Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)[CH2:15][CH2:14]1
Reactant: O=C1CCc2c(Cl)cccc2N1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: O=C1CCc2c(cccc2C2CC2)N1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (147-4; 1 g, 0.0055 mol) and cyclopropylboronic acid (0.95 g, 0.0110 mol) in tetrahydrofuran (30 mL) was added potassium phosphate (3.4 g, 0.0165 mol) and S-Phos (0.45 g, 0.0011 mol). Reaction mass was purged with argon for 20 min. Then catalyst palladium acetate (0.123 g, 0.00055 mol) was added and allowed to stir at 120° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic part was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. MS (M+1): 188.1.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[CH2:20][CH2:19]3)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[C:20](=[N:1][OH:2])[CH2:19]3)=[CH:26][CH:27]=1
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2cc(OCc3ccc(F)cc3)ccc21
Agent: Cl
Product: O=C1C(=NO)Cc2cc(OCc3ccc(F)cc3)ccc21
Reaction time: 0.5 h

Procedure:
Isoamyl nitrite (4.05 mL, 29.2 mmol) was added to a suspension of 5-(4-fluoro-benzyloxy)-indan-1-one (15 g, 58.5 mmol) in methyl cellulose (210 mL) and HCl (conc) (15.6 mL, 187 mmol) at room temperature. After some minutes (−10) a solid appears and another portion of the isoamyl nitrite (4.05 mL, 29.2 mol) was added. The mixture was stirred for further 30 minutes, poured on ice water and the product was filtrated, washed well with water and diluted EtOH and dried at the pump (15.2 g, 91%). MS: m/e =284.1 (M−H).
Reaction SMILES: CN(C)C[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.[CH2:23](C(C1C=CC=CC=1)C(=O)C1C=CC(O)=CC=1)C>>[CH2:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](=[O:13])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CC(C(=O)c1ccc(OCCN(C)C)cc1)c1ccccc1
Reactant: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Product: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1

Procedure:
4-(β-Dimethylaminoethoxy)-α-ethyldesoxybenzoin (b.p. 162° C./0.075 mm.) may be obtained from α-ethyl-4-hydroxydesoxybenzoin by an analogous procedure to that described below for the preparation of 4-(β-dimethylaminoethoxy)-α-methyldesoxybenzoin, and α-ethyl-4-hydroxydesoxybenzoin itself (m.p. 122°-124° C.) may be obtained from α-ethyl-4-methoxydesoxybenzoin by an analogous procedure to that described below for the preparation of 4-hydroxy-α-methyldesoxybenzoin.
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=1.Br>>[NH2:9][C:8]1[C:3]([OH:2])=[CH:4][C:5]([CH2:12][NH2:13])=[N:6][CH:7]=1
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ncc1[N+](=O)[O-]
Agent: Br
Product: NCc1cc(O)c(N)cn1
Reaction time: 2 h

Procedure:
A mixture of 2-(4-methoxy-5-nitro-pyridin-2-ylmethyl)-isoindole-1,3-dione (0.24 g, 7.7 mmole) and 48% hydrobromic acid (3 mL), is refluxed for 3 hours. The reaction mixture is cooled, evaporated to dryness in vacuo, dissolved in absolute ethanol (25 mL) and 10% Palladium on carbon (100 mg) is added under an inert atmosphere. This is then hydrogenated on a Par apparatus at 45 psi for 2 hours. The reaction mixture is filtered and evaporated to give a brown solid, 60 mg, (23%), MS (ES+): m/z 140.2 (M+H). Used as is for the next step.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].CC1C=CN=C(N)C=1C>C(Cl)Cl>[CH3:21][S:18]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCO
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 mg (1.08 mmol) of (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonanol was dissolved in dry DCM (10 ml) under argon atmosphere, followed by the addition of triethylamine (224 ul), MsCl (mesylchloride) (125 ul) and a catalytic amount of DMAP (dimethyl amino pyridine) at 0° C. After 15 minutes the cooling bath was removed and the reaction stirred at room temperature for 1.5 hours. TLC monitoring showed complete conversion in 100% DCM as mobile phase. Extraction with water and DCM afforded crude product that was obtained following evaporation of the solvent under reduced pressure. Column chromatography on silica (100% DCM) gave pure (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonyl methanesulfonate in high yields (following high vacuum). (90%, 526 mg, 0.97 mmol)
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[CH2:33][C:32](=[O:34])[N:31]([CH3:35])[C:30]2=[O:36])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:38]=[CH:37][C:27]([CH2:28][N:29]5[CH2:33][C:32](=[O:34])[N:31]([CH3:35])[C:30]5=[O:36])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CN1C(=O)CN(Cc2ccc(Br)cc2)C1=O
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C1=O
Temperature: 130 °C
Yield: 54.6 %

Procedure:
2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (3.34 mmol, 1.0 g), 1-(4-bromobenzyI)-3-methylimidazolidine-2,4-dione (1B6) (3.34 mmol, 0.946 g), tris(dibenzylidineacetone)dipalladium (0.167 mmol, 153 mg), tricyclohexylphosphine (0.401 mmol, 112 mg) and potassium phosphate (5.68 mmol, 1.2 mg) were suspended in a mixture of dioxane (10 ml) and water (5 ml) and heated at 130° C. in the microwave for 15 min. The reaction was quenched with sat. NaHCO3 and diluted with DCM and then passed through a hydrophobic fritted tube. The combined organic layers were concentrated and the residue purified on silica eluting with 75-100% EtOAc/Heptane to afford 1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione (Example 1a) (685 mg, 55%) 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H) 7.65 (d, 1H) 7.62 (d, 2H) 7.59 (s, 1H) 7.36 (d, 2H) 4.63 (s, 2H) 4.38 (s, 2H) 3.79 (s, 2H) 3.08 (s, 3H) 2.95 (m, 1H) 0.98-0.87 (m, 4H) LCMS m/z (M+H) 376.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C.[OH-].[Na+]>[Fe].C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: CNc1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncc(N)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A suspension of 329 mg of 3-chloro-N-methyl-5-nitropyridin-2-ylamine, 489 mg of iron powder, and 9 ml of acetic acid was stirred at 60° C. for 2 hours. After the reaction solution was cooled to room temperature, ethanol was added thereto and the solution was filtrated through celite. The filtrate was concentrated under reduced pressure and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added thereto. To the organic layer obtained by an operation of separation was added a 1M aqueous sodium hydroxide solution, followed by an operation of separation. The resulting organic layer was dried over anhydrous sodium sulfate and filtrated and then the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 193 mg of 3-chloro-2-methylamino-5-aminopyridine as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][C@H:5]1[O:7][C@@H:6]1[CH2:8][OH:9].O(O)O.[H-].C([Al+]CC(C)C)C(C)C>C1C=CC=CC=1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH:6]([OH:7])[CH2:8][OH:9]
Reactant: COC(C[C@H]1O[C@@H]1CO)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: OOO
Agent: [H-]
Solvent: c1ccccc1
Product: COC(CCC(O)CO)OC

Procedure:
The epoxy alcohol (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol is reacted with diisobutylaluminum hydride, in benzene, to obtain 5,5-dimethoxypentane-1,2-diol: ##STR11##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([F:38])[C:32]=2[F:39])[N:29]=[N:28][N:27]=1.[ClH:40].O1CCOCC1>>[ClH:40].[ClH:40].[F:39][C:32]1[C:33]([F:38])=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=1[N:30]1[C:26]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH:13]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]4)[CH:12]=3)[CH:4]=2)=[N:27][N:28]=[N:29]1
Reactant: Cc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCNCC4)c3)cnc2N)c(F)c1F
Yield: 99.3 %

Procedure:
tert-Butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methylphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1102, 3.5 g, 6.511 mmol) was treated with 4.0 M HCl/dioxane (50 mL, 200.0 mmol) for 1 h at RT. The precipitate was collected by filtration and dried under vacuum to give 3-(1-(2,3-difluoro-4-methylphenyl)-1H-tetrazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine dihydrochloride salt (Compound 11, 3.3 g, 99%) as a slightly yellow solid.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39]([C:14]4[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])=[CH:12][CH:13]=4)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=S(=O)(Nc1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccccc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
A mixture of 0.468 g of N-phenyl-4-bromo-benzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 16 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 28-15:1). Concentration of the chromatographically pure fractions and crystallisation from acetonitril gives 0.125 g of the title compound as a solid of m.p. 231-233° C. The mass spectrum shows the molecular peak MH+ at 507.3 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][Mg]I)=[CH:5][CH:4]=1.Br[CH2:14][CH:15]=[CH2:16]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:16][CH:15]=[CH2:14])=[CH:5][CH:4]=1
Reactant: C=CCBr
Reactant: COc1ccc(CC[Mg]I)cc1
Solvent: C1CCOC1
Product: C=CCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution containing 4-methoxyphenethyl magnesium iodide (prepared from 60 g, 0.23 mol of 4-methoxyphenethyl iodide and excess magnesium turnings) in anhydrous tetrahydrofuran (200 ml) at 0° C. under a nitrogen atmosphere was treated with 3-bromoprop-1-ene (46.7 g, 0.33 mol) and then stirred at room temperature for 14 hours. The resulting solution was washed with saturated aqueous ammonium chloride solution (3×100 ml) and the aqueous washings were back extracted with dichloromethane (3×100 ml). The tetrahydrofuran and dichloromethane solutions were combined, washed with aqueous sodium thiosulphate solution, dried (MgSO4) and the solvent was evaporated off under reduced pressure to yield an oil which was distilled to yield 5-(4-methoxyphenyl)pent-1-ene as a pale yellow oil (b.p. 65° C., 0.3 mm. Hg) having the following structural characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)CCc1c[nH]c2ccc(OC)cc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a cooled solution (0° C.) of indole-3-propionic acid methyl ester 4 (0.797 g, 3.42 mmol) in DMF (20 mL) was added sodium hydride (60%; 0.25 g; 0.0625 mol) was added in one portion and stirred for 30 min followed by the addition of 4-methoxybenzenesulfonyl chloride (1.3 g; 6.31 mmol). The reaction was allowed to warm up to room temperature and stirred for 16 h, subjected to aqueous work up, and product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by flash-chromatography (silica gel; 80% n-hexane-20% ethyl acetate) to afford the ester 5 as a white solid (0.83 g; 61% yield; M+1=404.1).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([F:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([F:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cc(F)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cc(F)cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a mixture of (1-methyl-5-fluoro-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.94 g, 4.0 mmol) and 2-(1H-indol-3-yl-acetamide (0.63 g, 3.64 mmol) in DMF (36 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 14.6 mL, 14.6 mmol) at room temperature. The reaction mixture was heated at 55° C. for 18 h, cooled to room temperature, and quenched with hydrochloric acid (conc.). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1-methyl-5-fluoro-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (0.72 mg, 55%). 1H NMR (d6-DMSO, 400 MHz) 3.67 (s, 3H), 6.34 (d, J=7.82 Hz, 1H), 6.48 (d, J=3.12 Hz, 1H), 6.54 (t, J=7.62 Hz, 1H), 6.77 (dd, J1=2.34 Hz, J2=9.77 Hz, 1H), 6.99 (t, J=7.42 Hz, 1H), 7.33˜7.42 (m, 3H), 7.97 (d, J=3.13 Hz, 1H), 11.20 (s, 1H), 11.93 (s, 1H); MS (ES, m/z): C21H14FN3O2: 360.15 (M++1), 358.23 (M+−1).
Reaction SMILES: C[C:2]1[N:3]([C@H:29]2[C@H:33]([OH:34])[C@H:32]([OH:35])[C@@H:31]([C:36]([NH:38][CH2:39][CH3:40])=[O:37])[O:30]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:7]=[C:6]([C:26]([NH2:28])=[O:27])[N:5]=2.[CH2:41](N)[CH2:42][NH2:43]>ClCCl>[NH2:43][CH2:42][CH2:41][NH:28][C:26]([C:6]1[N:5]=[C:4]2[C:9]([N:10]=[CH:2][N:3]2[C@H:29]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@@H:31]([C:36]([NH:38][CH2:39][CH3:40])=[O:37])[O:30]2)=[C:8]([NH:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1)=[O:27]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2c(C)nc3c(NCC(c4ccccc4)c4ccccc4)nc(C(N)=O)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@H]1O
Temperature: 105 °C
Yield: 86.1 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 9) (1.1 g, 2 mmol) and 1,2-ethylenediamine (1.1 g, 18.3 mmol) was heated at 105° C. for 2.5 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.99 g, 86%)
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][O:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3](=O)[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:18][CH2:19][OH:20])=[CH:16][C:12]1=2
Reactant: CN(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)COCCc1ccc2ccsc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCO)CCOCCc1ccc2ccsc2c1
Temperature: 5 °C
Yield: 50 %

Procedure:
In 20 mL of tetrahydrofuran is dissolved 2.07 g of N1-methyl-N1-[2-(trityloxy)ethyl]-2-(2-benzo[b]-thiophen-6-ylethoxy)-acetamide. The solution is cooled to 5° C., and 7.5 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the mixture at ambient temperature overnight, 1.9 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for one hour. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 10 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=30:1 to 20:1) to obtain 0.54 g of 2-[[2-(2-benzo[b]thiophen-6-ylethoxy)ethyl](methyl)amino]-1-ethanol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1([CH2:11][C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc3cc(F)ccc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c(CN3CCCNCC3)cc2c1
Reaction time: 1 h

Procedure:
The product from Example 11B (0.48 g, 1.40 mmol) in CH2Cl2 (20 mL) was treated with TFA (20 mL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (10% MeOH/CH2Cl2/1% NH4OH) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.85–1.98 (m, 4H), 2.58–2.68 (m, 2H), 3.45–3.57 (m, 4H), 3.67 (s, 2H), 6.25 (s, 1H), 6.75–6.90 (m, 1H), 7.10–7.25 (m, 2H); MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8](P(OC)(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:30][C:31]1([CH3:42])[O:35][C:34]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:33]=2[O:32]1>C(Cl)Cl.[Cl-].[NH4+]>[C:1]([O:5][C:6](/[C:8](=[CH:40]\[C:38]1[CH:37]=[CH:36][C:34]2[O:35][C:31]([CH3:42])([CH3:30])[O:32][C:33]=2[CH:39]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (5255 mg, 17678 μmol) in 25 mL of DCM at 0° C. was added DBU (2665 μl, 17678 μmol) dropwise. To the mixture was then added a solution of 2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde (3000 mg, 16836 μmol) in 10 mL of DCM over 5 minutes so as to maintain internal temperature below 10° C. The reaction was warmed to rt and stirred overnight before being diluted with DCM (25 mL) and poured in saturated ammonium chloride (100 mL). The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with 10% aqueous sodium bicarbonate then water then brine and dried over Na2SO4. Concentration under reduced pressure and purification by silica gel provided (Z)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5005 mg, 85.1% yield) as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH:17][CH2:18][CH:19]([OH:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26]CC1C=CC=CC=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16].C(O)C>[C].[Pd].O>[ClH:1].[CH3:2][CH:3]([NH:17][CH2:18][CH:19]([OH:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16]
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)c(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)c(OC)c1OC
Yield: 72.4 %

Procedure:
A mixture of 1.0 g of α-[(α-methyl-2,3,4-trimethoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol hydrochloride [the diastereoisomer of M.p. 135°-136° C.], 400 mg of 10% palladium-carbon, 45 ml of ethanol and 5 ml of water is treated in the same manner as described in paragraph (6-a). The crude product thus obtained is recrystallized from a mixture of isopropylalcohol and isopropyl ether (1:2). 590 mg of α-[(α-methyl-2,3,4-trimethoxyphenethylamino)methyl]-2-hydroxybenzylalcohol hydrochloride [the diastereoisomer of M.p. 145°-146° C.] are thereby obtained as colorless prisms.