Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(OCC)C>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Dissolving 853 mg of 2-piperazin-1-ylquinoline as prepared in above Step 1-1-A in 5 ml of acetone, 5 ml of an aqueous solution containing 160 mg of sodium hydroxide was added to the solution, and into which 0.5 ml of 1-bromo-3-chloropropane was dropped, followed by stirring for an overnight at room temperature. Then diethyl ether was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 1.10 g (95%) of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]>CN(C=O)C>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:1])[C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1ccc(O)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCn1ccc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution of intermediate D2 (2.0 g, 11.96 mmol) in DMF (30 ml). The mixture was stirred overnight at r.t. and was then concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 0-5% MeOH/DCM as eluent) to yield intermediate D3 (2.0 g, 83%).
Reaction SMILES: O1CCCC1.[C:6]([OH:14])(=[O:13])[C@@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[OH:8].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[CH2:15]([O:13][C:6](=[O:14])[C@@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[OH:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 150 ml of tetrahydrofurane of 14.50 of D-leucic acid, 15.2 g of triethylamine and then 14.4 ml of benzyl bromide are added, and the solution was stirred for 3 hours while refluxing. The insoluble matter produced from the reaction solution was filtered off, and the filtrate was concentrated in vacuo. The obtained residue was dissolved and extracted in 150 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated bicarbonate water, twice with 1N hydrochloric acid, and twice with saturated brine sequentially, and dried over sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dried, and the captioned compound was obtained. Yield: 18.34 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[N:25]1[N:26]=[CH:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=12>>[N:25]1[N:26]=[CH:27][N:28]2[CH2:33][CH2:32][N:31]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[CH2:30][C:29]=12
Reactant: c1nnc2n1CCNC2
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCn3cnnc3C2)cn1
Yield: 86 %

Procedure:
As described for example 40, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride instead of (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride, to the title compound (121 mg, 86%) which was obtained as a white foam. MS: m/e=417.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ncccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
3-Bromo-pyridine 1-oxide (9.4 g, 54 mmol) is dissolved in acetonitrile (60 mL) and triethylamine (15 mL) is added followed by trimethylsilyl cyanide (21.7 mL, 163 mmol). The mixture is heated to 100° C. and stirred for 16 h. The mixture is cooled to 0° C., poured into 250 mL of 5 M aqueous NaOH, and extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting material is purified using flash chromatography (Biotage® Si65M, 20% ethyl acetate/hexane) to yield 7.8 g (79%) of the title compound as a yellow solid. GCMS m/e 182, 184 [M]−.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([F:17])[CH:16]=1)[C:11](O)=[O:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
BH3.THF in THF (1.00 M, 4.44 ml) was added dropwise into the THF (10 ml) solution of 3-bromo-5-fluorobenzoic acid (447 mg, 2.00 mmol) at rt under an atmosphere of nitrogen. The combined solution was stirred at rt for 24 h. After that time, the mixture was diluted with EtOAc (50 ml) and treated with saturated Na2CO3 (30 ml). The aqueous layer was extracted with EtOAc (2×25 ml). The extracts were washed with water (3×30 ml), brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to give the title compounds as colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.83 (brs, 1H), 4.71 (s, 2H), 7.03-7.08 (m, 1H), 7.16-7.20 (m, 1H), 7.32-7.34 (m, 1H). HPLC: tR=2.87 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(O) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].CO>O>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)CCCCC(=O)[O-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCC(=O)O
Yield: 98.4 %

Procedure:
16 g of a strongly acidic ion exchanger (cross-linked polystyrene containing sulfo groups) were suspended in a solution of 160 g of monomethyl adipate prepared according to (c), in 270 g of water. The reaction mixture was heated in a 1 l three-necked flask with an attached spinning band column until no further methanol passed over. The ion exchanger was filtered off; 144.5 g (99% yield) of adipic acid of melting point 153° C. were obtained from the filtrate after crystallization and partial evaporation of the mother liquor.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:2]1.[C-:23]#[N:24].[Na+]>CN(C=O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][C:23]#[N:24])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1COc2ccccc2C1
Yield: 126.4 %

Procedure:
Compound 18B (1.25 g), NaCN (0.15 g) in 25 mL of DMF, were heated to 60° C. for 12 h. The solvent was removed, the reaction mixture was mixed with water (125 mL) and ether (125 mL). The ether layer was separated, washed with water, brine, dried (MgSO4), concentrated to afford compound 18C (0.67 g). mp 54-55.5° C.; MS: 174 (M+1)+. Preparation of 3-Cyanomethyl-chroman-6-sulfonyl chloride (Compound 18D)
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[Br:14]Br>CC(O)=O>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([Br:14])=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)c1nc2ccc(N)cc2[nH]1
Solvent: CC(=O)O
Product: CC(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.19 ml (3.7 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuc and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5 mmol, 95%) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-(2-quinolinylmethyloxy)benzaldehyde.
Reaction SMILES: COC1C=CC2N3C(=O)C(C(OCC)=O)=CN=C3SC=2C=1.[OH-].[Na+].Cl.[SH:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[N:34]1[C:39](=O)[C:38]([C:41]([OH:43])=[O:42])=[CH:37][NH:36][C:35]1=[O:44]>C(O)C>[CH3:33][O:32][C:30]1[CH:29]=[CH:28][C:27]2[N:34]3[C:35](=[O:44])[N:36]=[CH:37][C:38]([C:41]([OH:43])=[O:42])=[C:39]3[S:25][C:26]=2[CH:31]=1
Reactant: COc1ccc(-n2c(=O)[nH]cc(C(=O)O)c2=O)c(S)c1
Agent: CCOC(=O)c1cnc2sc3cc(OC)ccc3n2c1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12

Procedure:
4.5 g. Ethyl 8-methoxy-4-oxo-4H-pyrimido[2,1-b]-benzthiazole-3-carboxylate (prepared by the method described by Alaimo, J. Het. Chem., 10, 769/1973) are mixed with a mixture of 75 ml. 10% aqueous sodium hydroxide solution and 25 ml. ethanol and heated under reflux for 30 minutes. After neutralizing the reaction mixture with 2 N hydrochloric acid, 1-(2-mercapto-4-methoxyphenyl)-5-carboxypyrimidine-2,6-dione precipitates out. The yield is 3.5 g. (80% of theory); m.p. 266°-267° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-chlorophenyl) ureido]phenylacetate (1.35 g, 76%) as a colorless powder. 1H-NMR (CDCl3) δ 3.58 (s, 3H), 3.71 (s, 2H), 7.04 (m, 3M), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.27–7.39 (m, 3H), 8.07 (m, 2M); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (500 mg, 2.18 mmol) in THF (5.2 mL) at −30° C. was slowly added LiAlH4 (83 mg, 2.18 mmol). The reaction mixture was stirred for 15 min, quenched with a solution of methanol and water (4:1, 10 mL), and stirred at rt for 30 min. The mixture was neutralized with 6 N HCl to pH of 7 and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford (4-bromo-3-methylphenyl)methanol (420 mg; yield 96%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:37][CH3:38])=[CH:22][CH:21]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 4-(4-methoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiv.), and 6 mol % of dichlorobis(triiphenylphosphino)palladium (II) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodium carbonate (0.10 M). The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gel with a gradient or methanol/dichloromethane by flash chromatography afforded 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol as a tan solid (46% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=2.0, 8.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH]+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[CH:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH:8]=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C=O
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
In N,N-dimethylformamide (20 mL) was dissolved 5.01 g (41.1 mmol) of commercially available salicylaldehyde, 1.80 g (45.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and after stirring the mixture in an ice bath for 10 minutes, 3.43 mL (45.2 mmol) of chloro(methoxy)methane was gradually added dropwise to the mixture and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 6.54 g (39.4 mmol, Yield: 95.9%) of 2-(methoxymethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: C=COCCCC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylformanilide (100 g), butyl vinyl ether (74.12 g) in 85 ml of clorobenzene under stirring at 5° C., a solution of bis-trichloromethylcarbonate (87.84 g) in 170 ml of clorobenzene is added dropwise in 2 hours. The reaction mixture is kept under stirring at room temperature overnight. The mixture is cooled at about 5° C. and the pH is corrected to about 7 by adding sodium hydroxide 15% aqueous solution (348 ml). After separation of the phases, the aqueous layer is extracted with chlorobenzene (90 ml) and the combined organic layers are washed with water (100 ml) and evaporated under reduced pressure. The obtained residue (116.9 g, containing, according to HPLC assay, 104.8 g of pure product, 88% molar yield) is used for the next step of the synthesis without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16])=[O:6]
Reactant: COc1ccccc1N
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Yield: 80.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.1 mmol) in benzene (60 mL), followed by o-anisidine (2.6 mL, 23.4 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 2.61 g of a dark yellow oil (81%). 1H NMR (CDCl3) δ: 8.53 (dd, J=1.7, 7.9 Hz, 1H); 8.39 (br s, 1H); 7.11 (dt, J=1.6, 7.8 Hz, 1H); 7.09 (t, J=8.1 Hz, 1H); 7.02 (dt, J=1.4, 7.8 Hz, 1H); 6.92 (dd, J=1.4, 8.0 Hz, 1H); 6.62 (dd, J=0.9, 8.2 Hz, 1H); 4.66 (br s, 2H); 3.87 (s, 3H). MS (ES): m/z 277.0 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>CS(C)=O.O>[CH3:24][CH:22]1[NH:23][CH:18]([CH3:17])[CH2:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: CC1CNCC(C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (2.12 mL, 20 mmol) and potassium carbonate (3.5 g, 25 mmol) in DMSO (10 mL) was added 3,5-dimethyl-piperazine (2.5 g, 22 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAc/hexanes gave 3.9 g of 3,5-dimethyl-1-(4-nitro-phenyl)-piperazine, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.80 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.40 (br, 2H), 3.32 (d, J=9.5 Hz, 2H), 3.05 (m, 2H), 2.19 (t, J=10.5 Hz, 2H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2(CC3C=CC=CC=3[O:11]2)[CH2:3][NH:2]1.[H][H].C1C2C(=CC=CC=2)C(=O)CN1.FC1C=CC=CC=1CCl.FC1C=CC=CC=1CBr>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][NH:2]1
Reactant: [H][H]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Agent: Fc1ccccc1CBr
Agent: Fc1ccccc1CCl
Agent: O=C1CNCc2ccccc21
Product: OC1CNCc2ccccc21

Procedure:
To prepare the parent ring system 7, i.e., the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 1 wherein R is hydrogen, a 2,3-dihydro-4(1H)isoquinolone 3 wherein R is loweralkyl or benzyl is treated with a Grignard reagent 4, prepared from a 2-fluorobenzyl chloride or 2-fluorobenzyl bromide by conventional methods, to afford the 1,2,3,4-tetrahydro-4-isoquinolinol 2, which is cyclized to the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 5, wherein R is loweralkyl or benzyl and dealkylated or debenzylated to spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 7, via the alkoxycarbonyl or phenoxycarbonyl derivative 6 wherein R1 is loweralkyl or phenyl, respectively. (See Reaction Scheme I).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][P:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].Br[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([P:5]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:6])[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:32]2[C:28](=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44])[CH2:29][O:30][C:31]2=[O:41]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added a solution of 1N NaN (TMS)2 in THF (0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 30 minutes, whereupon a solution of 6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by addition of a saturated aqueous solution of ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg (48%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; MS (m/z) 701.2 [M+Na]+.