Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[C:13](=[O:19])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=[O:21].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([O:19][C:13]1[CH:14]2[CH2:18][CH:17]([C:11](=[O:10])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:21])[CH2:16][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CCC(C2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(OC(=O)c2ccccc2)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., a solution of 0.562 g (0.0004 mol) of benzoyl chloride in 1 ml of tetrahydrofuran is added to a solution of 1.14 g (0.0035 mol) of 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one and 0.517 g (0.004 mol) of ethyidiisopropylamine in 15 ml of tetrahydrofuran. The reaction mixture is stirred at 25° C. for 2 hours, evaporated and purified over silica gel (hexane/ethyl acetate 1:1). This gives 0.9 g (60%) of the title compound in the form of a yellowish resin. 1H NMR (CDCl3, ppm): 7.91-7.87, m, 3H; 7.64, t, J=7.5 Hz, 1 H; 7.5 0-7.40, m, 3H; 3.24, br t, J=4 Hz, 1 H; 3.14, br t, J=4 Hz, 1H; 2.70, s, 3H; 2.47, d, J=13.5 Hz, 1H; 2.40, 2.15, m, 3H; 1.95-1.8, m, 2H.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:20]
Reactant: COC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Product: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The title compound is prepared from benzyl 4-aminopiperidine-1-carboxylate and methyl chloroformate following a procedure analogous to that described for Intermediate 26 Step 1. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=293 [M+H]+.
Reaction SMILES: P(Br)(Br)[Br:2].C1C=CC=CC=1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([I:26])=[C:22]([CH:25]=1)[CH2:23]O>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([I:26])=[C:22]([CH:25]=1)[CH2:23][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)ccc1I
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Clc1ccc(I)c(CBr)c1
Yield: 247.4 %

Procedure:
A mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared while cooling and while stirring it is treated dropwise at a maximum temperature of 10° C. with 108.3 g of 5-chloro-2-iodobenzyl alcohol. Then, it is stirred for 4 hours at room temperature and for 1 hour at 50° C. After cooling, it is diluted with 120 ml of chloroform, the mixture washed with 25 ml of 5% hydrochloric acid, a 5% sodium hydroxide solution and with water, dried with magnesium sulfate and evaporated. There are obtained 126 g (95%) of crude 5-chloro-2-iodobenzyl bromide melting at 75°-79° C. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77°-79° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1)C.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C.[OH-].[Na+].[Cl-].[Na+].O>[C:26]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][C:29]([O:32][CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[O:16])=[CH:30][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C(=O)CBr)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CO[C@@H](Cc1ccc(C(=O)COc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from a solution of (2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester (25 mg, 0.076 mmol) in acetonitrile (5 ml). 4-phenylphenol (29 mg, 0.152 mmol) and K2CO3 (31,5 mg, 0.23 mmol) were added. The solution was stirred for 30 min at 80° C. and then cooled to room temperature. The mixture was concentrated to dryness under vacuum and chromatographed in silica gel (hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding to the coupled compound were collected (Rf0.27) and concentrated to dryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N and 12 mL of Methanol and stirred at room temperature until TLC indicates the disappearance of starting material. The methanol was eliminated under vacuum and the aqueous solution diluted with 20 mL of brine and washed with diethyl ether (3×15 mL). The aqueous phase was acidulated with HCl 1N (until pH 3); extracted with ethyl acetate (3×15 mL) and the organic layer dried (MgSO4) and concentrated under vacuum. Obtained a colorless oil (9.6 mg, 32%). 1H-NMR (200.15 MHz; CDCl3): δ 7.96 (d, 2H, J=8.4), 7.55–7.23 (m, 9H), 6.99 (d, 2H, J=8.8), 5.26 (s, 2H), 4.03 (dd, 1H, J=7.3, 5.6), 3.39 (s, 3H), 3.22 (dd, 1H, J=14.3, 5.5), 3.03 (dd, 1H, J=14.3, 7.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH2:12][CH2:13][CH3:14])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
To a solution of 7-chlorothiene[3,2-b]pyridine 2 (9.82 g, 57.89 mmol) in THF (290 mL) BuLi (2.5 N, 25 mL) was added at −78° C. and the mixture stirred for 20 min at the same temperature. Tributyltin chloride (63.68 mmol, 17.3 mL) was added dropwise and the mixture stirred for 2 h at −78° C. The homogeneous mixture thus obtained was poured in water (200 mL) and extracted with EtOAc (2×200 mL). The organic phase was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent EtOAc/Hex 1:4) to afford 7-chloro-2-(tributylstannyl)thieno[3,2-b]pyridine (6, 24.79 g, 93% yield) as a syrup. MS (m/z): cluster of signals centered around 460.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:23])([O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1>C(O)C.O>[OH:13][CH:5]([CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[C:4]([CH3:3])([CH3:23])[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(=O)Cc1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1cnccn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
0.107 g of sodium borohydride was added to a stirred suspension of 0.79 g of 4-[1,1-dimethyl-2-oxo-3-(2-pyrazinyl)propoxy]benzonitrile in 20 ml of ethanol. The mixture was stirred at 20° C. for 1.5 hours and was then diluted with water. The solution was extracted with ethyl acetate and the organic phase was then washed with sodium chloride solution and evaporated to give 0.5 g of 4-[2-hydroxy-1,1-dimethyl-3-(2-pyrazinyl)propoxy]benzonitrile in the form of a white solid of melting point 94°-95° C. (from diethyl ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[N:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]3[CH:16]=[N:17][N:18]=[C:13]3[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc3nncn3c2)cc1
Agent: [Pd]
Product: Nc1ccc(C2CCc3nncn3C2)cc1

Procedure:
6-(4-Nitrophenyl)-1,2,4-triazolo[4,3-a]pyridine is hydrogenated in the presence of palladium on carbon to give the product of the Example.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:11][CH:12]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:25]=1)[CH2:19][N:11]1[CH:12]=[C:8]([CH3:7])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: CCOC(=O)c1cc(C)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Under a nitrogen atmosphere with stirring add cesium carbonate (96 g, 295 mmoles) to a solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (30 g, 196 mmoles) in DMF (240 mL) and heat the reaction mixture to 40° C. to 45° C. for 1 hour. Cool the reaction mixture to room temperature and add a solution of 2-(bromomethyl)-4-chloro-1-nitro-benzene (54 g, 216 mmoles) in DMF (120 mL) drop-wise. Stir the resulting suspension for 1.5 h to 2.0 h, filter the solids and rinse the filtercake with DMF (45 mL). Transfer the solids to a clean reaction vessel, add water (200 mL) and cool the suspension to 10° C. to 15° C. with stirring for 1 h to 2 h. Filter the suspension, rinse with water (75 mL) and transfer the solids to another reaction vessel. Add ethanol (125 mL) and stir the suspension at 5° C. to 10° C. for 1 h to 2 h. Filter the solids, rinse the filtercake with ethanol (20 mL), and dry the solids in an oven at less than 50° C. under reduced pressure to give ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate as a yellow solid (54 g, 94.1% purity, 73.3% yield).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][C:6](Cl)=[O:7])[CH3:2].[NH2:9][CH2:10][C:11]([N:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][C:15]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:14]1=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH2:19][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:6](=[O:7])[CH2:5][CH2:4][S:3][CH2:1][CH3:2])[C:14]=2[CH:27]=1
Reactant: CCSCCC(=O)Cl
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
A solution of 3-(ethylthio)propanoyl chloride (0.87 grams) in methylene chloride (10 mL) was added dropwise to a stirred solution of 10-(aminoacetyl)-8- chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (1.50 grams) and triethylamine (0.84 mL) in methylene chloride (40 mL) in an ice bath at 5° C. under nitrogen. The ice bath was removed, and the reaction was stirred for 3 hours. The reaction was diluted with methylene chloride (50 mL) and washed with 50 mL each of 1N HCl, saturated aqueous sodium bicarbonate, and brine. The solution was then dried over MgSO4 and evaporated in vacuo. The yield of the title compound was 1.90 grams (90%). Mp: 148°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11]C2CCCCO2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=[O:6]>CO>[OH:11][C:9]1[CH:8]=[C:7]([CH3:18])[C:4]([CH:5]=[O:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1C=O
Solvent: CO
Product: COc1cc(O)cc(C)c1C=O
Temperature: 50 °C
Yield: 78 %

Procedure:
Crude 2-methoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde from the above step was diluted with MeOH (30 mL), then treated with Amberlyst® 15 (0.10 g). The suspension was heated at 50° C. for 1 h. The resin was removed by hot filtration and the filtrate was concentrated to a yellow semi-solid. The residue was recrystallized from MeOH and hexanes to give 4-hydroxy-2-methoxy-6-methyl-benzaldehyde (4.16 g, 78% over 2 steps), as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 6.32 (s, 1H), 6.25 (s, 1H), 5.49 (br s, 1H), 3.87 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[CH:34][CH:33]=2)[CH:3]=1)[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(ethyl-(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1 g, 2.82 mmol) and 4-((morpholino)methyl)phenylboronic acid pinacol ester (1.03 g, 3.38 mmol) in dioxane/water mixture (10 mL+2 mL), Na2CO3 (1.08 g, 10.14 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.325 g, 0.28 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.75 g, 59%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C@H:27]1[CH2:32][N:31]([CH:33]2[CH2:36][O:35][CH2:34]2)[C@H:30]([CH3:37])[CH2:29][N:28]1[C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]2[C:46](=[O:60])[N:47]([CH3:59])[CH:48]=[C:49](B3OC(C)(C)C(C)O3)[CH:50]=2)=[N:42][CH:43]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.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]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:49]3[CH:50]=[C:45]([NH:44][C:41]4[CH:40]=[CH:39][C:38]([N:28]5[CH2:29][C@@H:30]([CH3:37])[N:31]([CH:33]6[CH2:36][O:35][CH2:34]6)[CH2:32][C@@H:27]5[CH3:26])=[CH:43][N:42]=4)[C:46](=[O:60])[N:47]([CH3:59])[CH:48]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: CC1OB(c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (216 mg, 0.6 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (360 mg, 0.72 mmol), Pd(dppf)Cl2 (30 mg, 0.03 mmol), K3PO4 (270 mg, 1.2 mmol), and NaOAc.3H2O (180 mg, 1.2 mmol) in CH3CN (80 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 25:1 of CH2Cl2/MeOH to afford 110a (160 mg, 42%) as a yellow brown solid. MS: [M+H]+ 693.3.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[OH-:9].[Na+].C.OO>O.[Pd]>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: [OH-]
Agent: [Pd]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 92 %

Procedure:
13.8 g (0.1 mol) of ethyl(2-hydroxyethyl)phosphinic acid (prepared as in Example 8) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.25 g of charcoal with 5% Pd and 1% Bi is added, the suspension is heated to 70° C. and 30% strength hydrogen peroxide solution is passed into the suspension at a flow rate of 1 mol equivalent per hour. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction has ended, the reaction solution is filtered to remove the catalyst, which is washed, the filtrate is made acidic with hydrochloric acid and the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 14.0 g (92% of theory) of 2-(ethylhydroxy-phosphinyl)acetic acid as colorless solid.
Reaction SMILES: [CH:1]1([Li])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:12][Si:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[C:17]([NH:16][Si:13]([CH3:15])([CH3:14])[CH2:12][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: [Li]C1C=Cc2ccccc21
Reactant: CC(C)(C)N[Si](C)(C)CBr
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)CC1C=Cc2ccccc21
Yield: 29 %

Procedure:
A 20 g (182 mmol) solution of indenyl lithium in tetrahydrofurane was added to a solution of 41 g (182 mmol) of 2-bromo-1-tertbutylamino-1,1-dimethylsilaethane at 0° C. After the reaction was concentrated to dryness and the residue was extracted with hexane. Finally, the solution in hexane was concentrated to the obtainment of an orange oil: 13.5 g (52 mmol, yield: 29%). 1H-NMR (CDCl3): 7.50(m,1H), 7.39(m,1H), 7.35(m,1H), 7.23(m,1H), 6.17(m,1H), 3.42(m,2H), 2.17(m,2H), 1.22(m,9H), 0.20(m,6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 78%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][C:19]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: C#CCOCCn1c(C)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 20 h
Yield: 41.9 %

Procedure:
Using the general method of Example 12 Part A, 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (3.6 g, 13.57 mmol) was reacted with iodobenzene (1.7 mL, 14.92 mmol) at ambient temperature. After 20 hours the reaction was judged complete. The solution was basified with 5% aqueous sodium bicarbonate and then extracted with dichloromethane (3×). The organics were combined, washed with water (3×), washed with brine, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. Purification was completed by chromatography over silica gel (95/5 dichloromethane/methanol) and recrystallization from acetonitrile to provide 1.94 g of 2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[N+:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[O:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])([O-:17])=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)CC)C>CN(C)C=O.O>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:24]([C:23]2[C:22]([O:21][C:20]3[CH:31]=[CH:32][CH:33]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CCC(CN)CC1
Reactant: O=C(O)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(CNC(=O)c2cccnc2Oc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester hydrochloride (0.500 grams, 2.26 mmole), 2-(3-Nitro-phenoxy)-nicotinic acid (0.588 grams, 2.26 mmole), 1-hydroxybenzotriazole hydrate (0.366 grams, 2.71 mmole) and 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.564 grams, 2.93 mmole) in dimethylformamide (50 ml) was was added triethyl amine (0.456 grams, 4.52 mmole) and stirred over the weekend at room temperature. The mixture was diluted with water (150 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 40% ethyl acetate/hexane to give an oil. (1.05 g). MS (m/e) 428 (M++1); 1H NMR (CDCl3) d 1.01 (2H, m), 1.2 (3H, t), 1.4 (2H, q), 1.6 (1H, m), 1.90 (2H, d, J=12.5 Hz), 2.0 (1H, d, J=12.5 Hz), 2.2 (1H, m), 3.4 (2H, m), 4.10 (2H, q), 7.20-8.7 (7H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:26][CH3:27])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.I[Cl:29]>ClCCl>[Cl:29][C:6]1[C:7]2[CH:8]=[C:9]3[C:18]4[C:13](=[CH:14][C:15]5[O:21][CH2:20][O:19][C:16]=5[CH:17]=4)[CH2:12][CH2:11][N:10]3[C:22]([CH3:24])([CH3:25])[C:23]=2[C:3]([O:2][CH3:1])=[C:4]([O:26][CH3:27])[CH:5]=1
Reactant: ClI
Reactant: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Solvent: ClCCl
Product: COc1cc(Cl)c2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.8 %

Procedure:
To a solution of 9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (182 mg, 0.5 mmol) in anhydrous dichloromethane (20 mL) at 25° C. was added Iodine monochloride (0.57 g, 3.5 mmol). After stirring in the dark at 25° C. for 72 h, the reaction was washed twice with aqueous 10% sodium thiosulfate solution (2×50 mL) to remove excessive iodine monochloride, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters Automated Flash System (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 12-chloro-9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (9.6 mg, 4%). LC/MS m/e calcd for C22H22ClNO4 (M+H)+: 400.88, observed: 400.1; 1H NMR (400 MHz, MeOD) δ ppm 2.05 (s, 6 H) 3.14 (m, 2 H) 3.93 (s, 3 H) 4.01 (s, 3 H) 4.23 (m, 2 H) 6.22 (s, 2 H) 7.04 (s, 1 H) 7.32 (s., 1 H) 7.63 (s, 1 H).