Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][C:20]=2[O:29][CH3:30])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:33])=[CH:12][C:13]([CH3:32])([CH3:31])[NH:14]2.Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:29][CH3:30])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:33])=[CH:12][C:13]([CH3:31])([CH3:32])[NH:14]2
Reactant: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 424 mg, 0.888 mmol) was dissolved in 1,4-dioxane (5 mL), 4N HCl/1,4-dioxane solution (666 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (150 mL). The mixture was washed with water (100 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (241.7 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:29][C:30]([N:19]1[CH2:18][CH2:17][C:15]2[N:16]=[C:11]([NH:10][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)[N:12]=[CH:13][C:14]=2[CH2:20]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (11.0 g, 41.3 mmol) and triethylamine (7.48 mL, 53.7 mmol) in dichloromethane (200 mL), add 2-chloroacetyl chloride (3.61 mL, 5.13 g, 45.4 mmol) dropwise over five minutes at 23° C. Stir for 30 minutes and pour the reaction mixture into 1:1 50% saturated aqueous sodium bicarbonate: dichloromethane (75 mL). Separate the organic layer from the aqueous layer and further extract the aqueous layer with dichloromethane (2×25 mL). Combine the organic extracts and dry over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in chloroform (10 mL) and purify via silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (9.75 g, 69%). 1H NMR (CDCl3, *=minor amide rotamer) δ 2.77* (t, 2H), 2.84 (dd, 2H), 2.87 (t, 2H), 3.35 (dd, 2H), 3.76 (t, 2H), 3.85* (t, 2H), 4.12 (s, 2H), 4.52* (s, 2H), 4.57 (s, 2H), 4.72-4.82 (m, 1H), 5.48-5.64 (m, 1H), 7.12-7.21 (m, 4H), 8.03-8.10 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl>O=[Pt]=O>[NH2:11][CH:10]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]1[OH:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: O=[Pt]=O
Agent: Cl
Product: NC1CCCC(C(=O)O)C1O
Reaction time: 24 h

Procedure:
2-Hydroxy-3-nitro-benzoic acid (5.0 g, 27.3 mmol) was mixed with HCl (125 mL of 0.5 M, 62.5 mmol) and dioxoplatinum (1.0 g, 4.4 mmol) in a hydrogenation bottle. The mixture was placed on a Parr shaker (50 psi H2) for 24 hours. The catalyst was filtered and washed with hot H2O. The filtrate was evaporated to provide 3-amino-2-hydroxy-cyclohexanecarboxylic acid as a mixture of stereoisomers which was utilized to the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=C)[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[O:25]1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:25])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=Cc1cc2c(cn1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ncc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-vinyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (0.500 g, 0.00155 mol) was dissolved in Tetrahydrofuran (30 mL, 0.4 mol) and Water (20 mL, 1 mol). Osmium tetraoxide 4% (wt) in water (0.758 mL, 0.000124 mol) was added. Followed by sodium metaperiodate (0.664 g, 0.00310 mol). The reaction mixture was stirred overnight at room temperature. LC-MS analysis of the reaction mixture showed complete conversion to desired product [C]. The crude reaction mixture was quenched with saturated sodium thiosulfate, diluted with EtOAc, and extracted 3×. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness to give 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carbaldehyde.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=1.O>CS(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]2[CH2:7][C@H:21]2[N+:22]([O-:24])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-bromo-4-[(trans)-2-nitrovinyl]benzene (0.53 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.15 of 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene [27% yield].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)s1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7.35 g (27.1 mmol) of 2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63, Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1 mmol) in DCM (10 mL) slowly at 0° C. over 20 min. Then the reaction was allowed to warm to ambient temperature. After being stirred at 25° C. for two days, the reaction mixture was diluted with DCM and washed with 2N HCl, water and sat. aq. NaCl solution. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (220 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provided the title compound as a light-yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31]([NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CN3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and piperidine, in the manner of Example 42, m.p. 199-202° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:12][C:13]([CH:17]([F:19])[F:18])=[CH:14][C:15]#[N:16]>C(O)(=O)C.C1COCC1>[F:18][CH:17]([F:19])[C:13]1[NH:12][C:13]([CH:17]([F:19])[F:18])=[C:14]([C:15]#[N:16])[CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[C:14]=1[C:15]#[N:16]
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: N#CC=C(N)C(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1ccc2[nH]ncc2c1

Procedure:
A mixture of 80 mg (0.55 mmol) 1H-indazole-5-carbaldehyde, 142 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 1 (1984)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.53 ml) was heated to reflux temperature for 5 h. After cooling, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 95 mg (48% of th.) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:24]1([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:33]1[CH:34]=[C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:31][N:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccccc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1

Procedure:
Using an analogous procedure to that described for Example 2, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-phenyl-4,5-dihydro-1H-pyrazol-5-one (200 mg, 1.25 mmol), (J. Org. Chem., 1967, 32, 3321-3324), in the presence of sodium hydride (50 mg, 1.25 mmol, prewashed with pentane) in DMF (3 ml) to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline as the free base. The free base was dissolved in a mixture of methylene chloride/methanol (1/1) and 3M hydrochloric acid in methanol was added. The volatiles were removed by evaporation to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline hydrochloride (115 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:10]([N:12]1[CH:19]2[CH:15]([N:16]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH:18]2[C:20]([OH:22])=O)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C@@H:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:10]([N:12]1[CH2:13][CH2:14][CH:15]2[N:16]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:17][CH:18]([C:20](=[O:22])[NH:41][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:33])[CH:19]12)=[O:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2S(C)(=O)=O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 29 (115 mg, 0.24 mmol) in DCM (6 mL) was cooled to 0° C. and treated with (R)-(+)-α-methylbenzylamine (36 μL, 0.28 mmol), EDC (71 mg, 0.37 mmol), and HOBT (51 mg, 0.37 mmol). To this solution was then added DIPEA (0.2 mL, 1.2 mmol). The reaction mixture was allowed to warm to ambient temperature. After 16 h, the solution was diluted with DCM, washed with 1M HCl, dried over anhydrous Na2SO4, filtered and concentrated to give crude 30 as an off-white foam. The crude residue was diluted with ACN/H2O containing 0.1% HOAc and purified by reverse-phase HPLC (2″ Dynamax® C18, 10% ACN/H2O to 100% ACN over 30 min). The product-containing fractions were combined and concentrated, diluted with EtOAc and washed successively with saturated NaHCO3 and brine. The combined aqueous layers were back-extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford 30 as an off-white foam. Mass spectrum, m/z [577.6] (M+H)+.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:31]3[C:17]4=[N:18][N:19]([CH3:30])[C:20]5[CH:21]=[CH:22][C:23]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:15]([C:16]=54)[C:14](=[O:32])[C:13]=3[CH:12]=[N:11][CH:10]=2)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][NH:24][C:23]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:30])[N:18]=[C:17]3[C:31]4[C:9]([OH:8])=[CH:10][N:11]=[CH:12][C:13]=4[C:14](=[O:32])[C:15]=1[C:16]=23
Reactant: COc1ccc(COc2cncc3c2-c2nn(C)c4ccc(NCCN(C)C)c(c24)C3=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2c(O)cncc2C(=O)c13
Reaction time: 2 h

Procedure:
To a mixture of 10-(p-methoxybenzyloxy)-5-[[2-(dimethylamino)ethyl]amino]-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one of Example 28(0.010 g) in dichloromethane (1 mL) trifluoroacetic acid is added upon which all solid is in solution. After 1 h the mixture is diluted with dichloromethane (3 mL) and a saturated solution of sodium bicarbonate (5 mL) is added. The dichloromethane layer is separated and the aqueous phase extracted with dichloromethane (3×8 mL). The extracts are dried over magnesium sulfate and removed under a slow nitrogen stream. The material is placed under vacuum for 2 h to give 5-[[2-(dimethylamino)ethyl]amino]-2-methyl-10-hydroxyisoquino[5,6,7-cd]indazole-6(2H)-one as an amorphous solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[N+:24]([C:27]1[CH:28]=[N:29][NH:30][CH:31]=1)([O-:26])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N+:24]([C:27]1[CH:28]=[N:29][N:30]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:31]=1)([O-:26])=[O:25]
Reactant: OCCc1ccncc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(CCc2ccncc2)c1
Temperature: 0 °C

Procedure:
DIAD (7.27 mL; 37.2 mmol; 1.1 eq.) was added slowly into a solution of 4-(2-hydroxyethyl)pyridine (4.2 g; 34.1 mmol; 1.0 eq.), 4-nitro-1H-pyrazole (3.86 g; 34.1 mmol; 1.0 eq.) and triphenylphosphine (9.84 g; 37.5 mmol; 1.1 eq.) in THF (120 mL) maintained under nitrogen at 0° C. The reaction mixture was allowed to warm to RT and left O/N. THF was removed under reduced pressure and the crude was purified by flash chromatography on silica (EtOAc:heptane, gradient from 50:50 to 100:0) to afford the title compound in quantitative yield. MS (ESI+): 219.0, (ESI−) 272.1 (purity 92.2%). 1H NMR (400 Mz, DMSO-d6) δ 8.80 (s, 1H), 8.44-8.43 (m, 2H), 8.24 (s, 1H), 7.18-7.17 (m, 2H), 4.50-4.48 (t, J=7.04 Hz, 2H), 3.19-3.17 (t, J=7.0 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[CH2:25](O)[CH2:26][OH:27].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:8]12[CH2:16][CH2:15][C:14]3([O:27][CH2:26][CH2:25][O:17]3)[CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[CH:6][C:5]=12
Reactant: O=C1CCC2(Cc3ccccn3)c3cnc(O)cc3CCCC2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A flask fitted with a Dean-Stark apparatus was charged with rac-(7aR,11aS)-3-hydroxy-11a-(pyridin-2-ylmethyl)-6,7,7a,8,11,11a-hexahydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridin-9(10H)-one (132, R2=Pyridin-2-ylmethyl) (6.8 g, 21.09 mmol), toluene (250 mL), ethane-1,2-diol (4.76 mL, 85 mmol) and pTSA (0.401 g, 2.109 mmol). The mixture was heated to reflux for about 2 h, cooled to rt then concentrated on under reduced pressure. The material was treated with sat. aq. NaHCO3 (50 mL), water (50 mL) and EtOAc (˜100 mL). The mixture was stirred for about 10 min then the solids were collected by filtration and washed with EtOAc (˜15 mL). The material was dried under vacuum. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic solutions were dried over MgSO4, filtered then combined with solids from the first filtration and concentrated under reduced pressure to yield rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-ol (143, R2=Pyridin-2-ylmethyl) (7.25 g, 94%); LC/MS, method 3, Rt=1.49 min, MS m/z 367 (M+H)+. 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.37-8.36 (m, 1H), 7.51-7.46 (m, 1H), 7.10-7.07 (m, 1H), 6.54 (s, 1H), 6.51 (d, J=7.8 Hz, 1H), 6.14 (s, 1H), 3.92-3.81 (m, 4H), 3.33 (d, J=13.3 Hz, 1H), 3.20-3.13 (m, 1H), 3.04 (d, J=13.3 Hz, 1H), 2.69-2.64 (m, 1H), 2.14-2.06 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.77 (m, 1H), 1.75-1.47 (m, 7H), 1.41-1.23 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].O>C1(C)C=CC=CC=1>[OH:28][CH:25]([CH2:26][OH:27])[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: OCC(O)CCl
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(OCC(O)CO)cc2C1=Cc1ccnc2ccccc12
Yield: 70 %

Procedure:
To a solution of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) in toluene (100 ml) was added portionwise under nitrogen NaH 80% (0.300 g, 10 mmol). After salification was complete, 3-chloro-1,2-propanediol (1.547 g, 14 mmol) was added and the mixture heated to reflux for 5 h. After cooling, water was added, the organic phase washed and evaporated to dryness. The residue was submitted to flash chromatography, using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 70% yield.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH3:35])=[CH:27][CH:26]=1.C([O-])(=O)C.[NH4+].C(Cl)(Cl)Cl.CO>C(O)C>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:35][C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1cc[n+](C)c2ccccc12
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C=Cc2cc[n+](C)c3ccccc23)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
A suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.20 g, 0.63 mmol), 1,4-dimethylquinolinium iodide (0.18 g, 0.63 mmol) and ammonium acetate (0.15 g, 1.9 mmol) in ethanol (20 ml) was heated at 60°-70° C., with stirring for 1 h when t.l.c. (chloroform-methanol, 5:4) indicated that the aldehyde had been completely converted into the almost non-mobile yellow product. The reaction mixture was cooled, and filtered to give a yellow solid which was washed sequentially with ethanol, acetone and ether to give (23c) as mustard yellow solid (0.33 g, 90%), m.p. 216°-220° C. (decomp.), [α]D -17° (c 1, DMOS)(Found: C, 48.89; H, 5.28; N, 2.36. C25H28INO7.2H2O calc.: C, 48.63; H, 5.22; N, 2.27%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[O:12]=[C:13]1[N:22]2[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]2)=[CH:16][CH:15]=[C:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[N+:1]([C:16]1[CH:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:12])[N:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[CH:21]2)([O-:4])=[O:2]
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c2ccccn2c1=O
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
Nitric acid (1.08 g, 17 mmol) was added slowly to acetic anhydride (7 mL) at 5° C. Stirring was continued for 5 min and the reaction mixture was cooled to −10° C. (ice/salt bath). Ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (920 mg, 4.2 mmol) was added in one portion. After 5 min, an orange precipitate formed. The reaction was complete after 15 min as indicated by thin layer chromatography (ethyl acetate). The reaction mixture was poured into 250 g crushed ice and stirred for 30 min to give an orange suspension, which was extracted three times with 100 mL dichloromethane. The combined organic layers were washed three times with 100 ml water. Evaporation of the solvent gave a deep red solid. Purification by flash chromatography gave a bright yellow solid (497 mg, 50% yield). M.p. 169-170° C. 1H NMR (δ, CDCl3): 1.44 (t, J=7.0 Hz, 3H), 4.45 (q, J=7.0 Hz, 2H), 7.55 (dd, J=7.0 Hz, J=7.0 Hz, 1H), 8.15 (dd, J=9.7 Hz, 7.0 Hz, 1H), 9.31 (d, J=9.1 Hz, 1H), 9.47 (s, 1H), 9.60 (d, J=7.0 Hz, 1H). MS: m/z 262.0601; required for C12H10N2O5: 262.0590.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[CH:10]=[N:11][CH:12]=1.Br[C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:17]=[CH:16][N:15]([C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH:10]=[N:11][CH:12]=1
Reactant: Fc1cncc(-c2cc[nH]n2)c1
Reactant: COC(=O)c1cccc(Br)n1
Agent: O=[Cu]
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2ccc(-c3cncc(F)c3)n2)n1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
30 ml of DMF were added to 1.88 g (11.5 mmol) of 3-(5-fluoro-3-pyridinyl)-1H-pyrazole (preparation cf. step 2), 2.50 g (11.5 mmol) of methyl 6-bromo-2-pyridinecarboxylate, 92.0 mg (1.15 mmol) of copper (II) oxide, 7.54 g (23.10 mmol) of cesium carbonate and 1.22 g (3.47 mmol) of iron(III) acetylacetonate, and the mixture was stirred at 90° C. for 60 hours. The entire reaction mixture was then cooled to room temperature, and water was added. The reaction mixture was then extracted with ethyl acetate. The organic phase was separated off, dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel. This gave 191 mg (5.0% of theory) of methyl 6-[3-(5-fluoro-3-pyridinyl)-1H-pyrazol-1-yl]-2-pyridinecarboxylate.