Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>O1CCCC1.ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:33])[NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[C:16](Cl)(=O)C(Cl)=O.C(Cl)(Cl)(Cl)Cl.C1C(=O)N(Br)C(=O)C1.[BrH:35]>CN(C=O)C.CO>[Br:35][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:14])([F:15])[F:1])=[CH:9][CH:8]=1)[C:11]([O:13][CH3:16])=[O:12]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-trifluoromethoxyphenylacetic acid (5 g, 23 mmol) in carbon tetrachloride oxalyl chloride (25 mmol) and two drops of DMF were added at 0° C. After stirring the solution at room temperature for 1 h, NBS (25 mmol) and few drops of 48% HBr were added and the mixture was heated to reflux for 4 h. The solution was allowed to cool, MeOH (5 mL) was added and the mixture was stirred at room temperature for 1 h.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([Li])CCC.CI.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[CH3:10][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cccs1
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(Cc1ccccc1)(C(=O)O)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-thiopheneacetic acid (30 g, 0.211 mol) in THF (300 mL) was added dropwise n-butyl lithium (275 mL of a 1.6M solution in hexane). The ice-bath was removed and the reaction was stirred for 1 hour. The reaction mixture was again cooled to 0° C. and hexamethylphosphoramide (34.5 mL) was added dropwise. After 45 minutes a solution of methyl iodide (13.1 mL, 0.211 mol) in THF (75 mL) was added dropwise. The reaction was stirred to room temperature for 45 minutes, recooled to 0° C., n-butyl lithium (1 eq) was added and after 45 minutes a solution of benzyl bromide (36 g, 0.211 mol) in THF (75 mL) was added. After stirring for 3 days the reaction was quenched with 1N.HCl (400 mL). The reaction mixture was partitioned between ethyl acetate and aqueous HCl and the ethyl acetate layer was separated, washed with water, and dried (MgSO4). Concentration of the ethyl acetate afforded an oil which was chromatographed on silica gel and eluted with 40% ethyl acetate/hexanes to give the title product as an oil (63 g).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=C)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[F:24])#[N:2].I([O-])(=O)(=O)=[O:26].[Na+].C(#N)C.O>CC(C)=O.[Os]=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=[O:26])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[F:24])#[N:2]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C#N)c(F)c2)c(C)c1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cc2ccc(C#N)c(F)c2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a mixture of methyl 5-(4-cyano-3-fluorobenzyl)-3,4-dimethyl-2-vinylbenzoate (0.67 g) and sodium periodate (2.22 g) in acetone (15.0 mL)-acetonitrile (15.0 mL)-water (15.0 mL) was added osmium oxide (fixed catalyst I) (0.26 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:20])=O.[CH3:22]COCC>CO>[ClH:20].[CH3:22][O:16][C:15](=[O:17])[CH2:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][NH:10]1
Reactant: CCOCC
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: COC(=O)CC1NCCc2ccc([N+](=O)[O-])cc21
Product: Cl
Temperature: 0 °C
Yield: 93 %

Procedure:
To a suspension of 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetic acid (2.75 g, 11.5 mmol) in methanol (25 ml) at 0° C. was added dropwise thionyl chloride (3.6 ml, 41 mmol). After addition was complete, the reaction mixture was heated at reflux for 0.33 h. After cooling slightly, ether (50 ml) was added and the reaction mixture was cooled to 0° C. The precipitate was collected to give the title compound as a light yellow solid (3.09 g, 93%), m.p. 211-2° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Yield: 86.1 %

Procedure:
Methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (7.02 mmol) was dissolved in THF (50 mL), 1N sodium hydroxide (7.0 mL) was added followed by water (50 mL) and the resultant solution stirred at RT for 4 hours. The organics were removed in vacuo, the aqueous solution filtered and extracted with ethyl acetate (30 mL). The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL), and the organic extracts washed with water (10 mL), brine (10 mL) then evaporated to dryness to give the desired material as a white foam (2.33 g). 1H NMR δ (CDCl3): 2.14-2.30 (m, 2H), 2.34-2.42 (m, 2H), 3.89-3.94 (m, 2H), 3.97-4.02 (m, 2H), 4.28 (t, 2H), 4.69 (t, 2H), 4.97-5.00 (m, 1H), 6.94 (t, 1H), 7.48 (t, 2H), 8.34 (d, 1H), 8.85 (d, 1H); m/z 386 (M+H)+, 384 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[F:19][C:20]([F:27])([F:26])[C:21]1[N:22]=[CH:23][NH:24][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:24]2[CH:25]=[C:21]([C:20]([F:27])([F:26])[F:19])[N:22]=[CH:23]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
In a similar way a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.62 mmol), 4-trifluoromethyl-imidazole (0.945, 6.74 mmol) and ethyl-diisopropyl-amine (3.94 ml, 22.5 mmol) in 10 ml of dioxane is heated to reflux for 48 hours. After a similar workup procedure 1.4 g (3.65 mmol, 65%) of amorphous 5-(4-trifluoromethyl-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, ES-MS: m/z 384 [M+H]+.
Reaction SMILES: [ClH:1].Cl.C([O:10][C:11]1[CH:35]=[CH:34][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21](C=O)[CH2:20][CH:19]3[CH2:26][O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[S:17][C:13]=2[CH:12]=1)C1C=CC=CC=1.Cl.O>CCO>[ClH:1].[ClH:1].[ClH:1].[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:26][CH:19]2[CH2:20][NH:21][CH2:22][CH2:23][N:18]2[C:16]2[S:17][C:13]3[CH:12]=[C:11]([OH:10])[CH:35]=[CH:34][C:14]=3[N:15]=2)[CH:29]=1
Reactant: O=CN1CCN(c2nc3ccc(OCc4ccccc4)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1ccc2nc(N3CCNCC3COc3cccnc3)sc2c1
Temperature: 25 °C
Yield: 200.8 %

Procedure:
4-(6-(Benzyloxy)benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehyde dihydrochloride (130 mg, 0.244 mmol) and HCl (conc., 1.0 mL) were heated to 100° C. in EtOH (1 mL) and water (1 mL) for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 73.8 mg (67%) of the title compound as a white solid. LC-MS: RT=3.45 min, [M+H]+=343.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1COCC1.C(#N)C>C(N(CC)CC)C>[C:20]([O:12][CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:13])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H](O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: O[C@@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
5 grams (27.44 mmol) of (R)-(+)-3-benzyloxy-1,2-propanediol and 10 grams (35.87 mmol) of triphenylchloromethane were added to 100 ml dry THF and 25 ml dry acetonitrile. 8 ml of dry triethylamine were added and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (100 grams), transferred to a separatory funnel and extracted thrice with 100 ml diethyl ether. The organic phase was washed consecutively with 100 ml water, twice with 100 ml dilute (1.5%) sulfuric acid, 100 ml water, 100 ml concentrated sodium bicarbonate solution, and again with 100 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure, yielding 11 grams of 1-trityl-3-benzyl-sn-glycerol as a yellow oil. The yield was 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([NH:21]O)=O)[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]#[N:21])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(NO)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
0.9 g of the compound obtained in Step B is stirred for 2 hours at ambient temperature in a solution of 10 ml of dioxane, 0.8 ml of pyridine and 0.42 ml of trifluoroacetic anhydride. After evaporating off the solvent, chromatography of the residue on silica gel (dichloromethane/ethyl acetate: 96/4) enables isolation of the expected product, which crystallises in heptane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: COCC(COC)Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: COCC(COC)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(2-Methoxy-1-methoxymethyl-ethoxy)-benzene (1.0 g) was dissolved in 10 mL of chloroform and the solution was cooled to −30° C. Chlorosulfonic acid (1 mL) was added dropwise while maintaining the temperature of the mixture below −20° C. Stirring was continued in succession for one hour at −20° C., for one hour at 5° C. and for 30 minutes at room temperature. The mixture was poured on ice, the organic layer washed with cold water, dried (sodium sulfate) and concentrated yielding 0.8 g of 4-(2-methoxy-1-methoxymethyl-ethoxy)-benzenesulfonyl chloride as an oil. EI-MS: 294 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18](Br)[CH:19]=[CH2:20].C([O-])([O-])=O.[K+].[K+].[CH3:28][C:29]([CH3:31])=O>>[CH3:9][C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:31][CH:29]=[CH2:28])=[CH:15][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH:19]=[CH2:20])=[CH:7][CH:6]=1)[CH3:10]
Reactant: C=CCBr
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C(C)(C)c2ccc(OCC=C)cc2)cc1
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of bisphenol A (Sigma-Aldrich), 18.94 ml of allyl bromide (Sigma-Aldrich), 72.69 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 4,4′-(propane-2,2-diyl)bis(allyloxybenzene). The reaction scheme in the 1st step and the NMR data of the intermediate product (11) are as follows.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[N+:19]([O-])=[CH:18][C:17]3[N:24]=[C:25]([CH2:28][CH3:29])[N:26]([CH3:27])[C:16]=3[C:15]=2[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC(Cl)(Cl)C([N:34]=C=O)=O.C[O-].[Na+]>ClCCl.CO>[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]([NH2:34])[C:17]3[N:24]=[C:25]([CH2:28][CH3:29])[N:26]([CH3:27])[C:16]=3[C:15]=2[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 3.5 h
Yield: 73.3 %

Procedure:
A modification of the general method of Part C of Example 3 was used. Chloroform (10 mL) was added to the solution of 8-benzyloxy-2-ethyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline (1.30 g, 3.90 mmol) in dichloromethane (35 mL) to improve the solubility. After the addition of trichloroacetyl isocyanate (0.633 mL, 5.31 mmol), the reaction was stirred for 3.5 hours. In the second step, chloroform (10 mL) was also added to the suspension in methanol (30 mL). After the reaction with sodium methoxide, the reaction was stirred over two nights, and the precipitate was isolated by filtration, washed with hexanes, recrystallized from methanol (278 mL/g), isolated by filtration, washed with hexanes, and dried for two days in a vacuum oven. A second crop of crystals from the mother liquor was combined with the first to provide 0.95 g of 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp 238.4-238.9° C.
Reaction SMILES: [H-].[Na+].C[CH:4]([SH:8])[C:5]([O-:7])=[O:6].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[CH3:17]N(C=O)C>>[Br:9][C:10]1[CH:15]=[C:14]([S:8][CH2:4][C:5]([O:7][CH3:17])=[O:6])[CH:13]=[N:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: CC(S)C(=O)[O-]
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of sodium hydride (0.518 g, 21.0 mmol) in DMF (5 mL) at 0° C. was added dropwise a solution of methylthioglycolate (2 g, 18 mmol) in DMF (6 mL). Upon completion of addition, the reaction mixture was stirred at RT for 30 min. After this time, a solution of 3,5-dibromopyridine (4.46 g, 18 mmol) in DMF (10 mL) was added dropwise. The resulting reaction mixture was allowed stir at RT for 16 h. At the conclusion of this period, the reaction mixture was quenched by the addition of ice and the resulting slurry was extracted with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (1.5% methanol in DCM) to yield methyl 2-(5-bromopyridin-3-ylthio)acetate (1.2 g, 24% yield). LCMS Method A: retention time 1.49 min; [M+1]=262.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.[C:35]([BH3-])#[N:36].[Na+].[C:39](O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH3:39][N:36]([CH3:35])[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[OH:24]
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Yield: 25.4 %

Procedure:
An amount of 300 mg (0.51 mmol) of (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione and formylaldehyde (45.9 mg, 1.53 mmol) were dissolved in tetrahydrofuran (3 mL) and methanol (2 mL). After stirring for ten minutes, a mixture of sodium cyanoborohydride (64.1 mg, 1.02 mmol) and acetic acid (0.4 mL, 5.1 mmol) were added drop-wise. The mixture is allowed to stir for 2.5 hours. Tetrabutylammonium fluoride (2 mL) is added and stirred for additional 1 hour. The mixture is neutralized with 1 NHCl solution and extracted with dichloromethane (200 ml), dried over sodium sulfate and evaporated. The desired final product is purified by column chromatography to afford 60 mg (26% yield) of a light brown solid.; mp 198-199° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH2:11][CH2:10][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccnc2)OCCO1

Procedure:
3-Acetylpyridine (10 g), ethylene glycol (50 ml) and p-toluenesulfonic acid (0.5 g) were dissolved in toluene and the solution was refluxed at 150° C. for 1 day with the by-product water being constantly removed. After cooling, saturated aqueous sodium hydrogen carbonate and toluene were added and the mixture was stirred and allowed to stand. The aqueous layer was separated and extracted with 2 portions of toluene. The toluene layers were combined, washed sequentially with saturated aqueous sodium hydrogen carbonate, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 2-methyl-2-(pyridin-3-yl)-1,3-dioxolane (13.6 g).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:3]/[C:4]([O:6]C)=[O:5].[Li+].[OH-]>C1COCC1.O>[CH3:1]/[C:2](/[CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: C=CCC/C(C)=C\C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC/C(C)=C\C(=O)O
Reaction time: 96 h
Yield: 56.4 %

Procedure:
A solution of the title compound from Example 20 (6.8 g, 32.5 mmol) in THF (150 mL) was treated with 1 N LiOH (100 mL) and water (125 mL) and stirred vigorously for 4 days. The mixture was diluted with water and washed twice with ether. The aqueous phase was taken to pH 1.5 by addition of 2N HCl and extracted three times with ether. The organic extracts were dried and the solvents evaporated to give the title compound (2.57 g, 56%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:22]([O:24][CH3:25])=[O:23].O>C(Cl)Cl>[C:22](=[O:23])([O:24][CH3:25])[O:13][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCc1ccc(O)c(C(C)(C)C)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(OC(=O)OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 2-tert-butyl-4-ethyl-phenol (10 g, 56.1 mmol) in DCM (50 mL) was added Et3N (17 g, 168.0 mmol) and methyl chloroformate (11 g, 116.4 mmol) at 0° C. The mixture was stirred overnight at room temperature. Water was added to quench the reaction and the mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-tert-butyl-4-ethylphenyl methyl carbonate (12 g, 91%). 1H NMR (300 MHz, CDCl3), 7.06-7.02 (m, 2H), 7.02 (s, 1H), 3.92 (s, 3H), 2.64 (q, J=7.5 Hz, 2H), 1.37 (s, 9H), 1.54 (t, J=7.5 Hz, 3H)