Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:26])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.0 g, 16.3 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.7 g, 17.5 mmole). After 10 min, methyliodide (11.57 g, 81.5 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (5.17 g, 99%) as a white solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)Cc1cc(Cl)ccc1OC
Temperature: 82 °C
Yield: 85 %

Procedure:
A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet, thermocouple and reflux condenser, was vacuum/argon purged. The flask was charged with the product obtained in Step A (345.0 g, 1.72 mol), anhydrous potassium carbonate (285 g, 2.06 mol) and anhydrous acetonitrile (1.7 L). To the resultant suspension was added dimethyl sulfate (200 mL, 2.11 mol) over 5 minutes with stirring and then heated to reflux at about 82° C. for 1.5 h to complete the esterification. The reaction mixture was cooled to room temperature and the excess dimethyl sulfate was quenched with triethylamine (70 mL). The resultant precipitate was filtered and washed with ethyl acetate (2 L) and the combined filtrate was concentrated on a rotary evaporator to afford a residue. This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L). The organic layer was separated, washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) and dried over magnesium sulfate. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil. This residual oil was distilled under vacuum (170° C. at about 25 mm Hg) to afford 310 g (about 85% yield, 97% by HPLC) of the title compound as a viscous pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([S:26]([N:8]2[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 1.06 g. (0.005 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 100 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.21 g., 0.005 mole). The reaction mixture is heated at reflux for 1/2 hour, cooled and a solution of benzenesulfonyl chloride (0.88 g., 0.005 mole) is added. The reaction mixture is heated at reflux for 1/2 hour, cooled, filtered and concentrated to a solid. After recrystallization from acetonitrile 0.4 g. of 1-benzenesulfonyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 210°-212°C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH2:16]([S:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CSc1ccc2cc([N+](=O)[O-])c(N)cc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CSc1ccc2cc(N)c(N)cc2c1

Procedure:
To 0.025 mole of the 2-amino-7-isobutylthio-3-nitronaphthalene (prepared in Example 5) in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the refluxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 7.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)C.[OH-].[Na+:18]>CO>[C:1]12([C:11]([O-:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Na+:18]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C([O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
Approximately 10 g (0.06 mole) of adamantane carboxylic acid was added to 150 ml of ethanol. An equivalent number of moles (2.2 g) of sodium hydroxide also was added to the methanol and the solution was stirred for approximately 15 minutes. This resulted in the formation of sodium adamantane carboxylate. To this reaction mixture was added 7.72 g (0.05 mole) of o-nitrobenzyl chloride. The resulting solution was heated to reflux temperature and stirred at this temperature for 3 hours. The ester thus formed was precipitated by adding 250 ml, in 1 aliquot, of water. The mixture was cooled to ambient temperature and the precipitate was separated by vacuum filtration. The precipitate was recrystallized from 500 ml of a one-to-one by volume solution of ethanol and water to yield approximately 6.4 g of o-nitrobenzyl adamantane carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([O:36][CH2:37][CH2:38][NH2:39])[CH3:35]>>[CH2:34]([O:36][CH2:37][CH2:38][NH:39][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCOCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-y)-isonicotinamide with cesium carbonate and 2-ethoxyethylamine. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.Cl.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCN(CC)CC
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: Cl
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS, 2SR, 3RS)-3-(2-tert--butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1M HCl in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3:H2O(containing 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181-182° C. (dec).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]=[N:21][C:22]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)=[CH:23][CH:24]=4)[CH2:15][CH2:16]3)[C:7]=2[CH:17]=1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: Cl
Product: Cn1cc(-c2ccc(N3CCC(c4noc5ccc(F)cc45)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method B, reacting 5-fluoro-3-(piperidin-4-yl)benzisoxazole HCl salt and 3-chloro-6-(1-methyl-1 H-pyrazol-4-yl)pyridazine.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[Cl:38]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:31]([Cl:38])=[CH:32][CH:33]=[C:34]([F:37])[C:35]=3[F:36])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Cl)c(CBr)c1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2c(Cl)ccc(F)c2F)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1-chloro-3,4-difluorobenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.68-7.62 (m, 1 H), 7.44-7.39 (m, 1 H), 7.35 (d, J=7.8 Hz, 2 H), 7.31-7.25 (m, 1 H), 7.12 (d, J=3.5 Hz, 1 H), 6.96 (dd, J=8.4, 10.5 Hz, 1 H), 6.29 (d, J=3.5 Hz, 1 H), 5.64-5.52 (m, 3 H), 2.75 (s, 3 H), 2.48 (s, 3 H), 0.96 (s, 9 H); LCMS (m/z) ES+=513 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][N:42]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:43][CH2:44]1
Reactant: Fc1ccc(CCCN2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(CCCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(3-(2,4-difluorophenyl)propyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using DCM/MeOH/NH4OH-95/5.0/0.5 as eluent to give 7-(2-(4-(3-(2,4-difluorophenyl)propyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=507.2). 1H NMR (DMSO -d6, 400 MHz) δ 1.66 (quintuplet, 2H, J=7.2 Hz), 2.24 (t, 2H, J=7.2 Hz), 2.32 (m, 4H), 2.45 (m, 4H), 2.58 (t, 2H, J=7.2 Hz), 2.67 (t, 2H, J=6.4 Hz), 4.22 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 6.99 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.14 (m, 2H), 7.18 (d, 1H, J=3.2 Hz), 7.32 (m, 1H), 7.48 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C26H28F2N8O): C, 61.65; H, 5.57; F, 7.50; N, 22.12; O, 3.16. Found C, 61.38: H, 5.66; N, 22.07.
Reaction SMILES: [C:1]([NH:6][C:7](=[NH:10])OC)([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>CO>[C:1]([NH:6][C:7]([NH:21][CH2:20][CH2:19][S:18][CH2:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:11])=[NH:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)NC(=N)OC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CO
Product: CCOC(=O)NC(=N)NCCSCc1[nH]cnc1C

Procedure:
A solution of N-carbethoxy-O-methylisourea (1.46 g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.71 g.) in methanol (25 ml) was stirred at room temperature for 7 days. The white solid formed during the reaction was collected and recrystallised from methanol to give N-carbethoxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine m.p. 196°-197°.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Temperature: 35 °C
Reaction time: 46 h

Procedure:
To a solution of methyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)-ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoate (0.9 g, 2 mmol) in tetrahydrofuran (8 mL) was added a solution of lithium hydroxide (0.16 g, 6.7 mmol) in water (7.4 mL). The reaction mixture was then stirred at 35° C. The progress of reaction was monitored by LC/MS. After 46 hours, LC/MS data indicated that the main component of the reaction was the desired product LCMS m/z=530.2. The reaction mixture was diluted with water (5 mL), pH was adjusted to ˜4 with 1N HCl, and was extracted with ethyl acetate. Organic fraction was then washed water (1×), brine (1×), dried over sodium sulfate and then concentrated in-vacuo. The crude product was purified by flash chromatography on a silica gel column with methanol in methylene chloride to give the desired product (0.450 g, 50%). LCMS (M+H)+: m/z=530.2.
Reaction SMILES: [O:1]=[C:2]([Cl:8])[O:3][C:4](Cl)(Cl)Cl.[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])CO.CCN(CC)CC>C1COCC1>[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:4][O:3][C:2]([Cl:8])=[O:1]
Reactant: O=[N+]([O-])c1ccccc1C(Cl)CO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of diphosgene (1.7 ml, 14 mmol) in THF (10 ml, dist. over CaH2) was cooled by means of an ice bath to about 0° C. A solution of 2-chloro-2-(2-nitrophenyl)ethanol (705 mg, 3.5 mmol) and Et3N (354 mg, 0.485 ml, 3.5 mmol) in THF (10 ml, dist. over CaH2) was dropped thereto for about 30 min. After the solution had been stirred for a further hour, the ice bath was removed. The mixture was stirred for another 3 h at room temperature. The mixture was filtered over Celite. The precipitate was rewashed with THF (10 ml, dist. over CaH2). The combined filtrates were concentrated under reduced pressure and then dried in a high vacuum at room temperature. 2-chloro-2-(2-nitrophenyl)ethoxycarbonyl chloride (896 mg, 97%) was obtained as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(O)C>Cl>[ClH:1].[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[N:11]=[C:10]([NH:12][C:13]34[CH2:14][CH:15]5[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]5)[CH2:20]3)[CH2:22]4)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: Clc1nc(NC23CC4CC(CC(C4)C2)C3)c2ccccc2n1
Agent: Cl
Solvent: CCO
Product: c1ccc2c(NC34CC5CC(CC(C5)C3)C4)nc(N3CCOCC3)nc2c1

Procedure:
A mixture of 5 g of 2chloro-4-(1-adamantylamino)quinazoline, 5 ml of morpholine, and 10 ml of ethanol was refluxed for 16 hours. The reaction mixture was suspended in 100 ml of 6 N hydrochloric acid. The precipitate which resulted was collected by filtration and recrystallized twice from 95 percent ethanol, giving 3.5 g of 2-morpholino-4-(1-adamantylamino)quinazoline hydrochloride; m.p. 319°-321°. The following analytical data were obtained:
Reaction SMILES: [NH:1]([C:3](=[NH:18])[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH:9]=1)[NH2:2].[CH:19](O)=O>>[NH:2]1[CH:19]=[N:18][C:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=3)[CH:9]=2)=[N:1]1
Reactant: CCOC(=O)c1cn2cc(C(=N)NN)ccc2n1
Reactant: O=CO
Product: CCOC(=O)c1cn2cc(-c3nc[nH]n3)ccc2n1
Temperature: 85 °C

Procedure:
A suspension of 580 mg of ethyl 6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 6 mL of formic acid is heated for 20 hours at 85° C. The reaction mixture is concentrated to less than 20% of its initial volume and diluted with 20 mL of water. Solid sodium carbonate is added at 0-5° C. to obtain a pH of 8-9. The precipitate is filtered off by suction, and then purified by chromatography on silica, eluting with a mixture of dichloromethane and methanol (98/2) to give 320 mg of ethyl 6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>CN1C(=O)CCC1.CS(C)=O>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:2]([NH:34][CH2:33][CH2:31][OH:32])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n(CC3CCOCC3)c12
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n(CC3CCOCC3)c12
Temperature: 180 °C
Yield: 5.4 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 15) (14 mg, 0.033 mmol) and ethanolamine (0.020 ml, 0.327 mmol) were dissolved in NMP (2 ml) and heated at 180° C. in the microwave for 1 h, then cooled and loaded onto a 10 g SCX-2 cartridge, washing with methanol (30 ml). The cartridge was then eluted with 2M methanolic ammonia (30 ml) and the eluant evaporated in vacuo to give a sparingly soluble brown gum. This was dissolved in DMSO (1 ml) and purified by MDAP (formate) to give 2-{[7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]amino}ethanol (0.80 mg, 1.772 μmol, 5.40% yield) as a pale yellow glass. LCMS (formate) Rt 0.62 min, MH+ 452
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a solution of 3,4-dichlorophenol (30 g, 185 mmol) in DCM (300 mL) at −15° C., sulfuric acid (24 g, 278 mmol) was added. To this mixture, nitric acid (19 g, 194 mmol) was added dropwise (over 20 min) and the temperature was controlled between −15° C. to −5° C. The resulting mixture was stirred at 0° C. for 1 h. The mixture was poured into ice and extracted with ethyl acetate. The combined organic layer was washed with water, saturate NaHCO3 aqueous solution and brine, dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=100:1) to afford the desired product (16 g, 42% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 4-chloro-3-nitro-phenylamine (17.2 g, 0.1 mol) in 260 mL HBr (48%) at 0° C. was added dropwise NaNO2 (13.8 g, 0.2 mol) in water. The reaction mixture was stirred for 1 h at 0° C. then CuBr (24 g, 0.17 mol) was added in portions to the mixture and stirred for an additional 1 h. Water was added, the mixture allowed to warm to room temperature and was then extracted with EtOAc. The crude product was purified by silica gel column chromatography to give the title compound (13 g, 55%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:18]\[OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O/N=C\c1ccc(OCc2ccccc2)cc1

Procedure:
To 4-(benzyloxy)benzaldehyde (12.9 g) in MeOH (129 ml), Hydroxylamine hydrochloride (6.34 g) was added and the reaction mixture was refluxed for 3 hours and then cooled. The reaction mixture was concentrated to obtain pale brown residue. To this residue, water was added and it was extracted with EtOAc. Organic layer was collected, dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from DCM-Petroleum ether to obtain the title compound as white solid. Yield: 11.5 g (83%); 1HNMR (DMSO-d6; 300 MHz): δ 10.98 (s, 1H), 8.06 (s, 1H), 7.53 (d, 2H), 7.33-7.46 (m, 5H), 7.05 (d, 2H), 5.13 (s, 2H).