Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6](=[CH:9]NC1C=CC=CC=1)[C:7]#[N:8])=[O:5].FC(F)(F)C(O)=O.[CH:28]1([NH:31][C:32](=[O:42])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][NH2:41])[CH:34]=2)[CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[NH2:8][C:7]1[N:40]([C:35]2[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=2[CH3:39])[C:32]([NH:31][CH:28]2[CH2:30][CH2:29]2)=[O:42])[N:41]=[CH:9][C:6]=1[C:4](=[O:5])[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1ccccc1Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2Cl)c1N
Yield: 38.4 %

Procedure:
A solution of 2-(2-chlorobenzoyl)-3-phenylaminoacrylonitrile (93 mg, 0.33 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (104 mg, 0.33 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 20 mL of ethanol was heated to 60° C. for 48 h. After cooling, the mixture was concentrated and the residue was dissolved in minimal ethyl acetate. 100 ml diethyl ether was added and the precipitate was filtered and dried to provide desired product (50 mg, 39%). HPLC (4 minute 10-90 gradient) tR 2.51 min; MS m/z 395.1 [M+H]+; 1H NMR (DMSO), δ 8.50 (d, J=3.8 Hz, 1 H), 7.93 (d, J=8.0 Hz, 1 H), 7.84 (s, 1 H), 7.57 (m, 5 H) 7.32 (s, 1 H), 7.01 (s, 2 H) 3.37 (m, 2 H), 2.86 (m, 1 H), 2.14 (s, 3 H), 1.09 (t, 2H), 0.68 (m, 2 H), 0.58 (m, 2 H) ppm
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.BrC1C=C(O)C=CC=1.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:44])[C:24](=[O:43])[N:25]2[CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]([OH:44])([C:8]1[C:9]([OH:11])=[CH:10][C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=1)[C:24](=[O:43])[N:25]2[CH:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydro-1,4-benzodioxin-6-ol to replace 3-bromophenol, and 4-bromo-1-benzhydrylindoline-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (99%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ9.06 (s, 1H), 7.44-7.28 (m, 10H), 6.98-6.82 (m, 2H), 6.68 (s, 1H), 6.33 (d, J=7.4 Hz, 1H), 6.16 (s, 1H), 4.23-4.08 (m, 4H); MS (ES+) m/z 566.1 (M+23), 568.1 (M+23).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11]=[C:12]1[O:16][C:14](=O)[CH2:13]1.C(OC(=O)C)(=O)C>CC(C)=O.O1CCCC1>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(=O)Cc1nc2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a solution of anthranilic acid (290 g, 2.1 mol) in acetone (1000 mL), diketene (460 mL, 6.0 mol) was added dropwise at room temperature. The solution was stirred at room temperature for 16 hours, and the resulting crystals were collected by filtration, washed with acetone and diethylether, and air dried (170 g yield). The crude crystals were suspended in a mixture of acetic anhydride (320 mL, 3.4 mol) and tetrahydrofuran (1000 mL), and the suspension was heated and stirred at 80° C. for 12 hours. The suspension was cooled to room temperature, and concentrated under reduced pressure, and the resulting crude crystals were collected by filtration. The crystals were washed with acetonitrile and air dried to give the title compound (244 g, 57% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[O:6]1CCCCC1OC1CCCCO1.C[Si](C)(C)[O:21][C:22]1([CH3:36])[CH2:27][CH:26]([O:28][Si](C)(C)C)[C:25]([CH3:34])([CH3:33])[CH2:24][C:23]1=[O:35].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:35][C:23]1([CH:24]=[CH:1][CH:2]([OH:6])[CH3:3])[C:25]([CH3:33])([CH3:34])[CH:26]([OH:28])[CH2:27][C:22]1([OH:21])[CH3:36]
Reactant: [Li]CCCC
Reactant: CC1(O[Si](C)(C)C)CC(O[Si](C)(C)C)C(C)(C)CC1=O
Reactant: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)C=CC1(O)C(C)(O)CC(O)C1(C)C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To 5.2 ml of a 1.6M n-hexane solution of n-butyl lithium was added 15 ml of anhydrous THF at -78° C. (bath temperature) in a nitrogen atmosphere, and 1.3 g of a tetrahydropyranyl ether of 3-butyn-3-ol was added dropwise thereto under the same conditions over 10 minutes. After the addition, the mixture was stirred for 30 minutes. Then, 20 ml of an anhydrous THF solution containing 2.1 g of 2,4-bis(trimethylsiloxy)-2,5,5-trimethylcyclohexanone was added dropwise to the mixture under the same conditions over 20 minutes. After the dropwise addition, the mixture was stirred for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. After the diethyl ether was removed from the extract by distillation, a 1N hydrochloric acid aqueous solution and methanol were added to the residue, followed by stirring at room temperature for 5 hours. The methanol was removed by distillation under reduced pressure, and the residue was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 70%) of 4-(1,2,4-trihydroxy-2,5,5-trimethylcyclopentyl)but-3-en-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Yield: 81.2 %

Procedure:
To a 100 mL flask, ethyl 3-bromo-1-(3,5-dichloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (2.0 g, 5.4 mmol), acetonitrile (10 mL) and 98% sulfuric acid (1.1 g, 10.9 mmol) were added. The mixture was stirred for a few minutes, and then potassium persulfate (2.4 g, 8.7 mmol) was added. The reaction mixture was heated to reflux for 5 hours. The warm (50-65° C.) reaction mixture was filtered, a cake is obtained. The cake was washed by acetonitrile (10 mL). The filtrate was concentrated to about 10 mL on rotary evaporator. Then water (50 mL) was added. The solid product was isolated by filtration, washed with 25% aqueous solution of acetonitrile (3×15 mL) and dried to give the product (1.6 g) as orange solid in 80% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[CH:48]=[C:49]([S:53]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1.BrCCCCC>>[N:56]1([S:53]([C:49]2[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=2)[CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])(=[O:54])=[O:55])[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1
Reactant: O=S(=O)(c1cccc(CCl)c1)N1CCOCC1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2cccc(S(=O)(=O)N3CCOCC3)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 4-(3-(chloromethyl)phenylsulfonyl)morpholine to replace 1-bromopentane, 1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (40%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.64 (m, 4H), 7.29-7.18 (m, 2H), 7.05 (dd, J=7.3, 5.6 Hz, 2H), 6.52 (s, 1H), 6.11 (s, 1H), 5.09 (ABq, 2H), 4.74 (dd, J=9.3 Hz, 2H), 4.04-4.21 (m, 4H), 3.56 (t, J=4.5 Hz, 4H), 2.84-2.65 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 154.8, 144.2, 141.9, 138.0, 137.9, 134.7, 132.2, 131.6, 130.1, 128.8, 126.7, 125.9, 123.9, 123.3, 121.0, 110.9, 109.5, 98.9, 79.5, 65.2, 64.2, 63.6, 57.3, 45.8, 42.5; MS (ES+) m/z 534.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1.ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:37][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:9][N:8]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C(=O)NCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ncc(-c3ccc4c(c3)CCC(=O)N4)s2)cc1OC
Reaction time: 3 h

Procedure:
There were mixed, each in a powdery state, 500 mg of 6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), The mixture was stirred at 200° C. with heating. After 3 hours, the reaction was completed. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=49:1 by v/v), A solid obtained from the eluate was recrystallized from ethanol to obtain 98 mg of 2-(3,4-dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl) thiazole as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[N:10])=[CH:4][CH:3]=1.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:11])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: N#CC(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: NC[C@H](O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.9 g of (R (4-chloro-phenyl)-hydroxy-acetonitrile (11 mmol) were dissolved in 18 ml THF under a nitrogen atmosphere and the solution was cooled to 0° C. 58 ml of a 1M borane-THF complex solution in THF were then added dropwise, keeping the temperature between 0-2° C. After completion of the addition the reaction mixture was stirred at RT for additional 45 min and then refluxed for 16 h. The reaction mixture was then cooled down to 0° C. and 13 ml of methanol were added over a period of 35 min keeping the temperature of the mixture between 2 and 5° C. After refluxing the reaction mixture for 1 h it was concentrated, the remaining residue was dissolved in DCM and the mixture was extracted twice with 1N aqueous HCl. The combined aqueous phases are then treated with concentrated NaOH to adjust the pH to 12, and then extracted twice with DCM. The combined organic phases were then washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo leading to a colorless solid which was dissolved in 100 ml diethylether, treated with 4 ml 2.6N HCl in diethyl ether. After 1 h at RT the precipitate was filtered off and dried under high vacuum, leading to 1.24 g white solid (54%). MS (ISP) 172.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[C:12]=2[CH:21]=1.O>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][OH:2])[C:12]=2[CH:21]=1
Reactant: Clc1ccc2onc(OCC3CO3)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCC(O)COc1noc2ccc(Cl)cc12
Yield: 74.2 %

Procedure:
256 ml of a 10% w/v aqueous solution of potassium carbonate were added to a suspension of 21.0 g (92.7 mmoles) of 5-chloro-3-(2,3-epoxypropoxy)-1,2-benzisoxazole (prepared according to the method described in Japanese Patent Provisional Publication No. Sho. 52-31070) in 100 ml of acetonitrile, and the mixture was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then 500 ml of water were added. The reaction mixture was then extracted with 1 liter of ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation to give a solid residue. This was then recrystallized from a mixture of ethyl acetate and diethyl ether, to give 16.7 g (yield 74.2%) of the title compound as a colorless amorphous powder, melting at 61°-62° C.
Reaction SMILES: [Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5].[C:39](OC(=O)C)(=[O:41])[CH3:40].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:39]([N:6]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])[C:4](=[O:5])[C:3]1[CH:30]=[CH:31][CH:32]=[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)[C:2]=1[Cl:1])(=[O:41])[CH3:40]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(C(=O)c1cccc(C2(C#N)CC2)c1Cl)c1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide (180 mg, 0.328 mmol) in pyridine (2 mL) were added N,N-dimethylpyridine-4-amine (18.0 mg, 0.147 mmol) and acetic anhydride (138 μL, 1.46 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water (5 mL), and the mixture was extracted with ethyl acetate (5mL×4). The organic layers were combined, washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→20/80) and, preparative liquid chromatography (0.1% trifluoroacetic acid-containing acetonitrile/0.1% trifluoroacetic acid-containing water=45/55→60/40). The obtained residue was triturated with diisopropyl ether/acetone to give the title compound (68.5 mg, 35%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N2CCC[C@H]2C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-proline (57 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μ1, 1.0 mmol). The mixture was stirred at room temperature for 2 days. Thereafter, the reaction mixture was further treated in the same manner as Example 1 to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-proline (81 mg), melting at 131° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)(Cl)Cl.CO>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)Nc1ccccc1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.250 g, 0.795 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. under an atmosphere of nitrogen. The reaction mixture was treated dropwise with phenyl isocyanate (0.091 mL, 0.835 mmol). After 16 h, the reaction mixture was quenched by 10% Na2CO3 solution, diluted with CHCl3 and the phases were separated. The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield an off-white solid. Chromatography (SiO2, 95:5 CHCl3:MeOH) gave an off-white foam. The foam was triturated with diethyl ether and filtered to give 1-{3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-3-phenylurea (0.115 g) as an off-white solid. mp 177–179° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (dd, J=8.1, 1.0 Hz, 1H), 8.39 (s, 1H), 7.58 (dd, J=8.4, 0.9 Hz, 1H), 7.44–7.35 (m, 3H), 7.25–7.18 (m, 3H), 6.99 (t, J=5.6 Hz, 1H), 6.90–6.85 (m, 1H), 6.60 (s, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.76 (s, 2H), 3.60 (q, J=7.0 Hz, 2H), 3.26–3.18 (m, 4H), 1.76 (t, J=7.0 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 155.2, 151.8, 149.0, 144.8, 140.4, 132.0, 128.5, 126.9, 125.7, 123.7, 120.9, 120.8, 120.8, 117.6, 114.3, 65.4, 62.7, 49.7, 37.0, 28.1, 14.9; MS (APCI) m/z 434 (M+H)+; Anal. Calcd for C23H27N7O2: C, 63.72; H, 6.28; N, 22.62; Found: C, 63.45; H, 6.04; N, 22.28.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[C:13]([F:26])[C:12]=1[F:27])[CH2:2][CH2:3][CH3:4].[F:28][C:29]([F:48])([F:47])[C@H:30]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[CH3:49]N(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[F:28][C:29]([F:48])([F:47])[C@H:30]([O:37][C:38]([C:39]1[CH:44]=[CH:43][C:42]([O:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH2:4][CH3:49])=[C:12]([F:27])[C:13]=3[F:26])=[CH:22][CH:21]=2)=[O:25])=[CH:41][CH:40]=1)=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F
Reactant: CN(C)c1ccccn1
Reactant: CCCCOCCCCOc1ccc(-c2ccc(C(=O)O)cc2)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCOCCCCC)c(F)c3F)cc2)cc1)C(F)(F)F
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of 4′-(4-butoxybutoxy)-2′,3′-difluorobiphenyl-4-carboxylic acid (27) (1 equi.), (4-hydroxybenzoic acid (R)-1-trifluoromethyl-heptyl ester (7) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 2′,3′-difluoro-4′-(4-pentyloxybutoxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethylheptyl oxycarbonyl]-phenyl ester (28) as a white solid (65%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N+:5]([O-:36])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: COc1ccc(Cc2c3cc(OC)c(OC)cc3c(CCl)c[n+]2[O-])cc1OC
Temperature: 0 °C
Yield: 70.2 %

Procedure:
To an ice-cooled solution of 5.2 g 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl) methyl] isoquinoline in 150 ml methylene chloride, was added under stirring and nitrogen a solution of 3.04 g m-chloroperbenzoic acid in 100 ml methylene chloride over 2 hours, so that the temperature did not exceed 3°-5°. The solution was stirred over night at room temperature and the red solution applied to a column, packed with 100 g silica gel 60 Merck, 230-400 mesh ASTM. From elution with ether and ethyl acetate the unreacted base 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline was separated. Elution with ethyl acetate/ethanol (4:1) afforded 3.8 g of a brownish foam. The 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline 2oxide crystallized from methylene chloride/ethyl acetate: 3.5 g yellow crystals, mp 167°-168°.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3]1=[O:14]
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2S,5R)-2-methyl-5-phenylmorpholin-3-one from Step E (90 mg, 0.47 mmol) in DMF (2 mL) at 0° C. was added NaH (20 mg of a 60% dispersion in oil, 0.50 mmol). After 10 min, ethyl bromoacetate (79 mg, 0.47 mmol) was added and the mixture was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (3 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:25]=2[O:24][CH2:23]1>>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH:31][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([C:12]4[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=4)=[CH:15][CH:16]=3)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNc3ccc4c(c3)OCO4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,3-benzodioxol-5-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 408.4. HPLC (Condition A), Rt: 4.54 min (HPLC purity: 85.5%).