Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29]>CS(C)=O.O>[N:4]1([CH2:3][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:1][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: COc1ccc(COCC(O)Cn2ccnc2)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (20 g, 0.076 mol) was added to a stirred suspension of powdered potassium hydroxide (17 g, 0.30 mol) in dimethylsulphoxide (50 ml) at 18° C. and stirred for 0.5 hours. Ethyl 6-bromohexanoate (33.45 g, 0.15 mol) was then added and the resulting mixture was stirred at 18° C. for 12 hours. The reaction mixture was diluted with water (21) and washed with dichloromethane (2×100 ml), neutralised to pH 6-7 with sulphuric acid (2M) and extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which by column chromatography (silica gel, 20% methanol in ethyl acetate) gave pure 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid as a colourless oil.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[NH:3][CH:2]=1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[NH:3][CH:2]=[N:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1cnc[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3cnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (3H-imidazol-4-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.52 min, [M+1]+ 449. Potency class A.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1>C(O)(=O)C.O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][CH:12]=1)=[O:29]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC2OCCO2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC=O)cc1
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 4-[3-[4-[2-(1,3-dioxolan- 2-yl)ethyl]phenyl]-3-oxopropyl]-5-methyl-2-phenyloxazole (2.17 g) and 50% acetic acid-water (60 ml) was stirred at 75°-80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with ether-hexane (1:1), 3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propionaldehyde (1.5 g, 78%) was obtained, which was then recrystallized from ether-isopropyl ether to yield colorless needles having a melting point of 92°-93° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CN([CH:13]=[O:14])C>O>[OH:14][C:13]1[NH:1][C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(N)c1N
Solvent: O
Product: Cc1cccc2nc(O)[nH]c12
Temperature: 92.5 °C

Procedure:
2,3-Diaminotoluene (5 g, 41 mmol), 1,1-carbonyldiimidazole (7.3 g, 45 mmol) and 50 ml of anhydrous DMF are successively introduced into a 250 ml two-necked flask under an argon atomosphere, equipped with a magnetic stirrer. After heating the mixture at 90-95° C. for 4 hours, the solvent is distilled off under vacuum and the residue obtained is taken up in water (250 ml) and extracted with ethyl acetate (3×250 ml). The insoluble product formed during the extraction is recovered (4.8 g) and the combined organic phases are washed again with saturated NaCl solution, dried over MgSO4, filtered and concentrated, allowing a further 1.2 g of desired product (6 g, quantitative) to be recovered. 1H NMR (300 MHz, δ ppm) DMSO-d6: 2.27 (s, 3H), 6.72 (m, 2H), 6.82 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]2[O:33][C:32](=[O:34])[NH:31][C@H:30]2[CH3:35])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:31]2[C@@H:30]([CH3:35])[C@@H:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[O:33][C:32]2=[O:34])[CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccc(Cl)cc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]acetic acid methyl ester and (4S,5R)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: C(=O)(O)[O-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[C:7]=1[CH2:14]Br.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([N:23]1[CH2:14][C:7]2[C:8](=[CH:9][CH:10]=[CH:11][C:6]=2[Br:5])[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: BrCc1cccc(Br)c1CBr
Agent: O=C([O-])O
Solvent: CC#N
Product: Brc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Postassium bicarbonate (204 g, 2.04 mol) was suspended in CH3CN (12 L), and the mixture was heated to 80° C. Solutions of 1-bromo-2,3-bis(bromomethyl)benzene (280 g, 0.82 mol in 500 mL CH3CN) and benzylamine (87.5 g, 0.82 mol in 500 mL CH3CN) were added concurrently via addition funnels over 1 hour. The reaction mixture was then stirred at 77° C. for 16 hours. The contents of the reaction flask were cooled and filtered; the solvent was removed by evaporation; and the mixture was partitioned between 1M K2CO3 and EtOAc. The organic phases were washed with brine, dried with anhydrous Na2SO4, filtered, and evaporated. Flash column chromatography (gradient elution: heptane to 10% EtOAc in heptane) gave the title compound as a pale oil. 1H NMR (CDCl3) δ (ppm) 7.41-7.39 (m, 2H), 7.37-7.34 (m, 2H), 7.32-7.27 (m, 2H), 7.10-7.03 (m, 2H), 4.02 (s, 2H), 3.97 (s, 2H), 3.91 (s, 2H). LRMS (ESI) m/z 289 [(M+H)+; calcd for C15H15BrN: 289].
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][CH:17]3[O:21]CC[O:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.CCOC(C)=O>CC(C)=O.O.CCCCCC>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([OH:21])=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1-c1ccccc1C2CCC1OCCO1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc2c1-c1ccccc1C2CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(4-methylfluoren-9-yl)ethyl]-1,3-dioxolane (11.1 g, 39.6 mmol) in acetone (150 mL) at 0° C. was charged with Jone's reagent (16 g of CrO3 and I6 ml of H2SO4 (conc.) in 100 ml of water). The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC (silica, 25% EtOAc in hexane). The acetone was evaporated, the residue was diluted with water (100 mL). The product was extracted into EtOAc and the organic layer was washed thoroughly with water (×6), until aqueous washings were clear, then the product was extracted into 1N NaOH solution (3×70 mL), the water was washed again with ethyl acetate (1×30 mL) and acidified to pH=1. The solid formed was filtered off, washed with water and dried. This afforded 6.8 g (68.2%) of the 3-(4-methylfluoren-9-yl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.C(Cl)[Cl:20]>C(OCC)C>[ClH:20].[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1
Reactant: ClCCl
Agent: COc1cc(OC)nc(C#Cc2ccccc2)n1
Solvent: CCOCC
Product: Cl
Reaction time: 16 h

Procedure:
4,6-Dimethoxy-2-(phenylethynyl)pyrimdine (320 mg, 1.3 mmol) was dissolved in CH2Cl2 (1.0 mL), and treated with HCI in diethyl ether (1.6 mL of a 1.0M solution, 1.6 mmol). A yellow solid precipitated immediately. The mixture was diluted with ethyl acetate and allowed to stand in the freezer for 16 h. The cold supernatant was decanted and the remaining solids were triturated with ethyl acetate (1.5 mL), and then hexane (3.times.2 mL). The remaining solid was dried in vacuo to afford 4,6-dimethoxy-2-(phenylethynyl)pyrimdine hydrochloride (174 mg, 47% yield) as a yellow solid. M.p. 137-138. 1H NMR (CD3OD, 300 MHz) Δ7.65-7.62 (m, 2H), 7.46-7.42 (m, 3H), 6.16 (s, 1H), 3.97 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:54]=[CH:53][C:51]([NH2:52])=[C:50]([O:55][CH3:56])[CH:49]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(O)C>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:54]=[CH:53][C:51]([NH:52][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=5)[C:22]([NH:24][C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])=[O:23])[CH:5]=[CH:4][N:3]=4)=[C:50]([O:55][CH3:56])[CH:49]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 52 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.14 g, 0.28 mmol), 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (0.074 g, 0.25 mmol) and para-toluenesulfonic acid (0.12 g, 0.68 mmol) in iPrOH (5 mL) was heated at 180° C. for 10 min. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography followed by trituration with diethyl ether provided the title compound (0.099 g, 0.13 mmol, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 3H), 1.46 (s, 4H), 1.49-1.58 (m, 2H), 1.77 (d, J=10.4 Hz, 2H), 2.29 (s, 3H), 2.62 (t, J=12.0 Hz, 2H), 3.72 (d, J=11.9 Hz, 3H), 3.77 (s, 3H), 3.97 (s, 3H), 6.41-6.52 (m, 2H), 6.64 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 7.16 (t, J=8.1 Hz, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.32-7.43 (m, 3H), 7.67 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 8.13-8.21 (m, 1H), 8.42 (s, 1H), 9.34 (br. s., 1H), 9.76 (s, 1H). MS (M+H, ES+) 745.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20]#[N:21])=[C:11](I)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH2:28][CH2:29][O:30][CH2:31][CH:32]=1)CCC.[Cl-].[Li+]>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20]#[N:21])=[C:11]([C:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: N#Cc1c(I)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: N#Cc1c(C2=CCOCC2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Yield: 14.9 %

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-2-iodo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (180 mg, 0.4 mmol), tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.452 g, 1.2 mmol), lithium chloride (51.2 mg, 1.2 mmol), copper(I) iodide (7.6 mg, 0.04 mmol), tetrakis(triphenylphosphine)palladium (46.4 mg, 0.04 mmol) was dissolved in dioxane (20 mL) and heated to reflux for 3 hours under an atmosphere of argon. The solvent was removed and the residue was purified using ISCO chromatography on silica gel, elution 20% ethyl acetate in hexanes to ethyl acetate to afford the title compound (24 mg, 14%). LCMS: (FA) ES+, 403. 1H NMR (400 MHz, d4-methanol) δ: 8.35 (s, 1H), 7.59 (d, 1H), 7.43-7.36 (m, 2H), 6.72 (dd, 1H), 4.38-4.36 (m, 2H), 3.97-3.94 (m, 2H), 2.71-2.68 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.P(Br)(Br)([Br:12])=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:12][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)cc(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C)n1
Temperature: 100 °C
Yield: 220.7 %

Procedure:
2,6-Dimethyl-pyridin-4-ol 10I (6.16 g, 50 mmol), PBr5 (11.9 g, 27.65 mmol) and POBr3 (2.5 mL, 24.6 mmol) was combined and CHCl3 (2.5 mL) was added. The reaction was heated at 100° C. for 5 hrs and then cooled in an ice bath. Solid KOH was added till PH reached 7-8 followed by extraction with Et2O (3×75 mL). The combined ether layer was dried and evaporated in vacuo to give a thick clear crude oil (10.1 g) as the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CCN(Cc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
(3R)-1-Benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466 mg) were dissolved in N,N-dimethylformamide (15 ml), tert-butyldiphenylsilyl chloride (1.57 ml) was added under ice cooling., and the mixture was stirred at room temperature for 9 days. After the solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.27 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH3:15]>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:15])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCCCOc1ccc(C(N)=O)cc1

Procedure:
Chilled to 20°, a solution of 84 g (0.39 mole) of a solution of 4-n-butoxybenzoyl chloride in 700 ml of AR chloroform, then saturated with anhydrous ammonia. The mixture was stirred for 20 min. to 0°, then the white precipitate collected, washed with cold water and oven-dried to 60° to give 76 g, m.p. shrinks 160°, melts 162°-164°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH3:37][N:38]([CH3:51])[CH2:39][C:40]1[CH:50]=[CH:49][C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH2:48][C:42]=2[CH:41]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13]([N:46]1[CH2:45][CH2:44][C:43]2[CH:49]=[CH:50][C:40]([CH2:39][N:38]([CH3:51])[CH3:37])=[CH:41][C:42]=2[CH2:48][CH2:47]1)=[O:14])[CH3:2]
Reactant: CN(C)Cc1ccc2c(c1)CCNCC2
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCc3ccc(CN(C)C)cc3CC2)cc1CC

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and dimethyl-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylmethyl)-amine.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C.O1CCCC1>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)c1csc(N)n1
Yield: 90.1 %

Procedure:
Ethyl 4-chloro-2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 29.0 g.), thiourea (8.8 g.), sodium acetate (7.9 g.), water (72.5 ml.), tetrahydrofuran (60 ml.) and ethanol (72.5 ml.) were treated in a similar manner to that of Example C-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetate (syn isomer, 28.0 g.).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[NH2:20][NH2:21]>O>[N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]3[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)CCC(=O)c1ccc(Cn2cccn2)s1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(Cn3cccn3)s2)=NN1

Procedure:
Analoguous to Example 2(b), the reaction is carried out with 29 g of 4-[5-(pyrazol-1-yl-methyl)-thien-2-yl]-4-oxo-butyric acid and 6.6 g of hydrazin hydrate in 100 ml water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22](C(OCC3C=CC=CC=3)=O)[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[NH:22][CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2NCCC21
Reaction time: 3 h
Yield: 102.8 %

Procedure:
A mixture of compound 21 (3.8 g, 8.0 mmol) and 10% Pd-on-carbon (wet, 500 mg) in MeOH/EtOAc (1:1, 100 mL) was pressurized to 50 PSI H2 and shaken for 3 h using a Parr apparatus. The reaction mixture was filtered through a pad of celite and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to give 22 (2.8 g, 100%). The crude product was used without further purification. Mass spectrum, m/z [341.1] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)[C:8](=[O:31])[CH:7]=[N:6]2.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:31])[CH2:18][CH2:19]1
Reactant: COc1cc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncc(=O)n(CCN3CCC(N)CC3)c2cc1OC

Procedure:
tert-Butyl {1-[2-(6,7-dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 157, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6](OCC1N(CCCCNS(C)(=O)=O)C2C3C=CC=CC=3N=C(N)C=2N=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:52][OH:53])[N:46]([CH2:47][C:48]([CH3:51])([OH:50])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N:35]=1.NC1C2N=C(CO)N(CCCCNS(C)(=O)=O)C=2C2C=CC=CC=2N=1>>[NH2:1][C@H:2]([C:6]([O:53][CH2:52][C:45]1[N:46]([CH2:47][C:48]([OH:50])([CH3:49])[CH3:51])[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[C:34]([NH2:33])[C:43]=2[N:44]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reactant: CC(C)(O)Cn1c(CO)nc2c(N)nc3ccccc3c21
Agent: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Product: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl L-valinate was prepared according to the general method used to prepare (4-amino-1-{4-{(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl L-valinate using 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol in lieu of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide. The product was provided as off-white needles, mp 190-192° C.; MS (ESI) m/z 386 (M+H); Anal. Calcd for C20H27N5O3: C, 62.32; H, 7.06; N, 18.17. Found C, 62.08; H, 7.11; N, 17.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:60])[C:34]([CH3:59])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:60])[C:34]([CH3:59])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)=[C:46]([CH:50]=2)[C:47]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
3,4,5-Trimethoxyaniline (0.260 g, 1.42 mmol), triethylamine (0.144 g, 1.42 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.240 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.085 mmol, 18%).