Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14].[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:21](=[N:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CCC[C@H]1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of (1R,2R)-2-aminocyclopentanol TFA salt (630 mg, 2.93 mmol) was added diphenylmethanimine (490 uL, 2.93 mmol) and TEA (0.5 mL, 3.58 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure and purified by ISCO flash chromatography using EtOAc and hexane as eluting solvent to yield (1R,2R)-2-(diphenylmethyleneamino)cyclopentanol (697 mg, 90% yield) as a colorless gum. HPLC: RT=1.96 min [M+H] 266.13 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.64 (m, 2H), 1.66-1.91 (m, 3H), 2.08-2.24 (m, 1H), 3.55-3.71 (m, 1H), 4.31-4.47 (m, 1H), 7.15-7.25 (m, 2H), 7.29-7.53 (m, 6H), 7.61-7.67 (m, 2H).
Reaction SMILES: [N:1]([CH:4]([C:11]1([OH:34])[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:16])[CH2:12]1)[CH2:5][CH:6]1OCC[O:7]1)=[N+:2]=[N-:3].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]([CH:4]([C:11]1([OH:34])[CH2:12][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:16])[CH2:14]1)[CH2:5][CH:6]=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(CC1OCCO1)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(CC=O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 93.9 %

Procedure:
3-[1-Azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (24 mg, 0.041 mmol) was dissolved in tetrahydrofuran (0.5 mL) and treated with 5% aqueous hydrochloric acid (0.5 mL) at ambient for 15 h. The mixture was neutralised with saturated sodium bicarbonate solution and was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-azido-3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propanal (21 mg, 0.0385 mmol) which was suspended in ethanol (2 mL) and treated with sodium borohydride (5 mg, 0.132 mmol) at ambient for 2 h. The mixture was quenched with acetic acid (4 drops) and concentrated in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 70-80% ethyl acetate in hexanes) gave 3-(1-azido-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (14 mg, 0.0255 mmol, 62% yield from 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol): 1H NMR (400 MHz, CDCl3): 8.33 (br s, 1H), 7.40 (dd, 1H), 7.32 (br d, 1H), 7.13 (br t, 1H), 6.83 (br q, 1H), 6.61 (ddd, 1H), 4.32-3.94 (m, 4H), 3.92-3.84 (m, 1H), 3.82-3.71 (m, 2H), 2.56 (br, 1H), 1.94 (br, 2H), 1.26 (br, 1H); MS (EI) for C19H17F3IN5O3: 548 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23](I)[CH3:24]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH2:23][CH3:24])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Solvent: CC(C)=O
Product: CCn1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, orange gum, MS: m/e=338.3, 340.2 (M+H+), was prepared in accordance with the general method of example 2 from 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide in acetone instead of DME.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: COc1ccc(-n2cccn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Yield: 49.7 %

Procedure:
1-(4-Methoxy-phenyl)-1H-pyrazole (400 mg, 2.30 mmol) was dissolved in methylene chloride (8 ml) and the solution was cooled to −78° C. Boron tribromide (1.0 M in methylene chloride, 5.05 ml) was added dropwise to the solution over about five minutes to afford a brown-colored solution. The reaction mixture was allowed to stir for about thirty minutes, the cooling bath was removed, and the mixture was allowed to stir at room temperature for about an additional three hours. The mixture was poured into water, and the resulting mixture was adjusted to about pH 8. The mixture was extracted with methylene chloride (3×25 ml), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (25% ethyl acetate/hexanes) to afford 183 mg (50% yield) of the desired product as an oil. LRMS ([M+H+])=161.1.
Reaction SMILES: [N:1]([C@@H:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-]>CCO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[N:9]1[CH:10]=[CH:11][C:6]([C@H:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=1
Reactant: C[C@@H](N=[N+]=[N-])c1ccncc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: C[C@@H](N)c1ccncc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
4-[(1R)-1-Azidoethyl]pyridine (1.0 g, 6.7 mmol) was dissolved in 25 mL EtOH amd hydrogenated at 45 psi over 100 mg Lindlar's catalyst (5% w/w). After 2 h, the reaction mixture was filtered through Celite, concentrated and purified on SiO2 (DCM:MeOH:NH4OH 95:5:0.1) to provide the amine as a yellow oil (0.583 g, 4.78 mmol, 71%): 1H NMR (300 MHz, CDCl3) δ 8.44 (dd, J=4.5, 1.5 Hz, 2H), 7.34 (d, J=5.8 Hz, 2H), 3.93 (q, J=6.8 Hz, 1H), 3.3 (bs, 2H), 1.21 (d, J=6.5 Hz, 3H) ppm.
Reaction SMILES: C(N)C.C(N)CC.[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]#[C:11]/[CH:12]=[CH:13]/[CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[CH2:16]C.CC(C)(C)C#C/C=C/CN(CC1C=CC=C(O)C=1)CCC>>[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]#[C:11]/[CH:12]=[CH:13]/[CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[CH3:16]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: CCCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: CCN
Solvent: CCCN
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1

Procedure:
When the same reaction as above is carried out using ethylamine or propylamine instead of methylamine, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydoxybenzylamine used in Examples 101 to 103 or (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-propyl-3-hydroxybenzylamine used in Examples 104 and 105 is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)[CH2:2][CH3:3].[CH3:18][O:19][C:20]1[CH:21]=C(O)[CH:23]=[CH:24][CH:25]=1.OS(O)(=O)=O.C(OCC)(=O)C>ClCCCl.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[C:23]3[C:14](=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[O:13][C:11](=[O:12])[CH:10]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(C(=O)CC(=O)OC)c1
Reactant: COc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1cccc(-c2cc(=O)oc3cc(OC)ccc23)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
A solution of methyl 3-(prop-1-yloxy)benzoylacetate (745 g) (a compound of Formula (a)) in 1,2-dichloroethane was combined under nitrogen with a solution of 3-methoxyphenol (488 g) in 1,2-dichloroethane (2.5 L) and cooled to 0° C. Concentrated H2SO4 (626 mL) was added dropwise and the mixture was stirred vigorously at RT for 90 minutes. Ethyl acetate (3 L) and H2O (3 L) were added and the layers were equilibrated and separated. The aqueous layer was extracted again with ethyl acetate and the combined organic layers were washed with H2O, 5% aqueous Na2CO3, 5% aqueous NaOH, H2O, and brine (2 L each). The organic phase was dried with MgSO4 and concentrated to dryness to yield 841 g (86%) of 4-[3-(prop-1-yloxy)phenyl]-7-methoxycoumarin. The product was recrystallized from ethanol/isopropanol followed by ethyl acetate/isopropanol to give 533 g (63% recovery) of 4-[3′-(prop-1-yloxy)phenyl]-7-methoxycoumarin.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC>O1CCOCC1.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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (22.7 g, 61 mmol), Pd(PPh3)4 (3.53 g, 0.05 eq) and 2-(tributylstannyl)pyridine (33.8 g, 80%, 1.2 eq) in dioxane (840 mL) was heated to 100° C. under N2. After over night, LCSM showed around 50% starting material left. The reaction mixture was heated to 110° C. for additional 2 days. LCMS showed less than 10% starting material left. The reaction was heated to 120° C. for 5 h before cool to rt. Removal of solvent followed with column chromatography on silica gel (EtOAc/hexane, 0/1 to 1/3) gave an off white foam 14.2 g and the impure portions were combined and purified in the similar manner to give a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.70-7.65 (m, 4H), 7.50 (t, J=8.0 Hz, 1H), 7.33-7.29 (m, 1H), 6.58 (q, J=8.0 Hz, 1H), 2.02 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=414 (M+1).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C[O-].[Na+].CO.[CH3:13][C:14]([CH3:23])([CH3:22])[CH2:15][C:16](=O)[C:17](OC)=[O:18]>O.C(O)(=O)C>[OH:18][C:17]1[CH:16]=[C:15]([C:14]([CH3:23])([CH3:22])[CH3:13])[N:7]=[CH:5][N:6]=1
Reactant: N=CN
Reactant: COC(=O)C(=O)CC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
First, 7.2 g of formamidine acetate, 7.5 g of sodium methoxide, and 70 mL of methanol were put in a 100 mL three-neck flask. Then, 10 g of methyl 4,4-dimethyloxovalerate was added to this mixed solution. The mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, a mixed solution of 17 mL of water and 7.2 mL of acetic acid was added to the mixture, and the mixture was stirred at room temperature. This mixture was condensed, and the given residue was dissolved in water. The solution was subjected to extraction with ethyl acetate. The obtained solution of the extract was washed with saturated brine, and anhydrate magnesium sulfate was added to the organic layer for drying. The obtained mixture was subjected to gravity filtration, and the filtrate was condensed to give a solid. This solid was washed with ethyl acetate to give 4-hydroxy-6-tert-butylpyrimidine (white solid, yield of 49%). A synthetic scheme of Step 1 is shown in (b-1) below.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:3][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-4-hydroxymethylpiperidine (20.7 g, 96.1 mmol) in dichloromethane (200 mL) was cooled to 0° C. and treated with pyridinium chlorochromate (31.1 g, 144.2 mmol). The suspension was allowed to warm to room temperature and stirred for 3 h. The mixture was then diluted with diethyl ether (250 mL), filtered through a pad of silica gel (50 mm×10 cm), and the solids washed with 4:1 hexane/acetone (3×250 mL). The filtrate was evaporated to leave a pale green oil. This oil was dissolved in ether (200 mL) and washed sequentially with 1N hydrochloric acid (2×100 mL), 1N aqueous sodium hydroxide (100 mL) and brine (100 mL). The aqueous washes were extracted with fresh diethyl ether (2×150 mL). The combined organic extract was dried over sodium sulfate, filtered and evaporated to afford the crude aldehyde (16.3 g, 76.42 mmol), which was used without purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:32]1[CH2:33][CH2:34][C@@H:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[CH:28][CH:27]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(CN3C(=O)C4(COc5cc6c(cc54)OCO6)c4ccccc43)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(Cc2ccc(N[C@@H]3CCNC3)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 79.4 %

Procedure:
A solution of tert-butyl (3R)-3-({4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]phenyl}-amino)pyrrolidine-1-carboxylate (0.53 g, 0.94 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (5 mL) was stirred at ambient temperature for 70 min. The reaction was made basic with 1 M sodium hydroxide (50 mL) and extracted with dichloromethane (4×30 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol/ammonium hydroxide (14:1:0.15) afforded 1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.34 g, 78%) as an off-white solid: mp 118-121° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.23-7.13 (m, 4H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H), 6.52 (s, 1H), 6.12 (s, 1H), 5.87 (d, J=1.2 Hz, 1H), 5.85 (d, J=1.2 Hz, 1H), 4.99-4.94 (m, 2H), 4.71-4.66 (m, 2H), 3.94-3.85 (m, 1H), 3.83 (br s, 1H), 3.15-3.04 (m, 2H), 2.97-2.88 (m, 1H), 2.83 (dd, J=11.1, 3.0 Hz, 1H), 2.21-2.09 (m, 1H), 1.98 (br s, 1H), 1.67-1.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.9, 148.8, 147.2, 142.3, 132.3, 128.85, 128.80, 124.3, 123.8, 123.3, 119.6, 113.4, 109.6, 103.1, 101.5, 93.6, 80.5, 58.3, 53.9, 53.6, 45.7, 43.8, 33.6; MS (ES+) m/z 456.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:14])[C:7]([O:12][CH3:13])=[CH:8][C:9]=2[OH:11])[C:4](=[O:15])[O:3]1.CN(C)C(N(C)C)=N.[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:3][C:4](=[O:15])[C:5]1[C:6]([CH3:14])=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([OH:11])[C:10]=1[CH:2]=[O:1])[CH:25]=[CH2:24]
Reactant: COc1cc(O)c2c(c1C)C(=O)OC2O
Reactant: C=CCBr
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 42.0 g of (RS)-3,4-dihydroxy-6-methoxy-7-methyl-1,3-dihydro-isobenzofuran-1-one in 11 of N,N-dimethylformamide were added 23.0 g of 1,1,3,3-tetramethylguanidine. The solution was stirred for 30 min and then, 48.4 g of allyl bromide were added and stirring was continued for 3 h. The mixture was evaporated in vacuo and the residue was dissolved in 0.7 l of ethyl acetate. The solution was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was crystallized from tert-butyl methyl ether to give 37.3 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 73°-74° C.
Reaction SMILES: [CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[N:18]=4)[C:15]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:14]([O:39][CH3:40])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:41]=[C:3]2[O:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[N:18]=4)[C:15]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:14]([O:39][CH3:40])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:41]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c(CCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c(CCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
After 2,3-(methylenedioxy)-6-[3-(t-butyldimethylsiloxy)propyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (374.4 mg, 0.644 mmol) was dissolved in tetrahydrofuran (3.2 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.9 mL) was added to the solution. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture followed by extraction with methylene chloride. The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride) to provide 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (263.7 mg, yield 88%) as colorless powders.
Reaction SMILES: [CH2:1]([C@H:8]([NH:34]C(=O)OC(C)(C)C)[C@@H:9]([OH:33])[CH2:10][C@@H:11]([NH:25]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:34][C@H:8]([C@@H:9]([OH:33])[CH2:10][C@@H:11]([NH2:25])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution containing the product from Example 133A (0.60 g, 1.07 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL), stirred at 25° C. for 1 hour, concentrated and partitioned between chloroform and saturated NaHCO3. The organic was dried over Na2SO4, filtered and concentrated to give the title compound (0.386 g, 98% yield).
Reaction SMILES: C(Cl)(=O)C.C(O)(=O)C.[CH2:9]([NH:11][NH2:12])[CH3:10].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=O)[C:23]([O:25]C)=O)=[CH:14]1>C(O)C>[CH2:9]([N:11]1[CH:14]=[C:15]2[C:22]([C:23](=[O:25])[NH:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=32)=[N:12]1)[CH3:10]
Reactant: CCNN
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Acetyl chloride (0.7 mL, 9.8 mmol), acetic acid (1 mL), and ethylhydrazine (1.5 g, 9.8 mmol) were added sequentially to a suspension of methyl (1H-indol-3-yl)glyoxalate (1.0 g, 4.9 mmol) in ethanol (25 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was combined with acetonitrile. A pink solid was isolated by filtration and then purified by automated flash chromatography (Biotage, eluted with a gradient of 0-30% CMA in chloroform) to provide a white solid. This material was recrystallized from acetonitrile to provide 360 mg of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as white crystals, mp>250° C. MS (APCI) m/z 214 (M+H)+; Anal. calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.52; H, 5.14; N, 19.90.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([O:9]CC)=O.[NH2:12][NH2:13].O>C(O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([NH:12][NH2:13])=[O:9]
Reactant: CCOC(=O)CC1CCCO1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CC1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of ethyl 2-(tetrahydrofuran-2-yl)acetate (2.00 g, 12.6 mmol, 1.00 equiv) in ethanol (20 mL). NH2NH2.H2O (1.27 g, 25.4 mmol, 2.00 equiv) was added to the reaction. The resulting solution was stirred overnight at 80° C. in an oil bath, then cooled to room temperature and concentrated in vacuo. This resulted in 2.10 g (92%) of 2-(tetrahydrofuran-2-yl)acetohydrazide as a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]1([CH3:30])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]#[C:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2.Cl>CN(C)C=O.O>[CH3:7][C:8]1([CH3:30])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([C:20]#[C:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]4[NH:27][N:3]=[N:2][N:1]=4)=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(-c4nnn[nH]4)cc3)ccc21
Yield: 84.2 %

Procedure:
2.15 g (0.033 mole) of sodium azide, 1.77 g (0.033 mole) of ammonium chloride and 9.2 g (0.03 mole) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile in 30 ml of absolute dimethylformamide were stirred for 12 hours at 120° C. The cooled reaction mixture was then poured onto 0.5 liter of water and acidified with a little hydrochloric acid. The crystals which had separated out were filtered off under suction, washed on the filter several times with water and then with methanol, sucked dry while hot, and dried in a stream of nitrogen. 9.0 g (84%) of the title compound of melting point 227°-228° C. were obtained.