Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2C2C=C(C)C=CC=2S([O-])(=O)=O)[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>CO>[CH3:13][C:11]([C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][C@@H:26]2[CH2:27][CH2:28][CH2:29][C@H:30]2[S:6][CH2:5][C:4]([O:8][CH3:9])=[O:7])[CH:17]=[C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:19]=1)([CH3:10])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)[O-])c([C@@H]2CCC[C@@H]2CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CS[C@@H]1CCC[C@H]1CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
To a solution of sodium methoxide (prepared from 38 mg of sodium) in 10 ml of methanol is added 174 mg (1.64 mmoles) of methyl thioglycolate. After stirring for a few minutes, a solution of 500 mg (1.09 mmoles) of the title product of Example 38 in 5 ml of methanol is added, and stirring is continued until TLC indicates the reaction is complete. The mixture is then partitioned between diethyl ether and water, the organic layer dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][CH2:7][C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:7][C:6]=2[CH:16]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)CNc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cc(Cl)ccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a mixture of 0.229 g (1.0 mmol) of 2-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine in 1.0 ml of pyridine under nitrogen is added 0.30 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred at room temperature for 1 hour, heated on a steam bath for 5 minutes and 8 ml of 2N HCl added. The mixture is extracted with ethyl acetate and the extract washed three times with 1 ml of 1N sodium bicarbonate. The organic layer is dried (MgSO4) and the solvent removed. The residue is crystallized from ethyl acetate-hexane to give 0.24 g of crystals, m.p. 207°-208° C. Anal. Calc'd for C28H2N2 O3Cl: C,71.9; H,4.5; N,6.0; Cl,7.6. Found: C,71.6; H,4.6; N,5.9; Cl,7.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].[CH2:12]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:12])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C1CCOC1
Product: CC(O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethereal solution (17.41 ml, 52.24 mmol, 3M) of MeMgEr was slowly added at −78° C. to a solution of 3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 ml). The reaction mixture was stirred at room temperature for 16 h and was cooled (0° C.) and was quenched, sequentially, with excess ethyl acetate (10 ml) and water (5 ml). Excess anhydrous MgSO4 (5 g) was added and stirred for 30 minutes at room temperature. The suspension was filtered over celite and the solids were washed with ethyl acetate (2×25 ml). The combined filtrate was evaporated to obtain the product in quantitative yield (7.65 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][N:13]([CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[S:27][C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2Cl)[CH:20]=1)=[O:18]>>[CH3:12][N:13]([CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[S:27][C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:20]=1)=[O:18]
Reactant: CN(C)CCNC(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCN(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-dimethylamino-ethyl)-amide by a procedure analogous to Example 1C. MS: 394 (MH+), HPLC Rf: 3.43; HPLC purity: 98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:11])[C:7]=1[C:8]([OH:10])=[O:9].Cl.[CH3:13][N:14]([CH3:16])O.C(N(CC)CC)C.O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([O:10][N:14]([CH3:16])[CH3:13])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(O)cccc1F
Reactant: CN(C)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)OC(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.56 Grams of 6-fluorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.94 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 0.6 g of 3-fluoro-2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: [O:1]1[C:5]([CH:6]([C:23]2[O:24][CH:25]=[C:26]([CH:28]([O:58][Si](CCCC)(C)C)[CH2:29][CH:30]([O:50][Si](CCCC)(C)C)[CH:31]([O:42][Si](CCCC)(C)C)[CH:32]([O:34][Si](CCCC)(C)C)[CH3:33])[N:27]=2)[O:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][N:3]=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:1]1[C:5]([CH:6]([C:23]2[O:24][CH:25]=[C:26]([CH:28]([OH:58])[CH2:29][CH:30]([OH:50])[CH:31]([OH:42])[CH:32]([OH:34])[CH3:33])[N:27]=2)[O:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][N:3]=[CH:2]1
Reactant: CCCCCCCCCCCCCC(=O)OC(c1cnco1)c1nc(C(CC(O[Si](C)(C)CCCC)C(O[Si](C)(C)CCCC)C(C)O[Si](C)(C)CCCC)O[Si](C)(C)CCCC)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OC(c1cnco1)c1nc(C(O)CC(O)C(O)C(C)O)co1
Reaction time: 5 h

Procedure:
To a stirred solution of 2-[1-(oxazol-5-yl)-1-(tetradecanoyloxy)methyl]-4-[1,3,4,5-tetra(t-butyldimethylsilyloxy) hexyl]oxazole (8, 1.5 g, 1.5 mmol) in THF (100 mL) is added tetrabutylammonium fluoride (0.4 g, 1.5 mmol) in THF (1 mL). After five hours, the solvent is removed, water added, and the product extracted into ethyl acetate. Evaporation and purification bys ilica gel chromatography yields 2-[1-(oxazol-5-yl)-1-(tetradecanoyloxy) methyl]-4-(1,3,4,5-tetrahydroxyhexyl)oxazole (1, bengazole A).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[C:8]([Cl:21])[C:7]([O:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC([O-])(C)C.[K+].Cl>CC(O)(C)C>[Cl:21][C:8]1[C:7]([O:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COC(COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Temperature: 75 °C
Yield: 100 %

Procedure:
4-Isopropyl-thiazole-2-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (2.20 g, 5.16 mmol) and KOtBu (1.22 g, 10.84 mmol) were dissolved in tBuOH (50 mL) under an atmosphere of nitrogen. The reaction was heated to 75° C. for 4 hours. The reaction was cooled to rt and the pH was adjusted to 4 with 2N HCl(aq). The reaction mixture was concentrated and taken up in EtOAc (100 mL). The mixture was washed with ½ sat. brine. The organic layer was dried with Na2SO4, filtered and was concentrated. 8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinolin-4-ol (2.11 g, 99%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].O>CN(C)C=O>[N:1]([CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Yield: 94.7 %

Procedure:
In 40 ml of dimethylformamide was suspended 2.84 g of sodium azide, and 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added thereto and the mixture was reacted at room temperature for 2 hours. After addition of 32 ml of water to the mixture, precipitated crystals were filtered to give 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridine. Melting point: 190° C. (decomposed). These crystals were suspended in 500 ml of methanol, and hydrogenolysis was carried out by adding 0.5 g of palladium black at room temperature for one hour. After removal of the catalyst by filtration, the filtrate was condensed and recrystallized from methanol - isopropanol, and then filtered to give 7.4 g of the title compound. Melting point: 225° to 230° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:34][N:35]([CH:44]=[O:45])[O:36]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CO>[CH:1]1([CH2:6][C@H:7]([CH2:34][N:35]([CH:44]=[O:45])[OH:36])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ccncn1
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (4.22 g, 6.87 mmol) and Pearlman's catalyst (964 mg, 1.37 mmol) in methanol (381 mL) was degassed and placed under 1 atm of H2 at 25° C. After 2 hrs, the reaction mixture was filtered and concentrated to give a crude residue which was purified by RP-HPLC to provide (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-4-pyrimidinyl-3-pyrazolidinecarboxamide as a foamy solid (1.8 g, 67% yield). The material was dissolved and evaporated from acetonitrile (2×5 mL) to provide a white solid. MS (ES+) m/z 391.2 (MH+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.06-1.23 (m, 2H) 1.34-1.47 (m, 1H) 1.47-1.67 (m, 4H) 1.69-1.97 (m, 4H) 2.15-2.29 (m, 1H) 2.45-2.60 (m, 1H) 2.85-2.99 (m, 1H) 3.20-3.28 (m, 1H) 3.49 (dd, J=13.89, 4.55 Hz, 1H) 3.59-3.85 (m, 1H) 3.94 (dt, J=9.41, 4.77 Hz, 1H) 4.64-4.74 (m, 1H) 7.86 (s, 0.7H) 8.17 (dd, J=6.06, 1.26 Hz, 1H) 8.25 (s, 0.3H) 8.60 (d, J=6.06 Hz, 1H) 8.82 (s, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:8](=O)[C:9](=[CH:13]N(C)C)[CH2:10][CH2:11][CH:12]=1)(C)(C)C.[NH:20]([C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)[C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:6][C:7]1[C:8]2[N:23]=[C:21]([NH:20][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=3)[N:22]=[CH:13][C:9]=2[CH2:10][CH2:11][CH:12]=1
Reactant: CN(C)C=C1CCC=C(O[Si](C)(C)C(C)(C)C)C1=O
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)C(O)=CCC3)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 6.5 %

Procedure:
The crude 2-(tert-butyl-dimethyl-silanyloxy)-6-dimethylaminomethylene-cyclohex-2-enone in DMA (75 mL) was treated with 3-guanidino-benzenesulfonamide as the hydrochloride salt (7.79 g, 31.09 mmol) and potassium carbonate (2.13 g, 15.54 mmol) and the mixture stirred at 110° C. for 20 hours. The mixture was evaporated under high vacuum and triturated with dichloromethane (100 mL) to give a buff coloured precipitate. The precipitate was filtered, the mother liquors concentrated in vacuo and purified by flash chromatography on silica gel eluting with ethyl acetate to give 3-(8-hydroxy-5,6-dihydro-quinazolin-2-ylamino)benzenesulfonamide as a yellow solid (0.63 g, 6.5%). MS (ES+) 319, (ES−) 317. δH (d6 DMSO) 2.04-2.12 (2H, m), 2.66-2.74 (2H, m), 2.84-2.90 (2H, m), 7.33 (2H, s), 7.43 (1H, d), 7.48 (1H, t), 8.16 (1H, d), 8.25 (1H, s), 8.78 (1H, s), 10.25 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][C:23]([CH3:33])([O:25][Si:26]([CH2:31][CH3:32])([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:24]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:10]([O:11][CH2:21][CH2:22][C:23]([CH3:33])([O:25][Si:26]([CH2:27][CH3:28])([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:24])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: O=C1NCc2c(Cl)c(O)cc(I)c21
Reactant: CC[Si](CC)(CC)OC(C)(C)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)CCOc1cc(I)c2c(c1Cl)CNC2=O
Yield: 34.9 %

Procedure:
In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (70.8 mg, 0.229 mmol) was dissolved in DMF (2.1 mL), and the solution was treated with potassium carbonate (94.8 mg, 0.686 mmol), tetrabutylammonium iodide (8.5 mg, 0.023 mmol) and (4-bromo-2-methyl-2-butoxy)triethylsilane (193 mg, 0.686 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1) to obtain 4-chloro-5-[3-methyl-3-(triethylsiloxy)butoxy]-7-iodoisoindolinone (40.7 mg, yield 35%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].ON1C2C=CC=CC=2N=N1.[CH3:17][N:18]([CH2:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44](O)=[O:45])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=1[NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:18]([CH3:17])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:30]=2)=[CH:40][CH:39]=1
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)O)cc2)c1
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)NCCC(C)C)cc2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
95 mg (1.1 mmol) of 3-methylbutylamine and 160 mg (1.2 mmol) of 1-hydroxybenzotriazole are successively added to a solution of 500 mg (1.1 mmol) of 2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzoic acid (Example 6) in 15 ml of dichloromethane. The reaction medium is cooled to 0° C. and 230 mg (1.2 mmol) of EDCl are added portionwise. The reaction medium is stirred from 0° C. to room temperature over 6 hours, diluted with ethyl acetate, washed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 530 mg of N-(3-methylbutyl)-2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzamide are obtained in the form of a yellow oil, in a yield of 93%.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>CC#N>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][C:19](=[O:20])[O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[CH2:9]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
To a stirred mixture of 2-aminoadamantane HCl salt (1.24 g, 6.61 mmol) and powdered NaHCO3 (1.17 g, 13.9 mmol) in MeCN (40 mL) was added p-nitrophenyl chloroformate (1.40 g, 6.9 mmol). The mixture was stirred at rt for 1 d. The mixture was concentrated and the residue was taken up in ether (150 mL), washed with 5% aq HCl (50 mL) and brine (50 mL), and dried over MgSO4. Removal of the solvent left a white solid (1.81 g). Chromatography on a 40-g silica cartridge eluted with a 30-100% EtOAc in hexanes gradient to afford 4-nitrophenyl (2-adamantyl)carbamate (1.33 g, 63%).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][C:23]([C:25]5[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=5)=[O:24])[CH:21]=4)=[N:11][N:10]3[CH:33]=2)=[O:5])CC1.CO.Cl.C(OCC(O)=O)(=[O:39])C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.CN(C)C=O>[F:32][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:33]=[C:7]([NH:6][C:4](=[O:5])[CH2:1][OH:39])[N:8]=3)[N:11]=2)=[CH:21][C:20]=1[NH:22][C:23]([C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1)=[O:24]
Reactant: CC(=O)OCC(=O)O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CO)cn4n3)ccc2F)n(C)n1
Temperature: 50 °C
Reaction time: 23 h
Yield: 18.9 %

Procedure:
To N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (507 mg, 1.13 mmol) was added 10% hydrogen chloride methanol solution (30 mL), and the mixture was stirred at 50° C. for 23 hr. The solvent was evaporated under reduced pressure. To the residue were added acetoxyacetic acid (242 mg, 2.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (336 mg, 1.75 mmol), 1-hydroxybenzotriazole (167 mg, 1.24 mmol), N-ethyldiisopropylamine (0.60 mL, 3.51 mmol) and N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 62 hr. Methanol (10 mL), water (10 mL) and saturated aqueous sodium carbonate solution (2 mL) were added to the mixture, and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by NH silica gel column chromatography (ethyl acetate/hexane=0/100→100/0-methanol/ethyl acetate=2/98) and crystallized from ethanol to give the title compound (94 mg, 19%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:22]([OH:24])=[O:23])[C:16]=4[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[C:37](=[O:49])([O:45][CH:46](Cl)[CH3:47])[O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([O:38][C:37]([O:45][CH:46]([O:23][C:22]([C:17]2[C:16]3[CH:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]4[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]4)[N:13]([CH2:12][C:9]4[CH:8]=[C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)[O:11][N:10]=4)[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:24])[CH3:47])=[O:49])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Product: CC(OC(=O)OC1CCCCC1)OC(=O)c1cccc2c1cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
can be prepared from 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid and cyclohexyl 1-chloroethyl carbonate by the procedure described by K. Kubo et al., J. Med. Chem. 1993, 36, 2343-2349.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH:9](O)[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:3].C[OH:22]>N.[Ni]>[NH2:3][CH2:2][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:22])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NC(O)CCOc1ccc(Cl)cc1C#N
Reactant: CO
Agent: [Ni]
Agent: Cl
Agent: N
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1CN

Procedure:
6.3 gm (0.02 mol) of 1-(2-cyano-4-chlorophenoxy)-3-hydroxy-3-tert.-butylamino propane hydrochloride were dissolved in 100 ml of methanol containing 10 ml of NH3 and the mixture was hydrogenated under normal pressure at 20° C. over Raney-nickel. After separation of the catalyst, the solvent was distilled off in vacuo, and the residue was admixed with ether and water. After an addition of a small amount of NaOH, the aqueous phase was separated and the organic phase was washed with water and dried over MgSO4. After distilling off the ether, a solid residue remained which was recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(2-aminomethyl-4-chlorphenoxy)-2-hydroxy-3-tert.-butylamino propane. The base was dissolved in ethanol and ethereal HCl was added thereto. The precipitated crystals of the hydrochloride of the base were isolated to obtain 3.1 gm of the hydrochloride having a melting point of 118°-120° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C=NC1CCCCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)NC1CCCCC1
Yield: 48 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51 mmol) to provide 1.02 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylurea as a solid, m.p. 179–180° C. Analysis: Calculated for C23H32N6O2.0.75 H2O: % C, 63.06; % H, 7.71; % N, 19.18; Found: % C, 62.74; % H, 7.57; % N, 19.16.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:15])=[C:4]([CH2:13][OH:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([I:15])=[C:4]([CH2:13][O:14][C:16](=[O:18])[CH3:17])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)O)c1I
Solvent: c1ccncc1
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-Amino-3-hydroxymethyl-2,4,6-triiodobenzoic acid (41.2 g, 0.076 mol) was dissolved in pyridine (100 ml), and acetic anhydride (80 ml) was added slowly with efficient stirring at room temperature. Stirring was continued overnight. The reaction mixture was then evaporated to a semisolid mass and treated with hydrochloric acid (2M, 250 ml). The white to grey precipitate formed was filtered off and washed with water (2×40 ml) and then dried. 44.2 g (100%) of product was isolated.