C:9](/[CH:8]=[CH:7]/[CH:6]=[CH:5]/[CH2:4][OH:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/C=C/c1cccc(Br)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: OC/C=C/C=C/c1cccc(Br)n1
Yield: 99.4 %

Procedure:
A solution of 2.6 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienoic acid ethyl ester in 73 ml of toluene is mixed with stirring and under argon atmosphere at -70° C. by instillation with 15.4 ml of diisobutylaluminum hydride (20% solution in toluene) and the mixture is stirred for 45 more minutes at this temperature. The reaction mixture is mixed at -70° C. in succession by instillation with 5.5 ml of isopropanol and 7.3 ml of water, stirred for 1 hour at room temperature, suctioned off on diatomaceous earth, rewashed with dichloromethane, the filtrate is dried on sodium sulfate and concentrated by evaporation. 2.2 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadien1-ol is obtained as crude product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([CH:11]1[CH2:16][S:15][CH2:14][CH2:13][N:12]1[C:17]([O:19]C(C)(C)C)=O)=[O:10])C(OC)=O.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH2:2][C@H:3]1[C:17](=[O:19])[N:12]2[CH:11]([CH2:16][S:15][CH2:14][CH2:13]2)[C:9](=[O:10])[NH:8]1
Reactant: COC(=O)[C@H](CO)NC(=O)C1CSCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](CO)C(=O)N2CCSCC12
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
To a solution of the crude 1,1-dimethylethyl 3-({[(1S)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl]amino}carbonyl)-4-thiomorpholinecarboxylate (D118, 3.87 g) in 44 ml of dichloromethane were added under N2, at r.t., 22 ml of TFA. The reaction mixture was stirred at room temperature for 3 hrs. The solvents were removed under reduced pressure and the residue was purified on a SCX cartridge. The fraction eluted with 2M methanolic ammonia was evaporated to dryness and the residue was dissolved in MeOH and refluxed for 20 hrs. The reaction mixture was evaporated to dryness and the desired product was purified by SCX, eluting with MeOH. The title compound (1.1 g, y=92% over 2 steps) was isolated as a mixture of diastereoisomers (ratio ˜50/50).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21](O)=[O:22].[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]([N:32]1[CH2:33][CH2:34][CH:29]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][CH2:31]1)=[O:22]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(C(F)(F)F)nn1-c1cccc(C(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(C(F)(F)F)nn1-c1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
In analogy to the procedure described in Example 160E), 5-methyl-3-trifluoromethyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a yellow foam (88%). MS: 475.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:57][CH2:56][C:52]3[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccnc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (365 mg, 0.920 mmol), 1-hydroxybenzotriazole (249 mg, 1.839 mmol) and EDCI (353 mg, 1.839 mmol) were dissolved in DCM (Volume: 3.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.321 ml, 1.839 mmol) and pyridin-3-ylmethanamine (199 mg, 1.839 mmol) were added. The reaction was stirred at room temperature overnight. Solid precipitate formed overnight. The reaction was concentrated and triturated with ethyl acetate to afford product as a white solid. (Yield: 315 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.46, 8.40, 7.70-7.60, 7.54, 7.40-7.29, 7.21, 7.13-7.05, 6.73, 5.49, 4.38, 4.30, 4.04, 2.95, 2.47-2.39, 1.71, 1.42
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[CH2:22]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.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>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:12]([O:19][CH2:20][C@@H:21]([CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[C@H:24]([O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
To a cold (˜0° C., ice/water bath) mixture of 2-amino-6-chloropurine (2.2 g. 13.2 mmol), 4 (3.9 g, 12 mmol), triphenylphosphine (3.52 g, 13.4 mmol) in 50 ml of anhydrous THF was added with stirring 2.75 ml (13.9 mmol) of diisopropylazodicarboxylate. The reaction was stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue chromatographed on silica eluting with a gradient of ethyl acetate (20-66%) in hexane. The product-containing fractions were pooled and concentrated to afford a semi-crystalline material, which was re-suspended in 20% ethyl acetate/hexane and filtered to remove insoluble hydrazine bis(isopropyl)carbamate. Concentration of the filtrate and drying in vacuo afforded 4.3 g (75%) of 24 as a white solid. 1H NMR, (DMSO-d6): δ 8.09 (s, 1H), 7.4-7.2 (m, 5H), 6.85 (s, 2H), 4.36 (s, 2H), 4.19 (m, 1H), 4.06 (m, 1H), 3.96 (m, 1H), 3.38 (m, 2H), 2.33 (m, 1H), 1.16 (d, J=6 Hz, 3H), 0.85 (s, 9H), 0.17 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[C:8]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C=CC=CC=1.CC(C)[C:45](NC1C=CC=C(C2CCN(CCCCC(=O)C3C=CC=CC=3)CC2)C=1)=[O:46].Cl.COC1C=CC(NN)=CC=1>>[CH3:45][O:46][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:7][C:8]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[C:9]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 20 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide (15.6 mg, 38.2 mmol), and 1-(4-methoxyphenyl)hydrazine hydrochloride (8.00 mg, 0.0458 mmol) provided N-(3-{1-[3-(5-methoxy-2-phenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide (3.9 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.55 (d, 2H, J=7.4 Hz), 7.43-7.39 (m, 3H), 7.38-7.35 (m, 2H), 7.27-7.19 (m, 3H), 7.08 (d, 1H, J=7.4 Hz), 6.94 (d, 1H, J=7.6 Hz), 6.87 (dd, 1H, J=4.0, 6.6 Hz), 3.88 (s, 3H), 3.80-3.69 (m, 1H), 2.99 (d, 2H, J=11.7 Hz), 2.89 (t, 2H, J=7.3), 2.55-2.39 (m, 4H), 2.02-1.88 (m, 3H), 1.82-1.68 (m, 4H), 1.24 (d, 6H, J=6.9 Hz); ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH:24]C(OC(C)C)=O)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Methyl 3-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 99) (319 mg, 0.751 mmol) was added to a cold (ice bath) suspension of aluminium chloride (381 mg, 2.86 mmol) in dichloromethane (DCM) (5 mL). The resulting mixture was stirred at approximately 0° C. for 30 min then was treated with a solution of methanol (0.400 mL) and triethylamine (1.266 mL, 9.09 mmol). The reaction was stirred further at approximately 0° C. for 20 min then was diluted with EtOAc (35 mL) and a saturated NaHCO3 aqueous solution (35 ml). The reaction mixture was then filtered through celite and the insoluble residues were washed with EtOAc (25 mL) and NaHCO3 (25 mL. The filtered aluminum residues were suspended in MeOH and sonicated. The resulting suspension was filtered and the filtrate was concentrated in vacuo to yield a white solid which was loaded onto a 20 g SCX cartridge and eluted with MeOH and then with 2M NH3 in MeOH. The ammonia fractions were combined and concentrated in vacuo to give methyl 3-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (50 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[O:41]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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>[O:41]1[CH:45]=[CH:44][C:43]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)=[CH:42]1
Reactant: OB(O)c1ccoc1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1

Procedure:
To a 5 mL microwave vial were added ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (62 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), furan-3-boronic acid (18 mg, 0.16 mmol), K3PO4 (99 mg, 0.47 mmol), DME (1.1 mL) and water (0.56 mL). The vial was capped and irradiated in the microwave reactor at 120° C. for 30 minutes. The mixture was then partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous further extracted with EtOAc (2×20 mL). The organics were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified using reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C37H35N3O4, 585.26; m/z found, 586.2 [M+H]+.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([C:17](Br)([CH3:19])[CH3:18])=[O:16].CS(C)=O>O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([C:17]1[CH:19]=[CH:15][C:6]2[C:5](=[CH:14][CH:9]=[CH:8][CH:7]=2)[CH:18]=1)=[O:16]
Reactant: CC(C)(Br)C(=O)c1ccc2ccccc2c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Yield: 146.9 %

Procedure:
0.75 g of sodium azide was added to a mixture comprising 1.59 g of α-bromoisopropyl 2-naphthyl ketone and 40 ml of dimethyl sulfoxide, and the mixture was reacted at 50° C. for 1.5 hours. The reaction mixture was put into water and extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.19 g of oily α-azideisopropyl 2-naphthyl ketone.