Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 76.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (97 mg, 0.138 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (d, J=6.97 Hz, 1H), 9.29 (s, 1H), 8.63 (d, J=2.20 Hz, 1H), 8.30 (d, J=8.80 Hz, 1H), 8.23 (d, J=5.13 Hz, 1H), 7.87 (dd, J=8.43, 2.57 Hz, 1H), 7.66-7.75 (m, 2H), 7.30-7.38 (m, 1H), 7.15-7.23 (m, 1H), 7.13 (d, J=8.80 Hz, 1H), 6.94-7.01 (m, 2H), 6.84-6.90 (m, 1H), 6.78-6.82 (m, 2H), 6.64 (d, J=5.13 Hz, 1H), 4.11 (s, 3H), 3.92 (s, 3H), 2.75-2.86 (m, 2H), 2.43-2.74 (m, 10H), 2.32 (s, 3H). MS (ESI): 705 [M+H]+.
Reaction SMILES: C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.[CH:19]1([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[C:29]([N:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]4=[O:39])[CH:30]=[CH:31][C:24]=3[N:23]=2)[CH2:21][CH2:20]1.[Br:40][C:41]1[CH:42]=[C:43]([CH2:47]O)[S:44][C:45]=1[Cl:46].C(P(CCCC)CCCC)CCC>C1COCC1>[Br:40][C:41]1[CH:42]=[C:43]([CH2:47][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:24]4[N:23]=[C:22]([CH:19]5[CH2:20][CH2:21]5)[N:26]([CH3:27])[C:25]=4[CH:28]=3)[C:33](=[O:39])[CH:34]=2)[S:44][C:45]=1[Cl:46]
Reactant: OCc1cc(Br)c(Cl)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)c(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
1,1-(Azodicarbonyl)dipiperidine (269 mg) was added to a solution of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-bromo-5-chloro-2-thienyl)methanol (162 mg) and tributylphosphine (0.26 ml) in THF (5 ml) at room temperature. The mixture was stirred at 60° C. for 2 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) and preparative HPLC (L-Column 2 ODS, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (12 mg) as a white solid.
Reaction SMILES: O[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].C([O-])([O-])=[O:18].[Cs+].[Cs+].Br[C:24]([CH3:29])([CH3:28])[C:25]([NH2:27])=[O:26]>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:27][C:25](=[O:26])[C:24]([OH:18])([CH3:29])[CH3:28]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)C(N)=O
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)(O)C(=O)Nc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a solution of 2-hydroxydibenzofuran (682 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 18 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(2-dibenzofuranyl)-2-hydroxy-2-methylpropionamide as an off-white solid (580 mg, 2.15 mmol, 58.1% yield). This was recrystallized from toluene for an analytical sample: mp 134-137° C. 1H NMR (300 MHz, CDCl3) δ 8.83 (br s, 1H, N--H), 8.41 (d, 1H, C1 --H, J=2.34 Hz), 7.92 (m, 1H, Ar--H), 7.56-7.29 (om's, 5H, Ar--H), 2.46 (br s, 1H, O--H), 1.60 (s, 6H, C(CH3)2); 13C NMR (75 MHz, CDCl3) δ 174.2, 156.8, 152.9, 132.8, 127.3, 124.6, 124.2, 122.7, 120.8, 119.5, 112.0, 111.7, 74.3, 28.0; IR (KBr pellet) 1651, 1668 (amide C=O stretches), 3364 (NH stretch), 3383 (OH stretch); MS (EI) 269; Analysis: Calculated C 71.36 H 5.61 N 5.20 Found C 71.43 H 5.58 N 5.06.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][NH:36][CH2:37][CH:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:36]([CH2:37][CH:38]([OH:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:35])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.06 gm) from Preparation No. 35 in dry NMP (2 mL) containing diisopropylethylarnine (0.04 mL) is treated with α-(methylaminomethyl)-benzyl alcohol (0.04 gm). The reaction mixture is shaken at room temperature for 3 days then concentrated under reduced pressure. The residue is partioned between dichloromethane and water. The separated organic layer is washed with two additional portions of water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is adsorbed onto silica and purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([C@@H:9]1[C@H:5]2[O:4][CH2:3][C@@H:2]([OH:1])[C@H:6]2[O:7][CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
A solution of 2.5 g of toluene-4-sulfonic acid (3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester in 30 ml of DMF is heated with 0.8 g of sodium azide under reflux for 2 hours, solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with H2O. The organic phase obtained is dried and solvent is evaporated. (3R,3aR,6S,6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH3:19])([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[CH2:18]([C:11]1([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: CCC1(OCCO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Solvent: CCO
Product: CCC1(OCCO)CCNCC1
Yield: 78.9 %

Procedure:
A solution of 37 g of 2-(1-benzyl-4-ethyl-4-piperidyloxy)-ethanol in 300 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 4 g of 10% palladized charcoal until the theoretical amount of hydrogen was absorbed (about 3 hours) and the catalyst was filtered off. The ethanol was evaporated off and the residue was distilled to obtain 19.2 g of 2-(4-ethyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 102°-106° C at 0.5 mm Hg.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[OH:10][CH2:11][C:12](O)=[O:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(#N)C>[OH:13][CH2:12][C:11]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CC2CN(C(=O)CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyacetic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile, and hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were then added to the solution in an ice-water bath. The ice-water bath was then removed, and the reaction mixture was stirred overnight at 25° C. The solvent was evaporated, and 20 mL of ethyl acetate was then added to the residue. The mixture was filtered and the filtrate was washed with 20 mL of water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:19](=[O:20])[C:18]3[N:21]4[C:11](=[CH:12][N:13]=[C:14]4[CH:15]=[CH:16][CH:17]=3)[C:10]2=[O:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>C(Cl)Cl>[ClH:34].[CH3:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:19](=[O:20])[C:18]3[N:21]4[C:11](=[CH:12][N:13]=[C:14]4[CH:15]=[CH:16][CH:17]=3)[C:10]2=[O:22])=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Cn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Product: Cl
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a suspension of 877 mg (3.0 mmol) of 4-[4-(amino)phenylmethyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione and 0.63 ml (4.5 mmol) of triethylamine in methylene chloride (60 ml) was added dropwise 0.30 ml (3.9 mmol) of methanesulfonyl chloride while stirring at room temperature. The mixture was stirred for 72 hours at room temperature. The solvent was distilled off. To the residue was added chloroform, washed with 1N-HCl, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: chloroform/methanol=20:1) to afford 274 mg of the desired compound (24.7%, a pale yellow solid).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13](Br)=[C:12]([O:20][CH2:21][CH3:22])[CH:11]=2)=[CH:4][N:3]=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:11]=[C:12]([O:20][CH2:21][CH3:22])[C:13]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:26][CH3:23])[CH:11]=1)[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1Br
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(OC)c1
Temperature: 25 °C

Procedure:
Tetrakis-triphenylphosphine-palladium (57 mg; 0.050 mmol) is suspended in dimethoxyethane (1 ml), while gassing with argon, and 2,4-diamino-5-(4-bromo-3,5-diethoxybenzyl)pyrimidine (367 mg; 1 mmol) in dimethoxyethane (6 ml) is added. After stirring for a quarter of an hour at room temperature, 3-methory-phenylboron acid (228 mg; 1.5 mmol) in ethanol (1.5 ml) is added, the mixture is stirred for a further 5 minutes at room temperature, an aqueous 2 M sodium carbonate solution (4.2 ml; 8.5 mmol) is added and the mixture is then boiled under reflux (bath temperature 85° C.) for 2.5 hours. The reaction mixture is concentrated and the residue is stirred with water and a little methanol and filtered off with suction. The filter cake is stirred with water, filtered off with suction and dried under a high vacuum.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH:4]S(O)(=O)=O.[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([CH:19]([CH3:22])[C:20]#N)[CH:16]=[CH:15][C:13]=2[N:14]=1>O>[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([CH:19]([CH3:22])[C:20]([O:3][CH2:1][CH3:2])=[O:4])[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CC(C#N)c1ccc2nc(N)sc2c1
Reactant: O=S(=O)(O)O
Reactant: CCO
Solvent: O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Yield: 61 %

Procedure:
A stirred solution of 10 ml of 95% ethanol, 10 g of conc. H2SO4, and 0.5 g of the compound of Step A above was heated at reflux for 20 hours and the mixture was then cooled, diluted with water and the ethanol was evaporated off. The resulting solution was neutralized with sodium bicarbonate to obtain a solid which was collected and crystallized from methanol/water to obtain 0.38 g (61%) of ethyl 2-amino-α-methylbenzothiazole-6-acetate as off-white needles melting at 146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20]O.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1c(-c2cc(CO)c(Cl)cc2F)nn(C)c1C(F)(F)F
Solvent: CCOCC
Product: Cc1c(-c2cc(CBr)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 7.0 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol in 200 mL of diethyl ether was added 30 mL of phosphorus tribromide and the mixture allowed to stir overnight. The reaction mixture was poured into ice water, the ether removed by concd in vacuo and the resultant solid collected by filtration. The solid was washed with water and air dried to give a quantitative yield of 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole: 1HNMR (CDCl3) δ 2.17 (t. 3H, 2.0 Hz), 4.07 (s, 3H), 4.64 (s, 2H), 7.30 (d, 1H, 9.5 Hz), 7.62 (d, 1H, 7.5 Hz); 19FNMR (CDCl3) δ -58.5 (s, 3F), -111.6 (s, 1F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21](OS(C)(=O)=O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@H:21]([N:28]=[N+:29]=[N-:30])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H](N=[N+]=[N-])[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A mixture of 80B (650 mg, 1.53 mmol) and sodium azide (597 mg, 9.18 mmol) was heated at 80° C. for 2 days. The reaction was diluted with EtOAc (200 mL), washed with brine:water (1:1, 4×15 mL), dried (MgSO4), filtered and concentrated to give the crude product. Purification by chromatography (40 g ISCO silica gel cartridge, 0-20% EtOAc/hexane) provided 80C as a colorless oil (410 mg). MS (ES) m/z 271 [M-Boc+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]([C@@H:28]([CH2:46][C@H:47]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH2:61][CH2:62][CH2:63][O:64][CH3:65])[CH:53]=1)[CH:48]([CH3:50])[CH3:49])[C@@H:29]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:30][C@@H:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[N+:26]=[N-:27].[NH2:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1.CCN(CC)CC>CC#N.CCOC(C)=O>[N:69]1([CH2:68][CH2:67][NH:66][C:32](=[O:33])[C@H:31]([CH:35]([CH3:37])[CH3:36])[CH2:30][C@H:29]([O:38][Si:39]([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41])[C@@H:28]([N:25]=[N+:26]=[N-:27])[CH2:46][C@H:47]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH2:61][CH2:62][CH2:63][O:64][CH3:65])[CH:53]=2)[CH:48]([CH3:49])[CH3:50])[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1
Reactant: NCCN1CCCCC1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@H](C[C@H](C(=O)O)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@H](C[C@H](C(=O)NCCN2CCCCC2)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HBTU (1.20 g, 3.0 mmol) was added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1.50 g, 2.5 mmol) in CH3CN (50 mL). Then 2-aminoethylpiperidine (324 mg, 2.5 mmol) and NEt3 (3.9 mL) were added and the resulting solution was stirred at RT for 2.5 hours. For workup, EtOAc was added and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. Drying of the organic phase (Na2SO4) and evaporation of the solvent affords the crude product which is purified by flash column chromatography [CH2Cl2:MeOH (95:5)] to give the desired product as a colorless oil. MS (LC-MS): 705.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.82 minutes.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[N+]=[N-].C(#N)C>O.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Agent: [Pd]
Solvent: CC#N
Solvent: O
Product: NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 17-azido-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2(g) —Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:2].O.NN.N>CO.[Ni].CO.C(Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[CH2:8][CH2:9]2
Reactant: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCN(CC)CCN1C(=O)CCc2cc(N)ccc21
Yield: 81.2 %

Procedure:
A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.72 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (534 μL, 17.2 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was rinsed with 10 mL methanol. The filtrate was concentrated to give a dark brown residue which was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give a colorless oil (365 mg, 81.2%). 1H-NMR (CDCl3) δ: 6.88 (d, J=8.4 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.7, 9 Hz, 1H), 3.98 (t, J=7.8 Hz, 2H), 3.54 (br s, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.66-2.55 (m, 8H), 1.04 (t, J=7.2 Hz, 6H). MS (ESI): 262.2 (M+1, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C.[H-].[Na+]>[Si:32]([O:31][CH2:30][CH2:29][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1c(=O)n(C2CCOCC2)c2nc(-c3cnn4ccc(C#N)cc34)ncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added. The resulting solution was stirred at room temperature for 10 min. Then (2-bromoethoxy)-tert-butyldimethylsilane (0.074 mL, 0.34 mmol) was added and the reaction was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 55 mg of the desired compound (76% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:23][C:24]2[C:25]([NH2:33])=[CH:26][C:27]3[O:31][CH2:30][O:29][C:28]=3[CH:32]=2)=CC=1>>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:33][C:25]1[CH:26]=[C:27]2[O:31][CH2:30][O:29][C:28]2=[CH:32][C:24]=1[CH:23]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Product: COc1cc2c(cc1OC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 80.9 %

Procedure:
Using the procedure of Example 1, 5,6-dimethoxyindan-1-one (192 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7,8-dimethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (260 mg, 81% of theory).