Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1B(O)O.[CH2:13]([O:16][C:17]1([CH3:50])[CH2:22][CH2:21][N:20]([C:23]2[N:28]3[CH:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=4)[N:31]=[C:27]3[CH:26]=[C:25]([CH3:39])[C:24]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:19][CH2:18]1)[CH:14]=[CH2:15].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:13]([O:16][C:17]1([CH3:50])[CH2:18][CH2:19][N:20]([C:23]2[N:28]3[CH:29]=[C:30]([C:32]4[CH:33]=[C:34]([C:3]5[C:4]([OH:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[F:1])[CH:35]=[CH:36][CH:37]=4)[N:31]=[C:27]3[CH:26]=[C:25]([CH3:39])[C:24]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:21][CH2:22]1)[CH:14]=[CH2:15]
Reactant: Cc1cc(O)c(B(O)O)c(F)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(O)cc(C)cc5F)c4)cn23)CC1
Yield: 100 %

Procedure:
Prepared in 100% yield from (2-fluoro-6-hydroxy-4-methylphenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 630.3.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][C:13]2[O:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)=[N:15][N:14]=2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[O:17][C:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)=[N:14][N:15]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 68 °C
Reaction time: 2 h

Procedure:
A suspension of cesium carbonate (0.54 g, 1.66 mmol), 5-[5-(4-chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol (0.36 g, 1.20 mmol) (from Example 40 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 68° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.36 g, 1.08 mmol) (from Example 1 supra) was added. Heating was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue washed with ethyl acetate and dried to give 4-chloro-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Li+]>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C=CC(=O)Nc1ccccc1O

Procedure:
Among the (meth)acrylamide derivatives represented by the general formula (1), a compound (the above compound A-1) in which R1 is a hydrogen atom; R2 is an ethoxymethyl group; and R3 to R6 are a hydrogen atom can be synthesized, for example, by the following manner. In this manner, o-aminophenol is reacted with acryloyl chloride in N-methyl-2-pyrrolidone (NMP) in the presence of lithium chloride to obtain N-(2-hydroxyphenyl)acrylamide. N-(2-hydroxyphenyl)acrylamide is then reacted with chloromethyl ethyl ether in NMP in the presence of N,N-diisopropyl ethylamine to synthesize the above compound A-1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][S:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>>[CH:21]([C:3]1[S:4][CH:5]=[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]=1[CH3:1])=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1cscc1C1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C2CCCCC2)csc1C=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-methyl-4-cyclohexylthiophene (3 g, 17 mmol) in DMF (10 mL) was added 10 mL of a solution prepared from DMF and POCl3 (4:1, v:v). The temperature was maintained at about 0° C. during the addition. The reaction mixture was then stirred overnight at room temperature, and poured into ice water. After neutralization with 25% NaOH solution to pH˜8, the product was extracted with dichloromethane. The solvent was evaporated to afford the crude product 2-formyl-3-methyl-4-cyclohexylthiophene as a solid which was purified by column chromatography (dichloromethane-petroleum ether (1:3)) (2.85 g, yield: 83%). 1H NMR (CDCl3) δ 10.07 (s, 1, CHO), 7.28 (s, 1, thienyl-H), 2.58 (m,1,cyclohexyl methane), 2.53 (s, 3,CH3),1.89 and 1.37 m, 10, cyclohexyl).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CC1C=CC(C)=CC=1>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:8])[CH:7]=2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccc(C)cc1
Product: Clc1cc(N2CCN(Cc3ccccc3)CC2)ncn1
Temperature: 138 °C
Reaction time: 18 h

Procedure:
A mixture of 4,6-dichioropyrimidine (29.5 g), N-benzylpiperazine (44.0 g) and DIPEA (44 ml) was suspended in p-xylene (400 ml) and heated at 138° C. under reflux. After 18 hours the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was evaporated using high vacuum pump apparatus to obtain 1-(benzyl)-4-(4-chloropyrimidin-6-yl)piperazine a brown solid, 60.5 g (105% based on 4,6-dichloropyrimidine);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>C(OCC)(=O)C.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 8 h
Yield: 81.9 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.257 g, 0.72 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1:1 ethyl acetate/methanol. 5 wt % Platinum(sulfided)/C (0.165 g, 0.043 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with nitrogen six times to remove any oxygen. The vial was then pressurized with hydrogen (balloon) and the solution stirred overnight. The next morning the vessel was evacuated and filled with nitrogen six times to remove any hydrogen. The solution was filtered through celite and evaporated to afford 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.194 g, 0.59mmol, 82%). 1 H NMR (400 MHz, CHLOROFORM-δ ppm 6.54 (s, 2 H), 3.80 (s, 3 H), 3.30-3.37 (m, 2H), 3.07 (s, 3 H), 2.91-2.98 (m, 6 H), 2.82-2.90 (m, 4 H), 2.15 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[Br:15]Br>O>[Br:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Reaction time: 5 h
Yield: 170.7 %

Procedure:
4-Nitrophenol (5 g, 35.9 mmol) was added to acetic acid (20 ml) and to the mixture, there was slowly added a solution of a mixture of bromine (0.93 ml, 18 mmol) and acetic acid (5 ml) at 85° C. The reaction mixture was stirred at the same temperature for 5 h and, thereafter, it was added to water and subjected to extraction with ethyl acetate. The organic extract was concentrated and the residue was subjected to column chromatography using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent to yield the end compound 2-bromo-4-nitrophenol (6.7 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][NH:12][C:11](=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[N:19]=1>O1CCCC1>[Br:17][C:18]1[N:19]=[C:20]([CH2:24][N:12]2[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11]2=[O:14])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(Cc2cccc(Br)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}pyrrolidin-2-one (1.08 g, 5.02 mmol) was dissolved in tetrahydrofuran (21.13 mL) and cooled to 0° C. Sodium hydride (0.23 g, 5.86 mmol) was added and the solution was allowed to stir for 15 minutes. In a separate flask, 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.05 g, 4.18 mmol) was dissolved in THF (10.57 mL) and cooled to 0° C., and added dropwise to the reaction mixture. The solution was stirred for 15 minutes at 0° C. and then at room temperature. The reaction mixture was quenched with water, and the product extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br.C([O-])(O)=O.[Na+].O>CN(C=O)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2][CH2:3]1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2nc(N3CCN(Cc4c(Cl)cccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the benzoimidazole from step (a) above (96 mg, 0.36 mmol), 2,6-dichlorobenzyl bromide (86 mg, 0.36 mmol, Aldrich) and NaHCO3 (151 mg, 1.8 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. Water (10 mL) was then added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL) then dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 40% EtOAc/hexane. The material was recrystallized from EtOAc/hexanes to give the title compound as a white solid. M.p. 254-256° C. MS (ESI, pos. ion) m/z: 429 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([F:16])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)(=O)C.Cl.[CH3:18][O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:19][C:20]([C:22]1([NH:31][C:8](=[O:10])[C:7]2[CH:6]=[C:5]([OH:4])[C:13]([O:14][CH3:15])=[C:12]([F:16])[CH:11]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1c(F)cc(C(=O)O)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2cc(O)c(OC)c(F)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of step 3 (120 mg, 0.526 mmol) was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 1 of example 15. The obtained product was dissolved in methanol (0.77 ml), potassium carbonate (2 mg) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, the residue was partitioned between EA and a saturated sodium chloride solution, and the aqueous phase extracted with EA. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 60 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:1](=[O:5])[CH2:2][CH2:3][OH:4])=[CH:26][CH:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: O=C1CCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCO)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
Propiolactone (0.23 ml) was added to a mixture of 4-[3-(2-benzyloxyphenyl]propyl]benzeneamine hydrochloride (1.26 g) and triethylamine (0.5 ml) in methylene chloride (10 ml) and the mixture was stirred for 18 hours. A further equivalent of propiolactone (0.23 ml) was added and stirring continued for a further 24 hours. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica eluted with a stepwise gradient of methanol in methylene chloride. The fractions eluting with 5% methanol in methylene chloride were collected, concentrated and subjected to chromatography again, eluting with ethyl acetate to give, after crystallisation from dichloromethane/hexane (1:20 v/v) 4-[3-(2-benzyloxyphenyl)propyl]-N-(3-hydroxypropionyl]benzene amine m.p. 109°-110°, 0.22 g (15%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].C(N(CC)CC)C.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23]
Reactant: NCC1COc2ccccc2O1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NCC1COc2ccccc2O1
Reaction time: 3 h

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and cooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The reaction mixture was then stirred for 3 hr with continued cooling. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO4) and evaporated in vacuo to yield an oil. The oil was purified using flash column chromatography (ethyl acetate:Heptane—1:1) to yield a white solid, which was recrystallized (ethyl acetate/Hexane) to yield the title compound as a white floccular solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:9]([CH3:25])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+]>CO.O1CCCC1>[NH2:29][C:27](=[O:28])[C:26]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[CH3:25])=[O:30]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Yield: 69.5 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (95 mg, 0.23 mmol) in a 1:1 mixture of methanol/tetrahydrofuran (1 mL) was treated with excess 1M lithium hydroxide for 19 h at room temperature. The mixture was concentrated in vacuo, diluted with water, and acidified with 5N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and recrystallized (absolute ethanol) to provide 65 mg (71%) of the title product as yellow crystals: mp 255-257° C. 1H NMR (DMSO6) δ 12.84 (bs, 1H, —OH), 7.69 (bs, 1H), 7.33 (m, 4H), 6.92 (d, J=7.0 Hz, 2H), 6.46 (s, 1H), 5.54 (s, 2H), 4.61 (s, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H), 2.42 (s, 3H), 1.96 (quintet, J=7.0 Hz, 2H); MS ES+ m/e 407 (p+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3ccccc3)cc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of methyl 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoate (1.5 g, 3.41 mmol) dissolved in ethanol (85 ml) and ethyleneglycol dimethyl ether (3.41 ml), 10% NaOH (34.1 ml, aqueous solution) was added dropwise. The resulting mixture was stirred under reflux and the progress of the reaction was monitored by TLC. Upon completion of the reaction, ethanol was removed under reduced pressure and the resulting aqueous solution was cooled to 0° C., neutralized with HCl 6N and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure, to obtain 1.26 g of 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid: Yield 88%; m.p. 260° C. (dec); IR 3408, 3268, 1684, 1525, 1496, 1264 cm−1; 1H-NMR (300 MHz, δ ppm, DMSO-d6) 11.57 (s, 1H), 8.00 (t, J=5.9 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.80 (d, J=7.3 Hz, 2H), 7.46-7.35 (m, 7H), 7.27 (d, J=7.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.67 (d, J=2.2 Hz, 1H), 4.47 (d, J=5.5 Hz, 2H), 3.76 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 167.1, 160.9, 157.9, 144.8, 133.0, 131.5, 130.1, 129.2, 128.8, 128.5, 128.0, 127.3, 126.7, 124.6, 122.3, 113.1, 108.5, 55.0, 42.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:14]3[CH:21]=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])[CH:23]=[CH:24][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:14]3[CH:21]=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:40][CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[O:32])[CH:23]=[CH:24][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCN
Reactant: COCCCn1c(-c2ccc(C(C)(C)C)cc2)nc2ccc(OCCCCCC(=O)OC)cc21
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccc(C(C)(C)C)cc3)n(CCCOC)c2c1

Procedure:
2-(4-tert-Butyl-phenyl)-6-[(5-(methoxycarbonyl)pentyl)oxy]-1-(3-methoxy-propyl)-benzimidazole is reacted with 3-methoxypropylamine according to general operating instructions 7. 2-(4-tert-Butyl-phenyl)-1-(3-methoxy-propyl)-6-[(5-((3-methoxy-propyl)amino-carbonyl)-pentyl)oxy]-benzimidazole is obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][NH:30][CH2:31][CH2:32][CH3:33]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([N:30]([CH3:29])[CH2:31][CH2:32][CH3:33])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Reactant: CCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 25° C., 6.83 g (0.02 mole) 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 4.1 g (0.03 mole) K2CO3, 3.1 mL (0.03 mole) N-methyl-N-propylamine and a catalytic amount of CuF2 were slurried in 50 mL 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 35° C. for 2 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromatographically using 15% ethyl acetate in hexane as the eluent to give 6.8 g (86%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-2-nitro-N-propylbenzeneamine as an orange oil, nD25 1.5534.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[O:27][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.4 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (180 mg, 0.48 mmol, 1.0 eq) in DMF (4 mL) was added Cs2CO3 (233 mg, 0.72 mmol, 1.5 eq). The resulting mixture was stirred for 40 min at room temperature then ethyl bromoacetate (96 mg, 0.57 mmol, 1.2 eq) was added. The resulting mixture was stirred at room temperature for 2 h then water added and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (150 mg, 68%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:18][C:17]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:19](=[O:22])[NH:20][N:21]=[C:8]([C:9]=3[C:10]=45)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].CN(C)CCN1C2CC(C)(C)CC3=NNC(=O)C4C(C=23)=C1C=CC=4>>[CH:1]1([C:4]([N:6]2[CH2:18][C:17]3[N:16]([CH2:27][CH2:26][N:24]([CH3:25])[CH3:23])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:19](=[O:22])[NH:20][N:21]=[C:8]([C:9]=3[C:10]=45)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CN(C)CCCl
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Agent: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2
Product: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CN(C(=O)C1CC1)C2

Procedure:
Compound 48 was prepared from 2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4, 9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and N,N-dimethylamino-2-chloroethane according to the procedures similar to those for Compound 28. 1H NMR (DMSO-d6) δ 10.0 (s, 1H), 7.67 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.23 (dd, 1H, J=8.4, 7.8 Hz), 5.22 (s, 1H), 4.98 (s, 1H), 4.55 (s, 1H), 4.28-4.35 (m, 3H), 2.58-2.62 (m, 2H), 2.19 (s, 6H), 2.09-2.13 (m, 1H), and 0.79 (s, 4H). MS (ESI) m/e [M+1]+ 366.