Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([N:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[NH:39]C(=O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:39][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Yield: 81 %

Procedure:
5-Benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-benzyloxy-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.C(C1C=CN=C(C2C=C(C(C)(C)C)C=CN=2)C=1)(C)(C)C.[F:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1>CCCCCC>[F:30][C:31]1[CH:35]=[C:34]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)[S:33][CH:32]=1
Reactant: Fc1ccsc1
Reactant: CC1(C)OBOC1(C)C
Agent: CC(C)(C)c1ccnc(-c2cc(C(C)(C)C)ccn2)c1
Solvent: CCCCCC
Product: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Reaction time: 0.02 h

Procedure:
To a mixture of [Ir(μ-OMe(COD)](50 mg, 0.015 mmol, 3 mol %) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.292 g, 9.79 mmol) was added a solution of 4,4′-di-tert-butyl-2,2′-bipyridine (0.039 g, 0.147 mmol) in n-hexane (3 mL). The reaction mixture was stirred for 1 minute and then added to a vessel containing 3-fluorothiophene (0.5 g, 4.90 mmol) dissolved in hexane (3 mL). The mixture was allowed to react at room temperature for 1 hour. The mixture was subsequently evaporated and used without further work up.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:21](O)=[O:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:31][CH3:32])[C:21]([C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][CH:8]=1)=[O:22])[CH3:29]
Reactant: COc1ccc(-c2c(OC(C)C)cccc2C(=O)O)c(OC)c1
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cccc(OC(C)C)c1-c1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Prepare a stirred solution of 6-isopropoxy-2',4'-dimethoxy-biphenyl-2-carboxylic acid (8.60 g, 0.0276 mole) in CH2Cl2 (200 mL) at ambient temperature under argon. Dropwise add thionyl chloride (4.6 g, 54 mmol, 2.8 mL). Continue stirring for about 60 minutes. Cool the reaction to 0° C. and dropwise add diethylamine (19.7 g, 28 mL, 0.27 mole), ensuring the temperature does not rise above 25° C. Continue stirring the reaction for about 30 minutes after addition is complete. Wash the organic layer with water, separate, and wash twice with 100 mL 5% sodium bicarbonate. Separate again, wash with brine (sat'd NaCl) and dry over magnesium sulfate. Filter through celite and condense on a rotovap to give a viscous light brown liquid. Dissolve (partially) in methylene chloride (20 mL) and filter. Flash chromatograph, in 30% ethyl acetate/70% hexane, to remove a solid impurity which is discarded. Continue eluting to obtain a mixture of the discardable and desired product. Further chromatography isolates the title compound as a pale yellow liquid (6.80 g, 68%). (EtOAc/hexane 30:70; Rf =0.15).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=O)[CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[N:12]2)=[N:6][CH:7]=1.Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[N:12]2)=[N:6][CH:7]=1
Reactant: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1ccc(F)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CCNc2ccc(F)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To N-(5-fluoropyridin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (493 mg) in THF (2.0 mL), BH3 THF-complex solution (1 M in THF, 7.3 mL, 7.3 mmol) was added dropwise. After stirring at rt for 3 h, the reaction mixture was quenched with 1 N aq. HCl-solution (3 mL, 3 mmol). The mixture was stirred for 15 min at rt, and heated to 60° C. for 1.5 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. Na2CO3-solution. The aq. layer was reextracted with EtOAc and the comb. org. layers were evaporated, dissolved in DCM and washed with brine. The org. layer was dried (MgSO4), filtered and the solvent was removed by reduced pressure to yield 5-fluoro-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-amine as a yellow solid. LC-MS conditions A: tR=0.53 min, [M+H]+=252.36.
Reaction SMILES: [Li]CCCC.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(CCN(C)C)C.[I:29]I>CCOCC>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][C:18]=1[I:29])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -10 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
n-BuLi (52.4 mL, 0.12 mol, 2.5 M soln in hexanes) was added dropwise over 30 mins to a cooled −78° C. solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (10.0 g, 43.7 mmol) and TMEDA (19.8 mL, 0.13 mol) dissolved in ether. The solution was warmed to −10° C., stirred for 2 hours and then recooled to −78° C. A solution of iodine (22.75 g, 90 mmol) in ether (100 mL) was added via an addition funnel and the reaction was warmed to room temperature and stirred for 16 hours. The reaction was quenched with sat NH4Cl and sodium thiosulfite was added. The mixture was stirred for 30 mins and then extracted with ether. The organic extracts were washed with sodium thiosulfite, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0% to 15% EtOAc in hexanes) gave the product (8.6 g, 56%). 1H NMR (300 MHz, CDCl3): δ 1.52 (s, 9 H), 6.58 (s, 1 H), 7.26 (d, J=8.6 Hz, 1 H), 7.96 (m, 1 H), 8.23 (d, J=2.8 Hz, 1 H).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:10])[N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C(=O)O)c1c[nH]cn1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)-2-methylpropanoic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 161, (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (92.2 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 8.32 (br s, 1H), 7.49-7.45 (m, 3H), 7.38 (d, 1H), 7.22-7.18 (m, 2H), 7.02-6.88 (m, 7H), 6.83 (s, 1H), 4.72-4.68 (m, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 4.04 (dd, 1H), 3.63 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H). MS (EI) for C29H29F2N4O4 found 535 (MH+).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C>C(O)=O>[O:16]=[C:7]1[C:8]2[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:11])[N:6]1[CH2:5][CH:4]=[O:3]
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Solvent: O=CO
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Phthalimidoacetaldehyde diethyl acetal (76.40 g, 0.32 mol, Aldrich) was dissolved in 85% formic acid (300 mL) and stirred for 2 h at rt. After TLC analysis indicated full conversion to the aldehyde (Rf=0.34 1:1 hexanes/EtOAc, 2,4-DNP: yellow), the solvent was removed and the residue was dried under vacuum (150 mm Hg) to afford 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (56.34 g, 93%) as a white solid. 1H NMR: 4.57 (s, 2H), 7.76 (m, 2H), 7.77 (m, 2H), 9.66 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH2:2][CH3:3].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:23]=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](=[O:32])[CH2:30][CH2:31][C:4]2([CH2:1][CH2:2][CH3:3])[C:5](=[O:11])[CH2:6][CH2:7][CH2:8][C:9]2=[O:10])[CH:23]=[CH:24][CH:25]=1
Reactant: CCCC1C(=O)CCCC1=O
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCCC1=O

Procedure:
Dissolve 2-propylcyclohexane-1,3-dione (36.3 g) in benzene (400 cc) containing pyridine (21.2 cc). Add 6-m-methoxyphenylhex-1-en-3-one (43.2 g) and reflux the solution over night. Cool the reaction mixture, wash with water, aqueous sodium carbonate, and 10% aqueous sulfuric acid, dry and remove the solvents under reduced pressure to obtain 2-(6-m-methoxyphenyl-3-oxohexyl)-2-propylcyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3ccc(C)cc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(C)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(4-methylphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: IC1C=CC(N[C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=CC=1.C(OCC)(=O)C=C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>C(N(CC)CC)C.C(#N)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: COc1cc2ncnc(Nc3ccc(I)cc3)c2cc1OC
Agent: [Pd+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C
Yield: 169.8 %

Procedure:
Palladium (II) acetate (303 mg, 1.35 mmol) was added to a solution of 4-(4-iodoanilino)-6,7-dimethoxyquinazoline (see example 1c) (6.00 g, 13.5 mmol), ethyl acrylate (1.35 g, 13.5 mmol) and tri(o-tolyl)phosphine (821 mg, 2.70 mmol) in a mixture of triethylamine (60 ml) and acetonitrile (200 ml) and the reaction heated at reflux for 20 hours under an inert atmosphere. The reaction was cooled to ambient temperature, poured into water (600 ml), diluted with ethyl acetate (200 ml) and filtered through celite. The organic layer was separated, the aqueous was extracted with ethyl acetate (2×200 ml) and the combined organic layers were dried over magnesium sulphate before solvent evaporation in vacuo. Purification by flash chromatography on silica gel, eluting with ethyl acetate, yielded 4-(4-(2-carboethoxy)ethenyl)anilino)-6,7-dimethoxyquinazoline (4.36 g, 85% yield) as a yellow solid:
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]([CH3:22])[CH:12]=1)=[O:5].[H-].[Na+].IC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]([CH3:22])[CH:12]=1)=[O:5]
Reactant: CON(C)C(=O)[C@@H]1CCC[C@H]1c1cn(C)c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc([C@@H]2CCC[C@H]2C=O)c2cc(C#N)ccc21
Temperature: -45 °C
Reaction time: 0.25 h

Procedure:
A solution of trans-2-(5-Cyano-1-methyl-1H-indol-3-yl)-cyclopentanecarboxylic acid methoxy-methyl-amide (0.25 g, 0.84 mMol) in anhydrous tetrahydrofuran (15 mL) was treated with sodium hydride (0.067 g, 1.68 mMol). The mixture was stirred for 15 minutes and then treated with iodomethane (0.36 g, 2.52 mMol). After stirring 1.5 hours, the mixture was quenched with water and evaporated. The residue was dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a hazy oil. This residue was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to −45° C., and treated with lithium aluminum hydride (0.060 g, 1.57 mMol). The suspension was stirred for 1 hour and then quenched in the usual manner. The resulting mixture was filtered over sand and concentrated in vacuo. Silica gel flash column chromatography (50% hexanes, ethyl acetate) gave the product as a clear oil. 1H-NMR (400 MHz, CDCl3) δ 9.66 (1H, d, J=2.8 Hz), 7.94 (1H, m), 7.44 (1H, m), 7.42 (1H, m), 6.99 (1H, s), 3.76 (3H, s), 3.61 (1H, m), 2.98 (1H, m), 2.22 (1H, m), 2.02 (2H, m), 1.98 (1H, m), 1.87 (2H, m).
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: CS(=O)(=O)OC1CCN(c2ccncn2)CC1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(OC2CCN(c3ccncn3)CC2)c1C
Temperature: 60 °C
Yield: 41.7 %

Procedure:
A 250 mL round bottom flask was charged with 1-(pyrimidin-4-yl)piperidin-4-yl methanesulfonate (713 mg, 2.77 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.301 mL, 2.218 mmol), Cs2CO3 (867 mg, 2.66 mmol) and N,N-dimethylformamide (6 mL). The flask was equipped with a reflux condenser and heated at 60° C. for 3 days, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture filtered. LCMS showed some starting chlorophenol remained, so the EtOAc was removed in vacuo and the residue dissolved in N,N-dimethylformamide (6 mL). Cs2CO3 (867 mg, 2.66 mmol) was added and the reaction was heated to 80° C. overnight, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture was filtered. The EtOAc was removed in vacuo and crude residue was purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water). Two additional HPLC purifications using the same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water) were performed to provide methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate (335 mg, 0.926 mmol, 41.7% yield) as a yellow viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.34 (dd, J=1.52, 7.58 Hz, 1H), 7.44 (d, J=2.02 Hz, 1H), 7.34 (d, J=2.02 Hz, 1H), 7.27 (d, J=7.58 Hz, 1H), 4.85-4.96 (m, 1H), 4.05 (br. s., 2H), 3.91 (br. s., 2H), 3.83 (s, 3H), 2.30 (s, 3H), 2.01-2.13 (m, 2H), 1.71-1.87 (m, J=3.92, 7.03, 7.03, 13.61Hz, 2H). MS(ES) [M+H]+ 362.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>C1CCCCC1.O>[C:15]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-Indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (˜1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. The desired cyclohexane derivative was obtained as a beige solid (451.0 g, 100% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:15]=3)[N:10]3N=N[N:27]=[C:9]3[C:8]=2[N:28]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+]>C(Cl)(Cl)Cl.Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:27])[C:8]=2[N:28]=1)[CH3:2]
Reactant: CCOCc1nc2c(c3cc(OCc4cccnc4)ccc3n3nnnc23)n1CC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccc(OCc4cccnc4)cc3c2n1CC(C)C
Temperature: 150 °C
Reaction time: 4 h

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-8-(pyridin-3-ylmethoxy)-6H-imidazo[4,5-c]tetraazolo[1,5-a]quinoline (300 mg, 0.69 mmol) and triphenyphosphine (1 g, 4.17 mmol) were combined in a sealed vial and heated at 150° C. with stirring for 4 hours. The reaction was cooled to ambient temperature; diluted with chloroform; and purified by flash column chromatography on silica eluting with 5-10% gradient of methanol in chloroform. The clean fractions were concentrated under vacuum to provide a brown solid. This solid was refluxed for 1 hour in 4 mL of 3M aqueous HCl. The pH was adjusted to 14 by adding solid potassium hydroxide, and the resulting precipitate was filtered. The solid was dried under reduced pressure to provide 2-ethoxymethyl-1-(2-methylpropyl)-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 204.0-206.0° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH2:24][O:25][CH3:26])=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:28]1([NH:34][C:35]([NH2:37])=[NH:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH2:24][O:25][CH3:26])=[CH:20][N:37]=[C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:36]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Reactant: N=C(N)Nc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCc1cnc(Nc2ccccc2)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 90 °C
Yield: 2.7 %

Procedure:
4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the resulting suspension was heated at 90° C. for 35 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by prep HPLC (Gilson: Column=CombiHT SB-C189 5 μM, 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) to afford III-a-164 as a yellow solid (3.2 mg). LC/MS(m/z) 444.16 (M+1), 442.19 (M−1); HPLC Method B, Rt=5.16 minutes: 1H NMR consistent with structure.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC2C=CC=CC=2)[CH:13]=1.C(O)(C)C>[C].[Pd].O>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2cccc(OCc3ccccc3)c2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2cccc(O)c2)cc1OC
Yield: 91 %

Procedure:
2 g of α-(3,4-dimethoxyphenethylaminomethyl)-3-benzyloxybenzylalcohol hydrochloride, 0.5 g of 10 % palladium-carbon, 100 ml of isopropanol and 15 ml of water are treated in the same manner as described in Example 1-(c). 1.45 g of α-(3,4dimethoxyphenethylaminomethyl)-3-hydroxybenzylalcohol hydrochloride are obtained. M.p. 161° -162° C.(recrystallized from a mixture of isopropanol and ether).
Reaction SMILES: [C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7](=[N:10][N+:11]([O-:13])=[O:12])SC)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:21][NH2:22].CO.Cl>ClCCl>[C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7]([NH:22][CH3:21])=[N:10][N+:11]([O-:13])=[O:12])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CN
Reactant: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of N-iso-butyroyl-N-(2-chloro-5- thiazolylmethyl)-S-methyl-N'-nitroisothiourea (560 mg) in dichloromethane (5 ml) was added 40% methylamine-methanol solution (129 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 40% methylamine-methanol solution (64 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 5.5 hours. After addition of 2N hydrochloric acid (10 ml) under ice-cooling, the mixture was extracted with toluene (5 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in toluene. Crystallization by addition of n-hexane gave 190 mg of 1-iso-butyroyl-1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine (Compound No. 34) as a white crystal, m.p. 101°-104° C.