Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Li]CCCC.CCCCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[Br:10][C:4]1[CH:3]=[C:2]([C:23]([OH:24])([CH3:25])[CH3:22])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(Br)cc(C(C)(C)O)c1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,3-dibromo-5-methoxy-benzene (20.7 g, 78 mmol) in dry THF (100 mL) was added under nitrogen a 1.6 M solution of nBuLi in hexane (48.7 mL, 78 mmol) at such a rate that the reaction temperature did not rise above −50° C. After the addition the mixture was cooled to −70° C. and acetone (6.86 mL, 78 mmol) was added over a 5 min period. After 2 min the reaction was quenched with saturated NH4Cl solution and stirred for 10 min. The mixture was diluted with water and extracted with TBME. The organic layer was dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-EtOAc 95:5 to 85:15) provided impure 2-(3-bromo-5-methoxy-phenyl)-propan-2-ol as a yellow oil: TLC (hexane-AcOEt 6:1) Rf=0.22; HPLC RtH1=2.35 min; ESIMS [M−OH]−=227,229; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.02 (dd, 1H), 6.97 (dd, 1H), 3.83 (s, 3H), 1.59 (s, 6H). This material was treated with (±) camphor sulfonic acid (70 mg) in refluxing hexane with the azeotropical removal of water. After 1 h the cooled reaction mixture is diluted with TBME, washed with 5% aq. NaHCO3, dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-toluene 0-10%) gave impure 1-bromo-3-iso-propenyl-5-methoxy-benzene as a slightly yellow oil: 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 5.48 (s, 1H), 5.16 (s, 1H), 3.75 (s, 3H), 2.07 (s, 3H). This material was stirred in the presence of Ra—Ni catalyst (5 g) in EtOH (15 mL) under a hydrogen atmosphere for 18 h. The mixture was filtered over a bed of Celite and evaporated to obtain a yellow oil that contained still some starting material. It was taken up in CH2Cl2 (10 mL) and treated with meta-chlorperbenzoic acid (250 mg). The mixture was washed with sodium sulfite solution, followed by water and evaporated. Chromatography over silica gel (hexane-CH2Cl2 100:1 to 9:1) gave the title compound as a colorless oil: TLC (hexane-EtOAc 9:1) Rf=0.50; HPLC RtH1=3.79 min; 1H NMR (400 MHz, CDCl3): δ 6.97 (t, 1H), 6.86 (t, 1H), 6.69 (t, 1H), 3.78 (s, 3H), 2.84 (heptet, 1H), 1.22 (d, 6H).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OCC[O:19]3)=[CH:14][C:13]=2[O:23][CH3:24])[CH:9]=[CH:10][N:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=2[O:23][CH3:24])[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(C2OCCO2)ccc1-n1ccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1-n1ccnc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To a THF (40 mL) solution of 2-chloro-1-(4-[1,3]dioxolan-2-yl -2-methoxyphenyl)-1H-imidazole (3.19 g), 5N hydrochloric acid (15 mL) was added and the reaction solution was agitated for 2 hours. The reaction mixture was made basic with 5N sodium hydroxide aqueous solution, ethyl acetate was added and the organic layer was partitioned. The organic layer obtained was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 2.69 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[CH3:23][Zn]C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:23][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1
Reactant: Cc1cc(C#Cc2cn(-c3cncc(Cl)n3)c(C)n2)ccn1
Reactant: C[Zn]C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(-c3cncc(C)n3)c(C)n2)ccn1

Procedure:
2-Chloro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazine (27)(300 mg, 0.968 mmol) was dissolved in 5 mL dry tetrahydrofuran. Dimethylzinc (1.2 mL, 2M in toluene) and tetrakis(triphenylphosphin)palladium (23 mg, 0.02 mmol) were added. The reaction mixture was refluxed for 2 h and poured into 50 mL sat. sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and the desired product was obtained as a light yellow solid (240 mg, 85%), MS: m/e=290.1 (M+H+).
Reaction SMILES: C([Li])(CC)C.[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[CH:27][CH:26]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)[C:44]([C:46]1[N:47]=[C:48]([CH3:51])[O:49][CH:50]=1)=[O:45]>C1COCC1>[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[C:27]([C:44]([C:46]2[N:47]=[C:48]([CH3:51])[O:49][CH:50]=2)=[O:45])[CH:26]=1)([C:19]([CH3:21])([CH3:22])[CH3:20])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1coc(C)n1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)co1
Reaction time: 2 h

Procedure:
sec-Butyl lithium (1.4 M in cyclohexane, 3.2 eq) was added to a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1.0 g, 2.02 mmol) in anhydrous THF (10 mL) at −78° C., and the mixture was stirred for 2 h. N-methoxy-N,2-dimethyl-1,3-oxazole-4-carboxamide (1.0 g, 6.46 mmol) in THF (5 mL) was added dropwise and stirring was continued for an additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified by silica gel chromatography using ethyl lacetate-pet. ether gradient to obtain product. Yield: 600 mg, (50%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][S:19]C(=O)C)[C:13]([CH2:23][O:24][CH2:25][CH3:26])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][SH:19])[C:13]([CH2:23][O:24][CH2:25][CH3:26])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCSC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCS
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Nitrogen was bubbled through a solution of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester (1.93 g, 4.42 mmol) in methanol (45 mL), and then sodium methoxide (2.5 mL of 25% by weight in methanol, 11.1 mmol) was added dropwise over a period of three minutes. The yellow solution was stirred at ambient temperature for one hour and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 mL) and water (125 mL), and hydrochloric acid (˜3 mL of 2 M) was added to adjust the mixture to pH 7. The aqueous layer was separated and extracted with dichloromethane (50 mL); the combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.73 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-thiol as a tan solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][CH2:22]1)=[O:20])=[CH:12]2)C1C=CC=CC=1.CO>[C].[Pd].O1CCCC1>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[CH2:23][CH2:22][N:21]([C:19]([C:13]2[N:14]([CH3:18])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[O:20])[CH2:26][CH2:25]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(O)ccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 5-(benzyloxy)-2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indole obtained in Example 26 (830 mg), palladium carbon (contains 50% H2O, 100 mg), methanol (100 mL), and tetrahydrofuran (50 mL) was stirred at room temperature under hydrogen atmosphere (5 atm). The mixture was filtered and evaporated under reduced pressure to provide the title compound (540 mg, 80%) as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[OH:37].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[O:37][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](OS(C)(=O)=O)C1

Procedure:
Methanesulfonyl chloride (0.178 g, 1.55 mmol), compound of example 129 (0.55 g, 1.2 mmol) and triethylamine (1 mL) in CHCl3 (10 mL), were reacted as described in example 3, method A to obtain (±)-trans-methanesulfonic acid 4-[2-(2-chloro-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-propyl-piperidin-3-yl ester. This was dissolved in dry IPA at 80-90° C., anhydrous NaOAc (0.49 g, 5.98 mmol) was added, and the reaction mixture was processed as in example 3, method A to give an oily residue which was purified using a silica gel column and 1% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH:8]([OH:16])[CH2:9][S:10]([CH2:13][CH2:14][Cl:15])(=[O:12])=[O:11])(=[O:6])=[O:5].[CH:17]([S:25]([O-:27])=[O:26])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>O.CO>[Cl:15][CH2:14][CH2:13][S:10]([CH2:9][CH:8]([OH:16])[CH2:7][S:4]([CH2:3][CH2:2][S:25]([CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])(=[O:6])=[O:5])(=[O:12])=[O:11]
Reactant: O=S([O-])C=Cc1ccccc1
Reactant: O=S(=O)(CCCl)CC(O)CS(=O)(=O)CCCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)(C=Cc1ccccc1)CCS(=O)(=O)CC(O)CS(=O)(=O)CCCl
Temperature: 46 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
In a 3 liter reaction vessel were placed 1 liter of distilled water, 1 liter of methanol and 157 g of 1,3-di(2-chloroethylsulfonyl)-2-hydroxypropane. The vessel was heated to 46° C. for the purpose of dissolution. Thereto, a solution of 52 g sodium styrenesulfinate dissolved in a mixture of 100 ml of distilled water and 100 ml of methanol was added dropwise over a period of about 1 hour, and the heating and the stirring were further continued for 5 hours. A crystal deposited was filtered off, washed with methanol, and dried in vacuo. Thus, 55 g of M-6 was obtained. The yield was 49%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]=1B(O)O.[CH2:18]([O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][CH2:12][O:13][CH3:14])=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31])[CH3:19]
Reactant: COCOc1cccc(OCOC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OCOC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Di(methoxymethoxy)benzeneboronic acid (0.25 g) was coupled with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine ethyl ester in a similar procedure as described in Example 5-3) to afford N-(2,6-dichlorobenzoyl)-4-[2,6-di(methoxymethoxy)phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 562 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:21]([O:22][CH3:23])=[CH:20][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[NH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]3=O.[Cl:24]CCOC1C(OC)=CC2C=C3C(C(=O)C(C#N)=CN3)=CC=2C=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:24][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[C:21]([O:22][CH3:23])=[CH:20][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OCCCl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Yield: 87 %

Procedure:
To a slurry of 1.11 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (1:1 mixture) and 5 mL of phosphorus oxychloride is added 0.15 mL of anhydrous dimethylformamide. This is stirred and heated to reflux for 20 minutes using an oil bath, followed concentration in vacuo. The dark residue is quenched with 30 mL of cold water. The solid formed is collected, washed with water and dried to give 1.02 g (87%) of 4-chloro-7-methoxy-8(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a greenish yellow solid, m.p. 195-209° C. dec.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[O:11]=[S:12]1(=[O:34])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[N:13]1>CS(C)=O>[O:34]=[S:12]1(=[O:11])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:24]=[C:25]([C:26](=[N:9][OH:10])[NH2:27])[CH:28]=[CH:29][CH:30]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[N:13]1
Reactant: NO
Reactant: N#Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.17 h

Procedure:
616 μl (4.42 mmol) of triethylamine are added to a solution of hydroxylamine hydrochloride (307 mg, 4.42 mmol) in 1.5 ml of DMSO and the suspension is stirred for 10 minutes. The precipitate is filtered off and the filtrate is concentrated. 250 mg (0.737 mmol) of the product obtained in Step B of Example 1 are then added to that filtrate and the solution is stirred at 75° C. for 16 hours. The reaction mixture is allowed to return to ambient temperature, and precipitation is brought about using water. A gummy white paste is observed which is made harder by adding CH2Cl2. The precipitate is filtered off to yield the title product.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[NH:42][C:43](=[O:54])[C:44]2[N:45]=[CH:46][N:47]([CH2:50][C:51](O)=[O:52])[C:48]=2[N:49]=1)=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:47]2[CH:46]=[N:45][C:44]3[C:43](=[O:54])[NH:42][C:41]([NH:40][C:38]([O:37][CH2:27][C:28]4[CH:36]=[CH:35][C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=4)=[O:39])=[N:49][C:48]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(piperonyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.40 (brs, 2H), 8.36 (m, 1H), 8.27 (m, 1H), 7.84 (s, 0.6H), 7.78 (s, 0.4H), 7.73 (m, 2H), 7.02 (s, 1H), 6.93 (s, 2H), 6.04 (s, 2H), 5.15 (m, 3.2H), 5.05 (s, 0.8H), 4.55 (s, 0.8H), 4.30 (s, 1.2H), 4.27 (t, 1.2H), 4.11 (t, 0.8H), 4.07 (t, 1.2H), 3.88 (t, 0.8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)=[C:13]([C:27]([O:29][CH3:30])=[O:28])[C:12]2(O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)[C:13]([C:27]([O:29][CH3:30])=[O:28])=[C:12]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccc(OCc3ccccc3)cc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1=C(c2ccc(OC)cc2)c2cc(OCc3ccccc3)ccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of methyl (3RS)-5-benzyloxy-3-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indene-2carboxylate (crude material prepared above) in CH2Cl2 (75 ml) under an argon atmosphere at 0° C. was added triethylsilane (3.9 ml, 23.6 mmol), followed by boron trifluoride etherate (14.7 ml, 120 mmol). The reaction mixture was stirred for 10 min at 0° C., at which time the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 25-45% Et2 O/hexanes. The title compound (8.41 g, 83% for two steps) was isolated as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([NH:38][C:39]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])=[CH:9][CH:8]=3)[CH2:13]2)[CH2:27][CH2:26]1)=[O:40])([CH3:37])[CH3:36]
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-2,2,2-trifluoro-acetamide (1.7 mmol) in methylene chloride (20 mL) under an inert atmosphere was added triethylamine (1.0 mL, 6.6 mmol) and isopropyl isocyanate (230 μL, 2.3 mmol). The reaction was stirred for 20 h and then concentrated in vacuo. This material was partitioned between 5% KOH and water. The organic layer was dried (MgSO4) and concentrated to afford 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide as a clear oil (630 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[N:1]/[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11]
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccn3)cccc21
Yield: 49.9 %

Procedure:
4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), picolinaldehyde (856 mg, 8 mmol) and 1 g of MgSO4 were added into 40 mL of dichloromethane and the mixture was stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 476 mg of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one was obtained. A mixture of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), sodium methanolate (432 mg, 8 mmol) and ethyl propionate (40 mL) was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to give 30 mg of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate; yield 5%. LC-MS (ESI) m/z: 459 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[CH2:4]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.0 g of 4-n-butylphenol in 14 ml of water was added dropwise 3.7 ml of 70% nitric acid while cooling with ice and the temperature of the mixture was raised to room temperature and the reaction was carried out for 40 minutes. After 500 ml of water was added thereto, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was subjected to silica-gel column-chromatography [eluent: ethyl acetate] to give 6.20 g of 4-n-butyl-2-nitrophenol.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][CH2:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:25][CH2:24]1)=[O:37]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
tert-Butyl 3-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.020 g, 0.035 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give the product N-(4-(4-(3-aminopropanoyl)piperazin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyri din-3-yl)nicotinamide (0.015 g, 74% yield) as the trihydrochloride salt. MS APCI (+) m/z 473 detected.