Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]3[CH2:14][C:13](=[O:15])[N:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:11]=[C:10]3[C:4]=2[CH:3]=1.BrBr>C(O)(=O)C>[Br:1][C:2]1[S:23][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[C:10](=[N:11][N:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:13](=[O:15])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CC2CCCc3sc(Br)cc3C2=NN1c1ccc(Cl)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Br)sc1CCC2
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
To a solution of 2.5 g of 9-bromo-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in 40 ml of acetic acid is added a solution of 1.1 g of bromine in 5 ml of acetic acid with stirring at 40° C. over a period of 10 minutes. The mixture is stirred at 40°-50° C. for 20 minutes and poured into ice-cold water. The precipitated crystals are collected by filtration, washed with water, dissolved in chloroform and subjected to column chromatography on silica gel. The crystals obtained from the fraction which has been eluted with chloroform are recrystallized from a mixed solvent of ethanol and chloroform to give 1.5 g of 9-bromo-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as white crystals, melting at 143°-144° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2[O:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:28]([O:27][C:25]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2[O:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:26])[CH3:29]
Reactant: CCOC(=O)c1oc2cc(OCc3ccccc3)ccc2c1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1c(C(=O)OCC)oc2cc(OCc3ccccc3)ccc12
Yield: 82.3 %

Procedure:
A mixture of 40 g (0.13 mol) of ethyl 3-amino-6-(phenylmethoxy)benzofuran-2-carboxylate, 18 ml (0.19 mol) of ethyl chloroformate and 51 g (0.37 mol) of potassium carbonate in 400 ml of benzene is heated at reflux for 18 hours and is then cooled and filtered and the filtrate is concentrated under reduced pressure. 41 g of product are obtained by recrystallization of the residue from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C@@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([NH:34][C@H:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:33])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)N[C@@H](C)c1cccc2ccccc12)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100.0 mg (0.325 mmol) of 2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionic acid from Example 105A are placed in 2 ml of DMF and treated with 61.2 mg (0.357 mmol) of (1S)-1-(1-naphthyl)ethanamine, 52.7 mg (0.390 mmol) of HOBt and 81.0 mg (0.422 mmol) of EDC hydrochloride. The mixture is stirred overnight at room temperature, then partitioned between dichloromethane and water, and the organic is phase separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromato-graphy on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) and then further separated by preparative HPLC on chiral phase [Method 15]. 51 mg (34% of theory) of the diastereomerically pure target compound are thus obtained (see also Example 186).
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH:34]=[CH:33][C:32](B(OC(C)C)OC(C)C)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][N:8]=[C:7]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)=[CH:31]1
Reactant: CC(C)OB(OC(C)C)c1ccoc1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4ccoc4)cc23)ccc1OCc1ccccn1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 3-furylboronate to give 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-quinazoline in 55% yield, m.p. 206°-208° C.;
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[CH3:36][O:37][CH2:38][C:39]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])=[O:40]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1cc(C)ccc1NC(=O)COC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a cooled (0° C.) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g (19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxyacetylchloride. The mixture was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 and washed with H2O, 2 N citric acid, H2O, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2-{[2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzene-sulfonyl)-amino}acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([O:66]CC)=[O:65])=[CH:58][CH:57]=1>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:55][C:56]3[CH:57]=[CH:58][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([OH:66])=[O:65])=[CH:60][CH:61]=3)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2o1
Yield: 30.6 %

Procedure:
A solution of 2-(o-tolylaminobenzoxazol-6-yl)acetic acid (1.0 g, Reference Example 4) in dimethylformamide (75 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.35 g), then with diisopropylethylamine (1.2 mL) and then with ethyl (R)-3-(4-aminophenyl)butanoate (0.74 g, Reference Example 1). The mixture was kept at room temperature for an hour and then evaporated to low bulk. The residue was partitioned between hydrochloric acid (1M) and dichloromethane. The organic phase was washed with aqueous bicarbonate solution (5%) then with water, then dried, and then evaporated. The residue was suspended in ethanol (about 50 mL). The mixture was treated with aqueous sodium hydroxide (about 5 mL, 1M), then refluxed for 2 hours, then evaporated. The residue was triturated with aqueous hydrochloric acid (1M) then filtered. The insoluble material was washed with water, and then dried to give the title compound (0.48 g) as a white powder. MS: accurate mass=444.1936 (calculated 444.1923 MH+). LC-MS: RT=3.19 minutes (100% by ELSD); MS (ES+), 444 (MH+).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:31]([CH3:39])([CH2:32][CH2:33][C:34]=32)[C@@H:19]([C@H:20]([CH3:30])[CH2:21][OH:22])[CH2:18][CH:17]=4)[C:11]1([CH3:40])[CH3:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Yield: 67.2 %

Procedure:
vii)—A mixture of compound 8 (32.3 g), toluene (84 ml), ethanol (96%; 588 ml) and concentrated hydrochloric acid (84 ml) was heated under reflux for 3 h. The mixture was cooled and poured into a saturated aqueous solution of sodium hydrogen carbonate (1 l). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded a 3:1 mixture (17.4 g) of (3β,5α,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol 3-benzoate (9) and (3β,5α,20S)-4,4,20-trimethylpregna-6,8(14)-diene-3,21-diol 3-benzoate. The mixture was used as such in the next step.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (151 mg, 0.45 mmol) and the product from step 4 of Example 99 (200 mg, 0.42 mmol) were dissolved in pyridine (5 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.45 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-N2)+=764.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.220 g, 0.57 mmol) and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 was added trimethylacetyl chloride (0.11 mL, 0.86 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was concentrated to give the title compound.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Zn]>[C:16]1([S:15][CH2:14][CH2:13][CH:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(CCSc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(SCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.47 g (3.71 mmol) of 1-(2,2,2-trichloroethoxycarbonyl)-4-(2-(phenylmercapto)ethyl)piperidine in 20 mL of glacial acetic acid was heated at 40° C. To this solution was added portionwise 2 g of zinc powder over a period of 1 h with vigorous stirring. After 24 h at 40° C., the reaction mixture was cooled to rt and carefully poured into 250 mL of sat'd NaHCO3 solution. The mixture was extracted 5 times with CH2Cl2 and the combined organic fractions were washed with sat'd NaCl solution, and dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[N:11]([CH2:10][C@@H:9]([OH:20])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 4.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.300 g, 3.34 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (1.740 ml, 10.01 mmol) and benzyl chloroformate (0.683 g, 4.00 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (10% Et2O in CH2Cl2) gave 0.083 g of a white solid. MS (ES): 524 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][NH:14][CH3:15].C(=O)(O)[O-].[Na+].CO>C(O)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:14]([CH3:15])[CH3:13])=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 250 mg of 3-(2-bromoethyl)indole in a round-bottomed flask, a 10 M excess of dimethylamine (6 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After adding 5 mL sodium bicarbonate (2%), the reaction mixture was extracted with chloroform (3×5 ml) and back extracted with H2O (1×5 mL). The combined extracts were dried over MgSO4 and evaporation of the solvent gave the product in crystalline form. Yield: 0.21 g, 84%, yellowish crystals. m.p.: 45-47° C.; TLC (EtAc:MeOH:acetic acid, 8:2:0.5 v/v/v): RF=0.33. 1H NMR, δ: 10.43 (s, 1H), 7.42-7.06 (m, 5H), 2.68 (m, 4H), 2.26 (S, 6H). 13C NMR (CDCl3): δ 136.5, 124.3, 123.2, 121.2, 119.7, 117.6, 113.4, 111.1, 61.7, 41.2, 22.4. Anal. calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88%. Found; C, 76.60; H, 8.70; N, 14.70%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[N:8][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:6]=2.[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](O)=O)=[CH:34][C:33]([O:39][CH3:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O>C(#N)C>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]3[O:12][C:11](=[O:13])[C:10]4[C:9]5=[N:8][N:7]([CH2:14][C:15]6[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=6)[CH:6]=[C:5]5[CH:4]=[C:3]([CH3:23])[C:2]=4[N:1]=3)=[CH:34][C:33]([O:39][CH3:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: COc1ccc(Cn2cc3cc(C)c(N)c(C(=O)O)c3n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2cc3cc(C)c4nc(-c5cc(OC)nn5-c5ncccc5Cl)oc(=O)c4c3n2)cc1
Reaction time: 0.75 h

Procedure:
A suspension of 6-amino-2-(4-methoxy-benzyl)-5-methyl-2H-indazole-7-carboxylic acid (0.288 g, 0.925 mmol) in acetonitrile (4 ml) was stirred at 20° C. for 10 minutes before the acyl chloride prepared from 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid and oxalyl chloride (0.265 g, 0.971 mmol) was added. After 45 minutes stirring, 2,6-lutidine (0.215 ml) was added, followed 10 minutes later by methanesulfonyl chloride (0.072 ml, 0.925 mmol). After 18 hours of reaction, the mixture was concentrated under vacuum and water (25 ml) was added. The product was extracted with ethyl acetate and purified by flash chromatography on silica gel using a gradient from 50% to 100% ethyl acetate in cyclohexane. The desired product was obtained as light orange crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(O)=[O:29]>>[CH2:23]([O:22][P:20]([CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:29])[NH:10][C:9]([NH2:11])=[N:8][C:7]1=2)([O:25][CH2:26][CH3:27])=[O:21])[CH3:24]
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: O=CO
Product: CCOP(=O)(COCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
6-Chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]-2-formamidopurine (1.5 g, 3.56 mmol) was heated at 100° C. for 2 h in 80% formic acid (15 ml) then evaporated under reduced pressure. The residue was taken up in methanol (15 ml) and 0.88 ammonia (15 ml) and stirred at 25° C. for 1 h then evaporated to dryness. Precipitation from hot water afforded 9-[3-(diethoxyphosphorylmethoxy)propoxy]guanine (0.69 g, 52%) as a pale yellow solid; νmax 3335, 1694, 1475, 1390, 1249, 1026 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.90(2H, m, CH2CH2CH2), 3.68(2H, t, J6 Hz, CH2OCH2P), 3.83(2H, d, J8.3 Hz, CH2P), 4.03(4 H, m, (CH3CH2O)2), 4.31(2H, t, J6.6 Hz, CH2ON), 6.60(2H, br.s, D2O exchangeable, NH2) 7.95(1H, s, H-8), 10.50(1H, br.s, D2O exchangeable, NH); Found C, 41.90; H, 5.94; N, 18.65%; C13H22N5O6P requires: C, 41.60; H, 5 91; N, 18.61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3[C:15](=[O:23])[O:16][C:17]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:24][O:20][C:19]([C:17]1([CH3:22])[O:16][C:15](=[O:23])[C:14]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)=[O:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(C)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To 50 mg (0.15 mmol) of 44 in 2 mL of a 1:1 CH2Cl2/MeOH is added 0.07 mL (0.14 mmol) of 2 M trimethylsilyl diazomethane in hexanes. After stirring for 1 h another 0.07 mL (0.14 mmol) of 2M trimethylsilyl diazomethane is added. The mixture is stirred for 1 h, concentrated, dissolved in 50 mL of EtOAc, and washed with twice with 20 mL of H2O and once with 20 mL of brine. The organic phase is dried with MgSO4, filtered, and concentrated to give 21 mg (0.06 mmol) of 45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[C:18]1([CH3:40])[CH:23]=[CH:22][C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C(O[K])(C)(C)C.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([N:24]([C:25]3[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=3)[C:21]3[CH:22]=[CH:23][C:18]([CH3:40])=[CH:19][CH:20]=3)=[CH:38][CH:37]=2)=[CH:16][CH:17]=1
Reactant: CCOP(=O)(Cc1ccc(OC)cc1)OCC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1

Procedure:
Same mol of the diethyl 4-methoxybenzylphosphonate and 4-(di-para-tolylamino)benzaldehyde were dissolved in N.N-dimethylformamide, and tert-butoxy kalium was gradually added to the solution while water-cooled and stirred. After stirred for 5 hrs at a room temperature, water was added thereto to acidize the solution and a crude product is separated out. The crude product was further column-refined with silica gel to prepare 4-methoxy-4′-(di-para-tolylamino)stilbene.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][C:11]3=[S:19])[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: S=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 60 mg (0.18 mmol) of 3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridine-2-thione and 38 mg (0.21 mmol) of methyl 4-bromobutyrate and 58 mg (0.42 mmol) of potassium carbonate in 2 mL of DMF is stirred at room temperature for 18 h. The mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluted with 1˜5% methanol in dichloromethane to give the desired compound.