Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:35])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)Cl
Reaction time: 2 h

Procedure:
36.0 g of the 2-(2-hexyldecyloxy)benzoic acid was dissolved in 100 ml of methylene chloride, 0.5 ml of N,N-dimethylformamide was added, and 13 ml of oxalyl chloride was added dropwise over about 30 min at room temperature with stirring. After the addition the stirring was continued for 2 hours further and it was concentrated, to obtain 2-(2-hexyldecyloxy)benzoic acid chloride.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:6]1)(=[O:3])[CH3:2].CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][C:18]([OH:33])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
To 3β-acetoxy-24-hydroxy-5α-chol-8(14)-en-15-one (1.0 g) in acetone (50 ml) an 8N solution of Jones reagent was added dropwise with stirring at room temperature until the orange color of the reagent persisted. 2-Propanol (1 ml) was added, and the reaction mixture was filtered through a sintered glass filter and evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and the organic solution was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give 3β-acetoxy-15-keto-5α-chol-8(14)-en-24-oic acid (1.0 g) of over 98% purity as judged by 1H NMR. The product showed single component on TLC in three solvent systems (20% methanol in CHCl3, Rf 0.64; isooctaneethyl acetate-acetic acid 5:5:1, Rf 0.56; and CHCl3 -acetonemethanol 7:5:1, Rf 0.18. The structure was confirmed by I.R, N.M.R., and M.S. analyses.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[C:13]([C:14]#[CH:15])=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:25])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[O:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:1]1([C:4]([N:7]([C:8]2[C:13]([C:14]#[CH:15])=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[O:25])=[CH:21][CH:22]=3)[CH:11]=[CH:10][N:9]=2)[C:45]([CH:44]2[CH2:42][CH2:43]2)=[O:41])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: C1CCOC1
Reactant: C#Cc1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N
Solvent: CCN(CC)CC
Product: C#Cc1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N(C(=O)C1CC1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
After adding 57 mg of cyclopropanecarbonyl chloride to a solution of N-(4-{[2-amino-3-(1-ethynyl)-4-pyridyl]oxy}phenyl)-N′-(4-fluorophenyl)urea (100 mg), triethylamine (0.12 ml) and tetrahydrofuran (5 ml) while stirring at room temperature, stirring was continued for 1.5 hours. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The organic solvent was distilled off under reduced pressure, and methanol and water were added to the residue for solidification to obtain 15 mg of the target substance as a white powder.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:34]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 471.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([CH:15]=1)[C:13]#[N:14].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc(Br)cc1C#N
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 2.3 %

Procedure:
Potassium carbonate (2.07 g) was added to a DMF (20 mL) solution of 5-bromo-2-fluorobenzonitrile (2.00 g) and 4-methylimidazole (1.23 g) and the reaction solution was agitated at 100° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (962 mg) and 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile (60 mg) were obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-fluoro phenyl isocyanate (0.0652 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 44 as a colorless solid (0.050 g, 30%). LCMS m/z (%)=369 M+H+, (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 8.52 (bs, 1H), 7.42-7.35 (m, 4H), 7.28-7.27 (d, J=2.7 Hz, 1H), 7.057 (m, 3H), 6.07 (d, J=1.76 Hz, 1H), 4.10 (m, 1H), 3.66 (s, 3H), 1.24 (d, J=6.56 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2Cl.CN.C[CH2:23][N:24](CC)CC>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:24][CH3:23]
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)cc2c(Cl)nc(-c3cccnc3)nc12
Agent: CN
Solvent: CC(C)O
Product: CNc1nc(-c2cccnc2)nc2c(C)cc(Br)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 6-bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (200 mg, 0.60 mmol, 1.0 eq.), methylamine (81 mg, 1.20 mmol, 2.0 eq.) and Et3N (0.2 mL) in i-PrOH (10 mL) was stirred at 85° C. overnight. The resultant yellow precipitate was collected to afford 125 mg of vi-t as a beige solid (63.4%). LCMS m/z=328.8, 330.8 (M+1-1) (Method B) (retention time=1.95 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:17])=[N:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][C:3]=1[F:18].[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21]>ClCCl>[NH2:17][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:21])=[C:3]([F:18])[CH:4]=3)=[CH:9][S:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2csc3ccnc(N)c23)cc1F
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4ccnc(N)c34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A solution of Example 1C (125 mg, 0.48 mmol) in dichloromethane (1 mL) was treated with 1-isocyanato-3-methylbenzene (0.065 mL, 0.5 mmol), stirred overnight at room temperature, and filtered. The filter cake was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a solvent gradient of 10% to 100% acetonitrile/10 mM aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute to provide 74 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 5.48 (s, 2H), 6.83 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.22–7.29 (m, 2H), 7.28 (d, J=5.8 Hz, 1H), 7.32 (s, 1H), 7.38 (dd, J=12.0, 1.9 Hz, 1H), 7.50 (s, 1H), 7.84 (d, J=5.8 Hz, 1H), 8.31 (t, J=8.5 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 9.06 (s, 1H), MS (ESI(+)) m/e 393.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[C:18]([Br:27])[CH:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Br:27][C:18]1[CH:17]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:28])[CH:21]=[C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cc(-c2nnn[nH]2)c1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,3S,5R)-3-[3-bromo-5-(1H-tetrazol-5-yl)-phenylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (200 mg, 0.445 mmol) in CH2Cl2 (2 mL) was added TFA (0.686 ml, 8.9 mmol). The reaction mixture was stirred at RT for 4 h. After completion the reaction mixture was diluted with CH2Cl2 and MeOH and the volatiles were removed under vacuum. MeOH was added and the reaction mixture concentrated again under vacuum. This operation was repeated twice to afford a mixture in a 2/3 ratio of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [3-bromo-5-(1H-tetrazol-5-yl)-phenyl]-amide: MS (LC/MS): 349.2 [M+H]+; tR (HPLC conditions k): 3.06 min and (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [3-bromo-5-(1-tert-butyl-1H-tetrazol-5-yl)-phenyl]-amide: MS (LC/MS): 405.3 [M+H]+; tR (HPLC conditions k): 4.46 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]([NH2:19])=[N:8][C:6]=2[N:7]=1.[H-].[Na+].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([NH:26][C:27]([NH:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]([NH:19][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:8][C:6]=2[N:7]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2nc1N
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc2cnc(NC(=O)NC(C)(C)C)nc2nc1NC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 0.5 g of 2,7-diamino-6-o-tolyl-pyrido[2,3-d]pyrimidine, prepared as described above in Example 1, in 10 mL of dimethylformamide is reacted with 0.16 g of 60% sodium hydride and stirred at ambient temperature for 1.5 hours. To the suspension is added 0.49 mL of t-butylisocyanate and the mixture stirred overnight at ambient temperature. The reaction mixture is filtered to remove insoluble salts and the filtrate evaporated under reduced pressure. The residue is diluted with water, the insoluble crude product collected by filtration and dried in vacuo. Crystallization from a hexane:ethyl acetate: dichloromethane mixture (3:2:5 v/v/v) afforded the title compound, mp 209°-212° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH3:43]>COCCO>[CH3:35][O:36][CH2:37][CH2:38][N:39]([CH2:40][CH2:41][O:42][CH3:43])[CH2:33][CH2:32][CH2:31][O:30][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:17][C:3]3[C:4]4[O:8][CH2:7][O:6][C:5]=4[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:2]=3[Cl:1])=[N:19][CH:20]=[N:21]2)=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COCCNCCOC
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN(CCOC)CCOC)c(OC)cc23)c2c1OCO2
Yield: 61.1 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and bis(2-methoxyethyl)amine (264 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (147 mg, 66%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.91 (quintet, 2H), 2.65 (m, 6H), 2.72 (t, 2), 3.21 (s, 6H), 3.30 (s, 3H), 3.38 (t, 4H), 3.53 (t, 2H), 3.94 (s, 3H), 4.19 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 601/603.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of NaOH (0.7 g), and (Bu)4NI (0.15 g) in benzene (2.0 mL) and water (0.7 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (1.44 g, Aldrich), and 4-benzyloxybenzyl chloride (3.5 g, Aldrich) in benzene (5.0 mL). After the addition, the resulting mixture was stirred at 70° C. for 3 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried (anhydrous Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAC in hexane. The appropriate fractions (monitored by TLC and ES mass spectrometry) were combined and concentrated to dryness to give the desired product (2.0 g, ˜50%) as a white powder: Rf=0.28 (10% EtOAc/Hexane), 1H -NMR (CDCl3) δ9.56 (s, 1H), 7.4 (m, 5H), 6.99 (d, 2H), 6.83 (d, 2H), 5.02 (s, 2H), 2.71 (s, 2H), 1.02 (6H); ES-MS m/z 286 (M+18); HRMS calcd C18H20O20NH4 (M+NH4) 286.2100, found 286.1833.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:24][OH:25]
Reactant: C=O
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1ccnc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 2'-chloro-5-nitro-2-(imidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 2'-chloro-5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]-benzophenone.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([O:28]CC)([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Si](I)(C)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:31][C:2]([CH3:1])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([OH:28])([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])[CH:6]=1
Reactant: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)O
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CC1CCC(C(=O)N(CCP(C)(=O)O)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (108 mg, 0.225 mmol) was dissolved in acetonitrile (3 mL). This solution was cooled in an ice bath and TMSI (160 μL, 1.12 mmol) was added dropwise. The reaction turned yellow and some precipitate was formed. After approximately 1 minute 2,6-lutidine (156 μL, 1.35 mmol) was added, resulting in a clear solution. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. Additional TMSI (50 μL) and 2,6-lutidine (50 μL) were added. After 45 minutes the reaction was determined by LC/MS to be complete. The reaction was cooled in an ice bath and additional 2,6-lutidine (100 μL) was added, followed by MeOH (2 mL). The reaction was warmed to room temperature and concentrated under vacuum. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (37 mg, 36%) was isolated from the residue by reverse phase HPLC. MS (m/z): 453.93 [M+H]+; 31P NMR (161.9 MHz, CD3OD): d 49.909.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30](OCC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37].[C-]#N.[Na+]>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([NH:37][CH3:36])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 87 %

Procedure:
A solution of (S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (120 mg, 0.25 mmol) in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a pale yellow foam (102 mg, 87%). LC/MS (Method B) 3.34 min, [M+1]+ 366.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[C:11]1[CH:12]=[C:13]([C:18]([O:20]C)=O)[C:14](C)=[CH:15][CH:16]=1.[CH3:22][O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:18](=[O:20])[C:13]1[CH:12]=[CH:11][C:16]([CH3:22])=[CH:15][CH:14]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[O-]
Reactant: COC(=O)c1cc(C)ccc1C
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(C(=O)CC(=O)c2ccccc2)cc1

Procedure:
Acetophenone (30 grams; 0,25 mol), methyl p-methyltoluate (136 grams; 1.0 mol), xylene (300 ml) and sodium methoxide (17.3 grams; 0.3 mol) were placed into a four-necked round bottom one liter flask equipped as in Example 1. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours under a blanket of nitrogen. The procedure set forth in Example 1 was used to recover the desired product, benzoyl p-methylbenzoylmethane (40 grams; 67 weight percent yield) having a purity of 66%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (247 μL, 2.28 mmol) and Et3N (0.64 mL, 4.56 mmol) and allowed to warm slowly to room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to yield a yellow solid. The yellow solid was dissolved in a minimum amount of CH2Cl2 and EtOAc was added until the solution became turbid. The mixture was placed in a freezer overnight and white crystal formed. The crystals were isolated by filtration and were dried under vacuum to give 126 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea. mp 171.0-174.0° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:36](=[O:37])[C:35]2[CH:34]=[C:33]([Cl:32])[CH:41]=[C:40]([Cl:42])[CH:39]=2)[C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc(CN2CCN[C@H](Cc3ccc4ccccc4c3)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-1-benzyl-3-(2-naphthylmethyl)piperazine (3.23 g) and triethylamine (4.3 ml) in dichloromethane (60 ml) was added a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in dichloromethane (10 ml) at 0° C. After stirring at room temperature for 3 hours, the mixture was quenched with water and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was triturated with a mixture of dichloromethane and hexane to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(2-naphthylmethyl)piperazine.