Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:5][C:4]=2[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(CCC(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon catalyst (0.35 g, 0.1 eq. weight/weight (w/w)), methanol (50 mL) ethanol (50 ml) and Methyl(2E)-3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (3.5 g, 8.8 mmol). The vessel was evacuated and charged with hydrogen gas (45 psi, 3.1×105 Pa). The reaction was shaken at ambient temperature overnight (approximately 18 hours). The reaction mixture was filtered to remove the catalyst and concentrated to dryness. The crude product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide methyl 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Si:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=2)[CH2:23][CH2:24]1)([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10]
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCC1CCN(c2ccc(Cl)nc2)CC1
Temperature: 80 °C
Yield: 40.2 %

Procedure:
2-chloro-5-iodopyridine (1.00 g, 4.18 mmol), compound 292 (1.02 g, 4.18 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.191 g, 0.209 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.242 g, 0.418 mmol), and sodium t-butoxide (0.803 g, 8.35 mmol) were dissolved in 20 mL dioxane. The reaction was purged with argon and heated at 80° C. for 16 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes/0-10% ethyl acetate) afforded compound 293 as a beige solid (597 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:6]([S:8]([NH:11][C:12](=[O:20])[C:13]([O:16]C(=O)C)([CH3:15])[CH3:14])(=[O:10])=[O:9])[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:6]([S:8]([NH:11][C:12](=[O:20])[C:13]([OH:16])([CH3:14])[CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)NS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(=O)(=O)NC(=O)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of acetic acid 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonylamino)-1,1-dimethyl-2-oxo-ethyl ester (0.14 g, 0.21 mmol) in tetrahydrofuran (2 mL), methanol (0.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (0.020 g, 0.48 mmol). The resulting reaction mixture was stirred at ambient temperature overnight. Chromatography on silica gel of the reaction mixture provided the title compound (0.104 g, LRMS: 556.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:21][C:22]([N:24]([CH:34]1[CH2:36][CH2:35]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][O:17][CH2:18][O:19][CH3:20])[CH2:9][CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].CO.[Cl-].[NH4+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:34]1([N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])[C:22]([CH:21]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:15]2[CH2:16][O:17][CH2:18][O:19][CH3:20])=[O:23])[CH2:36][CH2:35]1
Reactant: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C(=O)CCN1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 62 %

Procedure:
Into a 100 mL round bottom flask was added 4E and toluene (42 mL) under nitrogen. Sodium metal (392 mg, 17.1 mmol, 1.3 eq) was added at once followed by methanol (160 μL, 3.9 mmol, 0.3 eq). The reaction was allowed to stir under nitrogen over 48 hours. After sodium metal had dissolved, saturated ammonium chloride (50 mL) was added to quench the reaction. Ethyl acetate (50 mL) was added and the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate and filtered. Solvent was removed under vacuum to leave a residue which was purified by column chromatography (20% ethyl acetate/hexanes) to give 4F (4.17 g, 62%). ESI-MS:m/z 459.3 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]2)[C:2]#[CH:3].[Br:25]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:25][C:3]#[C:2][CH2:1][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CC[C@]12CCC(=O)C=C1C(=C)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CC#CBr)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
A solution of 484 mg of 10β-(2-propynyl)-6-methylenestr-4-ene-3,17-dione in 20 ml of acetone is treated at room temperature with 312 mg of N-bromosuccinimide and 25 mg of silver nitrate, and stirred 4 hours at room temperature in the dark. The mixture is poured with stirring into ice-water and the formed precipitate is filtered off and dissolved in ethyl acetate. The resulting solution is washed with water, dried, evaporated to dryness in vacuo, and the crude is purified by flash chromatography on SiO2, eluting with n-hexane:diethylether 20:80 to give 363 mg of the title compound as a white crystalline product,
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:18](=O)[NH2:19])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:38](N)=[CH:39][CH:40]=1>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:18]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:37]2[CH:36]=[C:35]([F:34])[CH:40]=[CH:39][C:38]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(N)=O
Reactant: Nc1ccc(F)cc1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of ((S)-2-benzyloxy-1-carbamoylethyl)carbamic acid tert-butyl ester (820 mg, 2.8 mmol) in anhydrous THF (10 mL) was added triethyloxonium tetrafluoroborate (550 mg, 2.9 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue redissolved in absolute EtOH (10 mL). To the mixture was added 4-fluoro-N2-pyridin-2-yl-benzene-1,2-diamine (355 mg, 1.7 mmol) and the mixture stirred at 75° C. for 16 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions washed with water, dried (MgSO4) and concentrated in vacuo. The resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cHex) to afford the title compound as a yellow oil (420 mg, 53%). LCMS (Method B): RT 3.95 min [M+H]+ 463.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(COS(C)(=O)=O)O1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (400 mg, 3.03 mmol) in DCM (6 mL) at 0° C. was added methanesulfonyl chloride (381 mg, 3.33 mmol) and triethylamine (368 mg, 3.63 mmol. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The mixture was diluted with DCM (5 mL). The organic phase was washed with water (4 mL) and brine (2 mL), and dried (Na2SO4). The solution was concentrated under reduced pressure to give the product (642 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3,4-difluoro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 51 as a colorless solid (0.096 g, 80%). LCMS m/z (%)=467 M+H+ (81Br, 88), 465, M+H+ (79Br, 95), 1H NMR (400 MHz, DMSO-d6) δ: 8.816 (bs, 1H), 8.68 (bs, 1H), 7.5 (s, 1H), 7.412 (d, J=2.51 Hz, 2H), 7.389 (d, J=2.51 Hz, 2H), 7.199 (t, 1H), 7.167 (s, 1H), 6.983 (t, 1H), 3.989 (m, 1H), 3.596 (s, 3H), 1.225 (d, J=6.61 Hz, 3H), 1.078 (d, J=6.61 Hz, 3H.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(O)[CH2:17][CH3:18])[CH2:15][CH2:14]1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(OC)=C(F)C=2)C)CC1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([CH:13]2[CH2:15][CH2:14]2)[CH2:17][CH3:18])=[CH:21][CH:22]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCC(O)(c1ccc(Cl)cc1)C1CC1
Agent: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Product: CCC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 84 mg (0.48 mmol) of the compound from Example 8A and 100 mg (0.48 mmol) of the compound from Example 145A in analogy to the synthesis of the compound from Example 186. 38 mg (21% of theory) of the target compound were obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:34])([CH3:33])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[O:48][CH3:47])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:33])([CH3:34])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: COc1ccccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1O[C@@H]1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 52.4 %

Procedure:
Add dropwise diisopropyl azodicarboxylate (0.065 mL, 0.327 mmol) to a solution of (2R,4S)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.099 g, 0.218 mmol), 2-methoxy phenol (0.036 mL, 0.327 mmol) and triphenylphosphine (0.086 g, 0.327 mmol) in tetrahydrofuran (1.5 mL). Stir 18 hours. Purify reaction mixture on silica gel with ethyl acetate/hexane mixtures to give the desired compound as a foam (0.064 g, 53%). MS(ES): m/z=561 [M+H].
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH3:38])[CH:29]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[C:30]([CH3:38])[CH:29]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(3-methyl-4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.21 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 68%). MS (ISP) 484.2 [(M+H)+]; mp 222.5° C.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([O:12]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: COC(=O)c1ccccn1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A sodium methoxide solution (28% in methanol) was added dropwise to a mixture of 10 g (73 mmol) methyl picolinate and 25 ml (124 mmol) of acetone in 150 ml of tetrahydrofuran. The mixture was stirred at 20° C. for 3 hours and the solvent was removed under reduced pressure. The residue was taken up in water, acidified with 2 molar aqueous hydrochloric acid and extracted with dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 7.940 g of product (60% of theory); NMR (CDCl3, 400 MHz): 2.23 (s, 3H); 6.81 (s, 1H); 7.41 (m, 1H); 7.83 (m, 1H); 8.09 (m, 1H); 8.68 (m, 1H); 15.7 (br, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][OH:8].[CH2:9](OCC(=O)C)C1C=CC=CC=1>>[CH3:9][C:2]1([CH2:7][OH:8])[O:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: CC(=O)COCc1ccccc1
Reactant: OCC1OCCCO1
Product: CC1(CO)OCCCO1
Yield: 37 %

Procedure:
The same procedure as in the steps (32a) and (32b) of Example 32 was repeated using 1-benzyloxy-2-propanone to obtain the title compound (1.51 g, total yield: 37%) as a light yellow oil.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CN1[CH2:16][CH2:15][CH2:14][C:13]1=O>>[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1([CH:13]=[CH:14][C:15]2[CH:16]=[CH:5][CH:4]=[CH:3][CH:8]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a 2-liter four-necked flask equipped with a thermometer, stirrer and condenser were added 245.2 g of 48.3% aqueous sodium hydroxide solution and 552 g of N-methylpyrrolidone, and the inner atmosphere was replaced by nitrogen. Under nitrogen flow, the temperature of the solution was raised to 140° C. To this, was added dropwise 225.6 g of the phenol intermediate obtained in Synthetic Example 1 and 676 g of N-methylpyrrolidone solution at 140° C. for 1.5 hours and kept at that temperature for 2 hours. Then, the reaction mixture was cooled to 60° C. and neutralized with 226 g of concentrated hydrochloric acid. The solvent was recovered under reduced pressure, the reaction mixture was charged into 1000 g of ion-exchanged water, and the precipitated crystals were filtrated. The crystal was washed with water (1000 g×3 times) and dried under reduced pressure for 8 hours at 80° C., to obtain 208 g of ayellow crystal (stilbene bisphenol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30]3([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]3)[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(N)=O)CC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (1.68 g, 6.81 mmol) was added to a suspension of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarboxamide (1.70 g, 5.24 mmol) in chloroform (25 mL); the reaction was stirred for two hours at ambient temperature and then cooled to 0° C. Ammonium hydroxide (5 mL) and p-toluenesulfonyl chloride (1.10 g, 5.76 mmol) were added. The reaction was stirred for one hour at 5° C. and then filtered to isolate a precipitate. The precipitate was triturated with 2 M aqueous sodium hydroxide, isolated by filtration, triturated with hot acetonitrile, isolated by filtration, and recrystallized from ethanol. The crystals were dried overnight at 85° C. in a vacuum oven to provide 0.78 g of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarboxamide as tan needles, mp 230.5-232.5° C.
Reaction SMILES: C1C2[CH:12]([CH2:14][CH2:15][C:16]([N:18]([C@@H:20]([CH2:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]([OH:23])=[O:22])[CH3:19])=[O:17])[C:11]3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)CC)(C)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(=O)CCC=C.N1C2C(=NC=CC=2)N(O)N=1.C(=NC(C)C)=NC(C)C>ClCCl.CN(C)C=O>[C:26]([O:25][CH2:24][C@H:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][CH2:14][CH:12]=[CH2:11])[C:21]([OH:23])=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C(=O)CCC1c2ccccc2-c2ccccc21)[C@@H](COC(C)(C)C)C(=O)O
Agent: C=CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(=O)N(C)[C@@H](COC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
(S)-2-(3-(9H-Fluoren-9-yl)-N-methylpropanamido)-3-(tert-butoxy)propanoic acid (Compound SP745) (4.35 g, 11.0 mmol) and diisopropylethylamine (EtN(iPr)2) (10.4 mL, 60.0 mmol) were dissolved in dehydrated dichloromethane (46 ml), to the solution above, 2-chlorotrityl chloride resin (100-200 mesh, 1% DVB, purchased from Watanabe Chemical Industries, 4.65 g, 7.30 mmol) was added, and the amino acid was supported on the resin by shaking at room temperature for 60 minutes. The reaction solution was removed, and the resin was washed with dehydrated dichloromethane (46 ml) four times. A 20% solution of piperidine in N,N-dimethylformamide (15 ml) was added to the resin, and the Fmoc group was deprotected by shaking for 90 minutes. The reaction solution was removed, and the resin was washed with N,N-dimethylformamide (15 ml) three times. Subsequently, pent-4-enoic acid (2.3 ml, 21.9 mmol), 3H-(1,2,3)triazolo(4,5-b)pyridin-3-ol (HOAt) (1.99 g, 14.6 mmol) and N,N′-methanediylidenebis(propan-2-amine) (DIC, 3.71 ml, 24.1 mmol) were dissolved in N,N-dimethylformamide (15 ml), the solution was added to the resin, and the mixture was shaken at room temperature for 60 minutes for pentenoylation. The reaction solution was removed, and the resin was washed with N,N-dimethylformamide (15 ml) three times and then further washed with dichloromethane (15 ml) three times. Subsequently, a 1% solution of trifluoroacetic acid in dichloromethane (1% TFA in CH2Cl2) (40 ml) was added to the aforementioned resin, and the amino acid was cleaved from the resin by shaking for 30 minutes. The reaction solution was collected, and the resin was washed with dichloromethane (40 ml) three times. The collected reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol solution) to afford (S)-3-(tert-butoxy)-2-(N-methylpent-4-enamido)propanoic acid (Compound SP746) (1.02 g, 54%). Dichloromethane and N,N-dimethylformamide used for this synthesis were special grade solvents for peptide synthesis. (purchased from Watanabe Chemical Industries).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1>C(OCC)(OCC)OCC>[CH2:5]([O:8][CH:9]=[N:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:5]=12)[CH3:4]
Reactant: Cn1nc2c(oc3ccccc32)c1N
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1c2oc3ccccc3c2nn1C
Reaction time: 4 h
Yield: 185 %

Procedure:
A suspension of 2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (3.8 g, 20 mmol, described in Example 6) in triethyl orthoformate (40 mL) was refluxed with stirring for 4 hr. The excess solvent was removed under vacuum and the residue was triturated with diethyl ether to give 4.5 g of N-ethoxymethylene-2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine, mp 120°-122° C., and NMR (CDCl3) δ1.4 (3H, t), 3.95 (3H, s), 4.4 (2H, q), 7.5 (4H, m) and 8.5 (1H, s). The latter compound was suspended in ethanol (100 mL) and sodium borohydride (1 g, 26 mmol) was added in portions. The mixture was stirred at room temperature for 1 hr and at reflux temperature for 0.5 hr. The solution was evaporated to dryness and the residue was taken up in ethyl acetate. The solution was washed with water, dried and evaporated to dryness. Chromatography on silica gel and elution with 2% EtOH--CH2Cl2 (v/v) gave 2.5 g of crystalline product, mp 150°-156° C. The latter product was triturated with diethyl ether to obtain the title compound: mp 154°-156° C.; IR (mineral oil) 3190, 1640, 1600 and 1547 cm-1 ; UV max (MeOH) 301 nm (ε=4820), 271 (14800), 251 (18900), 212 (20090) and shoulder 246; NMR (DMSO-d6) δ2.97 (3H, d), 3.68 (3H, s), 5.51 (1H, q) and 7.0-8.0 (4H, m).