Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9]N(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O)[CH3:5])[CH3:2].CNC[C@H]1[O:38][C@@H:37]([N:39]2[C:48]3[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=3[N:41]=[C:40]2[NH:49][CH3:50])[C@H:36]([OH:51])[C@@H:35]1[OH:52].C[CH2:54][N:55]([CH:59]([CH3:61])C)[CH:56]([CH3:58])C>>[CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9][CH2:61][CH2:59][N:55]([CH3:54])[CH2:56][C@H:58]1[O:38][C@@H:37]([N:39]2[C:48]3[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=3[N:41]=[C:40]2[NH:49][CH3:50])[C@H:36]([OH:51])[C@@H:35]1[OH:52])[CH3:5])[CH3:2]
Reactant: CNC[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: CCOC(C)=NOCCCCN(C)C[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 8a was prepared by the same procedure as reported for 6a using 4c (1.00 g, 3.23 mmol), ethyl N-(4-bromobutoxy)ethanimidate49 (924 mg, 3.87 mmol), and DIEA (209 mg, 0.28 mL, 1.6 mmol): yield 635 mg (42%), MS: m/z 467 (M+H)+; 1HNMR (DMSO-d6) δ 7.89 (s, 1H, H-2), 6.87 (q, 1H, 8CH3—NH), 6.46 (bs, 2H, 6-NH2), 5.69 (d, 1H, H-1′, J1′,2′=4.8 Hz), 5.25 (d, 1H, 2′-OH, J2′-2′OH=5.6 Hz), 5.06 (d, 1H, 3′-OH, J3′-3′OH=5.4 Hz), 4.91 (ddd, 1H, H-2′, J1′,2′=4.8 Hz, J2′,3′=5.4 Hz, J2′-2′OH=5.6 Hz), 4.16 (ddd, 1H, H-3′, J2′,3′=5.4 Hz, J3′,4′=4.9 Hz, J3′-3′OH=5.4 Hz), 3.85-3.94 (m, 1H, H-4′), 3.92 (q, 2H, OCH2CH3), 3.80 (t, 2H, NO—CH2), 2.88 (d, 3H, 8NH—CH3, J=4.6 Hz), 2.65-2.74 (m, 1H, 5′-CH2), 2.46-2.58 (m, 1H, 5′-CH2), 2.34 (t, 2H, N(CH3)—CH2), 2.17 (s, 3H, N—CH3), 1.83 (s, 3H, C—CH3), 1.37-1.61 (bm, 4H, NOCH2—CH2CH2), 1.19 (t, 3H, OCH2CH3).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[S:3].Cl[CH:35](OC(Cl)CCl)[CH2:36]Cl.C(O)(C)C>O>[C:28]1([CH:21]([NH:20][S:17]([C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:2]4[S:3][CH:35]=[CH:36][N:1]=4)[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCC(Cl)OC(Cl)CCl
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(N)=S)c2)c1)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
0.97 g of Ethyl 3-[({3′-[(aminocarbothioyl)amino][1,1′-biphenyl]-3-yl}sulfonyl)-amino]-3-phenyl-propanoate 14.1.1 and 0.48 g of 1,2-dichloroethylether were heated in water and i-propanol was added such that a clear solution resulted. After 1 h an additional 100 mg of 1,2 dichloroethylether were added and reflux was continued for 1 h. After aqueous work-up and flash chromatography, 0.62 g of the title compound resulted.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]O)(=[O:4])=[O:3].P(Br)(Br)[Br:14]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:14][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1CBr
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of (2-methanesulfonyl-phenyl)methanol (735 mg, 3.99 mmol) in dry DCM (2 mL) at 0° C., add a solution of 1M phosphorous tribromide in DCM (6.0 mL, 6.0 mmol) and continue stirring for 1 h. Dilute with saturated aqueous NaHCO3, extract three times with ethyl ether, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (12:1) to provide the title compound as a white solid (950 mg, 97%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:44])[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:35])[CH:28]=2)=[CH:23][CH:22]=1)[C:17](O)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:47][CH2:46]1>>[CH2:54]([O:53][C:51]([CH:48]1[CH2:49][CH2:50][N:45]([C:17](=[O:18])[C@@H:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:44])[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:35])[CH:28]=3)=[CH:23][CH:22]=2)[CH2:46][CH2:47]1)=[O:52])[CH3:55]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)N3CCC(C(=O)OCC)CC3)cc2)c1
Yield: 107.7 %

Procedure:
In a similar manner, using 20 mg (33.8 μmol) of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2) and 4.8 mg (30.5 μmol) of ethyl piperidine-4-carboxylate, 24 mg of expected product are obtained with a quantitative yield.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([OH:25])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)C1C=CC=CC=1>C(O)C.O.[Pd]>[NH3:8].[NH2:8][CH2:9][CH:10]([OH:25])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:13]=1
Reactant: OC(Cc1cccc(CN2CCCCC2)c1)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: N
Product: NCC(O)Cc1cccc(CN2CCCCC2)c1
Yield: 104.4 %

Procedure:
11.5 g (0.027 mol) of 1-dibenzylamino-3-[3-(1-piperidylmethyl)phenyl]-2-propanol in 90 ml of ethanol and 10 ml of water are hydrogenated at 35° C. and atmospheric pressure in the presence of 0.5 g of palladium/active charcoal (10% Pd). After removal of the catalyst by filtration and evaporation of the solvent, the residue consists of 5.8 g of a colourless oil which, after chromatographic purification with methanol/conc. ammonia (95:5), yields 3.5 g (52%) of the title compound in the form of a colourless oil. ##STR5##
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][CH:5]=1)[CH3:2]>O1CCOCC1.[Pd]>[NH2:12][C:7]1[C:8]([NH:10][CH3:11])=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(NC)n1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOc1ccc(N)c(NC)n1
Yield: 100.1 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 4.95 g of 6-ethoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 96) were hydrogenated in 100 ml of 1,4-dioxane in the presence of 1.00 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.20 g of the title compound having Rf=0.57 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC(C)C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Methyl 3-hydroxybenzoate (1 eq.) and 2-bromopropane (2 eq.) were dissolved in DMF. Subsequent to addition of potassium carbonate (2 eq.), the resulting mixture was stirred at 100° C. for 24 hours. The mixture was charged into water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby the title compound was obtained (yield: 49%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH:36]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:28]3[N:27]([CH3:26])[C:35]4[C:30]([CH:29]=3)=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cn1c(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 1-methyl-1H-indole-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 489.1.
Reaction SMILES: [CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:17]2[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:52][CH2:51]OCCOCCOCCOCCOC1>CN(C)C=O.[Cu]>[CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:17]2[C:16]([N:23]([C:7]3[C:6]4[C:5]([CH2:19][CH2:20][CH2:51][CH3:52])([CH2:1][CH2:2][CH2:3][CH3:4])[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11]=4[CH:10]=[CH:9][CH:8]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)c2ccccc2-c2cccc(N(c3ccccc3)c3cccc4c3C(CCCC)(CCCC)c3ccccc3-4)c21

Procedure:
40 parts of 9,9-dibutyl-2-iodofluorene, 3.7 parts of aniline, 30 parts of potassium carbonate, 6 parts of copper powders (200 meshes), and 0.87 parts of 18-crown-6 were dissolved in 50 parts of dimethylformamide (DMF), and the obtained solution was reacted in a nitrogen atmosphere at 160° C. for 24 hours. After completion of the reaction, the reaction product was filtrated, and the filtrate was then extracted with ethyl acetate-water. The ethyl acetate phase was dried over magnesium sulfate, and the ethyl acetate was then distilled away, thereby obtaining a brown tarry substance. This brown tarry substance was separated and purified by column chromatography (hexane-ethyl acetate) to obtain 15 parts of 9,9-dibutyl-N-(9,9-dibutylfluorenyl)-N-phenylfluorenamine (the following Compound (344)) in the form of a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:39]4[CH2:44][CH2:43][S:42][CH2:41][CH2:40]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Reactant: C1CSCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCSCC3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (16 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 2 h and then thiomorpholine (0.83 mL) is added. The mixture is stirred at room temperature for 3 d and is then poured into water (50 mL). The resulting off-white solid is filtered off and recrystallized from ethanol to yield 0.222 g (60%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)ethanol (3.48 mL, 24.87 mmol), p-toluenesulfonyl chloride (5.69 g, 29.8 mmol), and 4-(dimethylamino)pyridine (0.304 g, 2.487 mmol) in anhydrous dichloromethane (70 mL) was treated with triethylamine (6.93 mL, 49.7 mmol). The reaction stirred for 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10 to 20% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m/z 356.9 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[O:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][C:14]([O:16][CH:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=O>C(O)(=O)C>[C:20]1([C:18]2[N:5]=[C:14]([CH2:13][CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:7]3=[O:6])[O:16][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CC1CCCCC1=O)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1CCCCC1Cc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
A mixture of ammonium acetate (6.3 g), acetic acid (30 ml) and 1,2-diphenyl-2-oxoethyl (2-oxocyclohex-1-yl)acetate (15.0 g) was heated under reflux for 2.5 hours. After used workup, the crude product was purified by column chromatography (silica gel 100 g, eluent; hexane:ethyl acetate=20:1 then 9:1 then 6:1) to give 2-[(4,5-diphenyl-oxazol-2-yl)methyl]cyclohexanone as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:30][CH3:31])[C:28]=1[CH3:29])[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[CH3:29])[C:23]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][C:9]=1[N+:15]([O-:17])=[O:16])=[O:24]
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Reactant: Cc1nc(-c2ccc(CN)c([N+](=O)[O-])c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2[N+](=O)[O-])cc(OC)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of compound 1e (3.34 g, 14.3 mmol), 3,5-dimethoxy-4-methylbenzoic acid (4.2 g, 21.4 mmol), EDCI (4.1 g, 21.4 mmol), and HOAt (190 mg, 1.4 mmol) in a mixture of dichloromethane (60 mL) and DMF (30 mL) was stirred at rt for 12 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl. The solid which precipitated was recovered by filtration. The ethyl acetate layer was washed with saturated NaHCO3 solution and brine, dried Na2SO4, and concentrated on a rotary evaporator. The residue was recrystallized (ethyl acetate/hexane/petroleum ether) and combined with the filtered solid to afford compound 1f (5.55 g, 94%) as a cream colored solid. ESI-MS m/e 413.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1nc2cc(Cl)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Preparation 59 was repeated, except that 3.00 g of 6-chloro-2 -hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 63), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.03 ml of methyl iodide and 50 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.87 g of the title compound, melting at 141-142° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[Br:25]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([Br:25])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccc(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 1-benzenesulfonyl-7-fluoro-1H-indole (1.00 g, 3.63 mmol) in CCl4 (20 mL) was added a solution of saturated sodium bicarbonate (40 mL) and bromine (0.19 mL, 3.81 mmol) at room temperature. After stirring at room temperature for 16 hours, the reaction was diluted with DCM and water. The organic extract was washed with saturated sodium bicarbonate, 10% aqueous sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The product was obtained as an off-white solid (1.22 g, 95%)
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N2CC3C(=CC=C(O)C=3)C2)C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:42]([N:45]([CH:78]([CH3:80])[CH3:79])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[CH2:54][N:53]([C:58]1[CH:63]=[C:62]([O:64]C)[CH:61]=[CH:60][C:59]=1[CH:66]1[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76]C)[CH:72]=3)[CH2:67]1)[CH2:52]2)([CH3:44])[CH3:43]>>[CH:78]([N:45]([CH:42]([CH3:44])[CH3:43])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[CH2:54][N:53]([C:58]1[CH:63]=[C:62]([OH:64])[CH:61]=[CH:60][C:59]=1[CH:66]1[CH2:75][CH2:74][C:73]3[CH:72]=[C:71]([OH:76])[CH:70]=[CH:69][C:68]=3[CH2:67]1)[CH2:52]2)([CH3:79])[CH3:80]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(OCCN(C(C)C)C(C)C)cc3C1)C2
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(O)cc3C1)C2
Agent: Cl
Product: CC(C)N(CCOc1ccc2c(c1)CN(c1cc(O)ccc1C1CCc3cc(O)ccc3C1)C2)C(C)C
Yield: 52 %

Procedure:
Synthesized from 2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-ol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl{2-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-yloxy}ethyl}amine (126 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:5][C@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][CH:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CCCCC(Br)C(=O)O[C@H](C)C(=O)N1CCCC1
Reactant: COc1ccc(N)cc1
Agent: O=S([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(Nc1ccc(OC)cc1)C(=O)O[C@@H](C)C(=O)N1CCCC1
Temperature: 37 °C
Reaction time: 1 h
Yield: 150.8 %

Procedure:
To (1R)-1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromohexanoate (4.8 g, 15 mmol), NaI (2.3 g, 15 mmol), triethylamine (2.4 g, 24 mmol) and tetrahydrofuran (5 mL) were added. To the solution, p-methoxyaniline (2.4 g, 20 mmol) and tetrahydrofuran (5 mL) were added. The mixture was stirred at 37° C. for 1 hour and then at 20° C. for 5 hours. To the mixture, a saturated sodium sulfite aqueous solution and ethyl acetate were added for extraction. The obtained extract was dried with anhydrous magnesium sulfate, and then the solvent was removed away in reduced pressure in order to obtain 8.2 g of oil. The conversion ratio to the obtained compound was 1000, and the diastereo ratio calculated by NMR analysis was 94.5:5.5.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=[O:7].Cl[C:15]1[CH:16]=[C:17](C=C(C)N=1)C(O)=O.C(NC)C(C)C>>[CH2:1]([N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=[O:7])[CH:16]([CH3:17])[CH3:15]
Reactant: Cc1cc(C(=O)O)cc(N(C)C)n1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CNCC(C)C
Product: Cc1cc(C(=O)O)cc(N(C)CC(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-dimethylamino-6-methyl-isonicotinic acid starting from 2-chloro-6-methyl-isonicotinic acid and using isobutyl-methyl-amine; LC-MS: tR=0.61 min, [M+H]+=223.10.
Reaction SMILES: Cl.NC1N2N=C(C3[O:13][CH:14]=[CH:15]C=3)N=C2C=C(N2CCNCC2)N=1.[C:23]1(CCBr)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CN(C=[O:43])C>>[C:14]([O-:43])(=[O:13])[CH3:15].[CH3:27][CH2:28][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Reactant: BrCCc1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)[O-]
Product: CCCCCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 10 ml of DMF, 400 mg (1.04 mmol) of Compound 43 obtained in Example 43 was dissolved, and 0.51 ml (3.6 mmol) of 2-phenylethyl bromide and 1 ml of triethylamine were added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was extracted by adding chloroform and water, and the organic phase was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography [chloroform-methanol (97:3)] and recrystallized from ethyl. acetate-hexane to give 369 mg (yield: 95%) of Compound 46 as light gray powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:25]([CH:33]4[CH2:35][CH2:34]4)=[CH:24][C:18]=3[C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[CH:27]=[C:26]([N:28]([CH2:42][C:41]4[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=4)[S:29]([CH3:32])(=[O:30])=[O:31])[C:25]([CH:33]4[CH2:35][CH2:34]4)=[CH:24][C:18]=3[C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)oc2cc(N(Cc3ccc(OC)cc3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 90.2 %

Procedure:
A mixture of Example 18G (4.0 g, 8.14 mmol), 4-methoxybenzyl bromide 2.21 g, 11 mmol) and potassium carbonate (1.35 g, 9.76 mmol) in N,N-dimethylformamide (25 mL) under N2 was heated at 50° C. for 2 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried (MgSO4), filtered and concentrated. The solid was triturated in hexanes and the solid was collected by filtration and dried to give the title compound as a white solid (4.49 g, 90% yield). MS (ESI+) m/z 612 (M+H)+.