Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C@@H:11]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:57]O.[OH-].[Na+]>C1COCC1>[CH2:50]([O:49][C@H:11]1[C@H:12]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[C@@H:15]([OH:57])[C@@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: OO
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2[C@@H](O)[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred 0° C. THF solution of ((1S,2S,3R,6R)-4-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohex-4-ene-1,2,3-triyl)tris(oxy)tris(methylene)tribenzene (27, 150 mg, 0.196 mmol) was added dropwise BH3OEt2 (2M, 0.98 mL, 1.962 mmol). After stirring for 2 h at 0° C., the mixture was warmed to 25° C. and stirred overnight. H2O2 (30%, 4.2 mL) was added, followed by added aqueous NaOH solution (1M, 3.93 mL, 3.93 mmol) to the reaction mixture at 0° C. After complete addition, the reaction mixture was warmed to 25° C. and stirred for 3 h. The reaction was quenched by addition of dilute HCl (1N, 10 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were washed with water and brine prior to drying over anhydrous Na2SO4. The residue was purified by preparative TLC (EA:PE=1:8 v/v) to obtain 59 mg of (1S,2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohexanol (28).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].O[C:15]1[C:23]2N=N[NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C=CC(C2S[S:49][C:48](=S)C=2)=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][C:16]1[CH:17]=[CH:18][C:19]([N:20]=[C:48]=[S:49])=[CH:23][CH:15]=1)=[O:12])(=[O:3])[CH3:1]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(N=C=S)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To the solution of 1 (aspirin, 1200 mg, 6.67 mmol) in 60 mL of dimethylformamide, hydroxybenzotriazole (992 mg, 7.34 mmol) and DCC (1520 mg, 7.34 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxyphenylisothiocyanate (2; 1109 mg, 7.34 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate and the precipitate was removed. The solvent was evaporated and the crude product was loaded on a silica gel open column and eluted with chloroform/n-hexane 6:4, from which 4-isothiocyanatophenyl 2-acetoxybenzoate (3) was obtained (150 mg, 7% yield).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([S:20][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccccc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 14.2 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 5.5 g of thiophenol in methanol to yield white crystals, mp 62.5°-65° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]([Br:17])=[C:15]([NH2:18])[N:14]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:13]3[N:12]=2)[CH2:7][NH:6]1)=[O:4].[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.[OH-].[Na+].Cl>C1COCC1.CN(C=O)C>[NH2:18][C:15]1[N:14]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][N:6]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:16]=1[Br:17]
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Reactant: COCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(=O)N1CC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CCC1C(=O)O
Yield: 35 %

Procedure:
A mixture of 5-(7-amino-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-piperidine-2-carboxylic acid methyl ester (20 mg, 0.042 mmol), methoxy-acetyl chloride (13 mg, 0.071 mmol) and triethylamine (0.024 ml, 0.167 mmol) in THF:DMF (0.5 ml:0.5 ml) was stirred at room temperature for 16 h. The crude mixture was treated with 2.0 N sodium hydroxide solution (0.14 ml) at room temperature for 16 h. The reaction mixture was acidified with 1.0 N aqueous hydrogen chloride solution (0.5 ml), concentrated and purified by prep-LC to afford the title compound (7.94 mg): LC/MS RT=3.06 min. Mass calculated for, M+H 539.10, observed 539.10.
Reaction SMILES: [OH-].[K+].[C:3](O)(=O)[CH:4]=C.C(O)[C@H]1O[C@H:13]([O:15][C@:16]2([CH2:25][OH:26])O[C@H:19]([CH2:21]O)[C@@H:18](O)[C@@H:17]2O)[C@H:12](O)[C@@H](O)[C@@H]1O.C(OCCO)(=O)C(C)=C.C([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C>O>[CH2:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:21]=[CH:4][CH:3]=1)[C:25]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:26])[CH3:12]
Reactant: CC(=O)c1ccccc1
Reactant: C=CC(=O)O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: C=C(C)C(=O)OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(C(=O)c1ccccc1)c1ccccc1

Procedure:
The powdered KOH is added slowly to the acrylic acid and the saccharose and water in a reaction flask kept in an ice-water bath. The temperature is kept between 40° and 50° C. After neutralization, the pH-value of the resulting solution is adjusted to 7.8. Then 2-hydroxyethyl methacrylate and the acetophenone are added. The mixture is then poured into the polymerization trough and polymerization is effected by UV-radiation at a bath temperature of 50° C. and a reaction temperature of 60° C. The product is readily millable.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:3].[CH3:26][Cl:27]>C(O)(C)C>[Cl-:27].[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:26])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCCOCCCN(C)C
Reactant: CCl
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCOCCC[N+](C)(C)C
Product: [Cl-]

Procedure:
A 1-L autoclave equipped with a stirrer and a thermometer was charged with N,N-dimethyl-3-octadecyloxy-propylamine (300 g) obtained in Example 1A, isopropyl alcohol (90 g) and methyl chloride (100 g) to conduct a reaction at 90° C. for 6 hours. Excessive methyl chloride was topped to obtain an isopropyl alcohol solution of N,N,N-trimethyl-3-octadecyloxypropylammonium chloride. The quaternizing rate was 98% (KSTM 20082).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]([CH3:59])[C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:52](=[O:53])[C@H:51]([C:55]([CH3:57])([CH3:56])[CH3:58])[NH:50][C:48](=[O:49])[N:47]([CH3:59])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 63C (0.013 g, 0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.022 g, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75(m, 9H), 0.78(m, 9H), 1.35-1.22(m, 1H), 1.65-1.54(m, 1H), 2.77-2.60(m, 4H), 2.79(s, 3H), 3.57(s, 3H), 3.83-3.77(m, 1H), 3.94-3.83(m, 1H), 4.09-4.06(d, J=8.82 Hz, 1H), 4.21-4.10(m, 1H), 4.51-4.38(m, 2H), 4.77-4.75(d, J=5.52 Hz, 1H), 5.43-5.40(d, J=8.82 Hz, 1H), 6.85-6.82(d, J=9.52 Hz, 1H), 7.26-7.10(m, 10H), 7.35-7.30(m, 1H). 3H), 7.60-7.57(d, J=9.19, 1H), 7.79-7.77(d, J=7.72 Hz, 1H), 7.93-7.82(m, 4H), 8.65-8.62(m, 1H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2/[C:23](/Cl)=[N:24]/[OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:3]=[C:2]([C:1]([NH2:5])=[O:4])[O:25][N:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(N)=O
Reactant: O=C1N2C[C@@H](CC[C@H]2/C(Cl)=N/O)N1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Propiolamide (0.30 g, 4.37 mmol) was added to a solution of (2S,5R,Z)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carb imido yl chloride (3.64 mmol) in dry DCM (10 mL), followed by the addition of TEA (0.56 mL, 4.0 mmol) in DCM (2 mL) over a 30 minute period. The reaction mixture was stirred at rt overnight. Then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 5:1 to 1:2, petroleum ether/EtOAc containing 1% TEA) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.4 g, 32%) as a yellow solid. ESI-MS (EI+, m/z): 343 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]=O.[ClH:14].[CH3:15][NH:16][CH3:17]>>[ClH:14].[CH3:15][N:16]([CH2:12][CH:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[CH3:17]
Reactant: C=O
Reactant: O=C1CCCc2ccccc21
Reactant: CNC
Agent: Cl
Product: CN(C)CC1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Specifically, first, a mixture liquid was obtained by feeding 73 g (0.5 mol) of α-tetralone, 47.3 g (0.55 mol) of a 37% by mass aqueous formalin solution, and 45 g (0.55 mol) of dimethylamine hydrochloride to a 500-ml three-necked flask. Next, a bulb condenser was set to the three-necked flask, and then the inside atmosphere of the three-necked flask was replaced with nitrogen. Thereafter, the three-necked flask was immersed in an oil bath of 100° C., and the mixture liquid was stirred for 60 minutes with heating. After thus stirred, the mixture liquid was cooled with ice to 25° C., and was washed twice with diethyl ether (twice with 30 ml each). Subsequently, the thus washed mixture liquid was allowed to stand one day and one night (24 hours). White crystals formed in the mixture liquid were separated by filtration, and washed with acetone. The thus obtained white crystals were vacuum dried. Thus, 12.9 g of N,N-dimethylaminomethyl-1-tetralone hydrochloride was obtained (yield: 11%). Note that the thus obtained compound was subjected to NMR measurement. As a result, it was found that a purity of N,N-dimethylaminomethyl-1-tetralone hydrochloride was 85.7%, and that 14.3% of dimethylamine hydrochloride was included as a by-product.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([CH2:12][P+](CCCC)(CCCC)CCCC)[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[CH:28]([C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=O>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10](/[CH:12]=[CH:28]/[C:30]3[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=3)[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1nc2cc(Br)cnc2[nH]1
Reactant: CC(=O)Nc1cc(C)cc(C=O)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)cc(/C=C/c2nc3cc(Br)cnc3[nH]2)n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 6-brom-3H-midazo[4,5-b]pyridin-2-yl-methyl-tributyl-phosphonium-chloride (compound A5) are suspended in 50 ml of tetrahydrofuran and added to a suspension of sodium hydride (60% strength) in 50 ml tetrahydrofuran at room temperature. After vigorously stirring for 10 min, 1.43 g of N-(6-formyl-4-methyl-pyridin-2-yl)-acetamide (compound B11) is added in portions (10 min). Subsequently, the suspension is heated at 90° C. for 22 h. Thereafter, the mixture is filtered with suction and the remaining residue is rinsed with tetrahydrofuran. The pure title compound is obtained by evaporating the filtrate to dryness to afford 1.88 g of an amorphous solid. M.p. >350° C. ESI-MS: 372.1/374.1 (MH+; 99%/100%). TLC: Rf=0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C(=O)([O-])O.[Na+].[C:21](OC)(=[O:24])[C:22]#[CH:23]>ClCCl.CO>[C:8]([C:7]1[CH:23]=[CH:22][C:21](=[O:24])[N:2]2[CH:6]=[CH:5][NH:4][C:3]=12)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ncc[nH]1)c1ccccc1
Reactant: C#CC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(=O)n2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
500 mg (2.25 mmol) of 2-(1H-Imidazol-2-yl)-1-phenylethanone hydrochloride (example L, step 1) are suspended in dichlormethane. Sodium hydrogen carbonate is added to the suspension and stirred for 1 h at rt. The suspension is filtrated and the solvent is evaporated under vacuum to yield the free base. The crude is dissolved in 3 ml methanol. 188.78 mg (2.25 mmol) of methyl propiolate are added dropwise to the solution. The mixture is stirred for 24 h at rt. The suspension is filtrated and the precipitate is washed with methanol and diethylether to yield 214 mg (40.0% of th.) 8-Benzoylimidazo[1,2-a]pyridin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24].C(O)(=O)C.N>CCO>[OH:24][CH2:23][C:22]1[C:21]([CH3:28])=[C:20]([CH:27]=[CH:26][CH:25]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: Cc1c(N)cccc1CO
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(CO)c3C)c2cc1OC
Yield: 48.6 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.15 g, 0.56 mmol), 3-amino-2-methylbenzylalcohol (0.1 g, 0.73 mmol), acetic acid (0.2 ml) in EtOH (10 ml) was refluxed for 4 h. After cooling the pH was adjusted to 9 with aqueous NH3. The resulting precipitate was filtered off and washed with cold EtOH and dried in vaccum at 40° C. to give 0.1 g (49% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH:13][CH3:14]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:12]=[C:13]([CH3:14])[C:3]=12
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC=C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Cl)ncc(Br)c12
Temperature: -40 °C

Procedure:
To a solution of 5-bromo-2-chloro-3-nitro-pyridine, (10.28 g) in dry tetrahydrofuran (450 ml) at −78° C. under an atmosphere of nitrogen was added dropwise, a solution of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran; 305 ml), keeping the internal temperature below −70° C. The solution was allowed to warm to −40° C. over 1 h then quenched with saturated ammonium chloride (350 ml). The aqueous was extracted twice with ethyl acetate (2×200 ml) and the combined organics were dried (MgSO4), filtered and evaporated to give a brown oil. The mixture was dissolved in ether, a solid filtered off then evaporated. The residue was dissolved in ether, loaded onto four Biotage silica samplets and purified by Biotage chromatography over silica gel (4×100 g), eluting with 10% ethyl acetate/isohexane (1 L) followed by 15% ethyl acetate/isohexane (1 L). The fractions containing product from the four columns were combined and evaporated to afford an orange solid. The orange solid was triturated with isohexane, filtered and washed with isohexane and dried to give the title compound as an off white solid. (1.07 g).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[Li]CCCC.[P:13](Cl)([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:16]([O:15][P:13]([CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: CCOS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]1[C:21]([CH3:35])=[C:22]2[C:27](=[C:28]([CH3:31])[C:29]=1[CH3:30])[O:26][C:25]([CH2:33]I)([CH3:32])[CH2:24][CH2:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[C:21]([CH3:35])=[C:22]2[C:27](=[C:28]([CH3:31])[C:29]=1[CH3:30])[O:26][C:25]([CH2:32][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:33])[CH2:24][CH2:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CI)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(COc1ccc(C=O)cc1)O2
Yield: 97.6 %

Procedure:
A mixture of 1.63 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and 20 ml of dimethylformamide was cooled in an atmosphere of nitrogen; to the cooled solution were then added dropwise a mixture of 4.58 g of p-hydroxybenzaldehyde and 30 ml of dimethylformamide, whilst ice-cooling. 10.9 g of 6-benzyloxy-2-iodomethyl-2,5,7,8-tetramethylchroman (prepared as described in Preparation 2) and 50 ml of dimethylformamide were then added to the resulting solution, and the resulting mixture was heated under reflux for 5.5 hours. At the end of this time, the reaction mixture was extracted twice, each time with 100 ml of ethyl acetate. The combined extracts were washed with water, and the solvent was then removed from the extract by distillation under reduced pressure to afford 10.5 g of the title compound as an oil. Nuclear Magnetic Resonance Spectrum (CDCl3, 60 MHz), δ ppm: 1.43 (3H, singlet); 1.63-2.27 (2H, multiplet); 2.03 (3H, singlet); 2.13 (3H, singlet); 2.20 (3H, singlet); 2.43-2.90 (2H, multiplet); 4.00 (2H, singlet); 4.63 (2H, singlet); 6.97 (2H, doublet, J=9 Hz); 7.10-7.60 (5H, multiplet); 7.77 (2H, doublet, J=9 Hz); 9.77 (1H, singlet).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH3:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([C:17](=[O:19])C)=[CH:11][CH:10]=3)(=[O:3])C.[OH-:22].[Na+].Cl[O-:25].[Na+].S(=O)(O)[O-].[Na+].Cl[O-].Cl>N1C=CC=CC=1>[CH2:20]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([C:17]([OH:22])=[O:19])=[CH:13][C:14]=2[C:15]2[C:7]1=[CH:6][CH:5]=[C:4]([C:1]([OH:25])=[O:3])[CH:16]=2)[CH3:21]
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(C)=O)ccc21
Reactant: [OH-]
Reactant: [O-]Cl
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Nineteen (19) grams of the 3,6-diacetyl-N-ethylcarbazole from Example 1 was dissolved in 800 ml pyridine and added to 400 ml of 5% aqueous sodium hydroxide in a 6-liter Erlenmeyer flask. While cooling the mixture in ice, 1429 ml of 5% sodium hypochlorite (bleach) was added. The reaction was allowed to stir 3.5 hours at room temperature. A concentrated solution of sodium bisulfite was added until no hypochlorite remained (starch-iodine test). The basic solution was neutralized with concentrated HCl and the precipitated diacid filtered. The yield of N-ethylcarbazole-3,6-dicarboxylic acid was 13.12 g. Elemental analysis was as follows. Calculated for C16H13NO4 :%C, 67.84; %H, 4.63; %N, 4.94. Found: %C, 67.60; %H, 4.64; %N, 4.88.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[S:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C.ClC1C2C=CSC=2N=CN=1>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[S:31][CH:30]=[CH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2ccsc12
Agent: Cl
Agent: Clc1ncnc2sccc12
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 49.8 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2, 50 mg, 0.166 mmol), 4-chlorothieno[3,2-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 50° C. for 24 hrs and at 80° C. for 27 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (33 mg, 50%).