Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.[BH4-].[Na+]>C(O)C.C1COCC1>[OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
A solution of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (10.0 g, 29.2 mmol, 1.0 eq) in a mixture of ethanol (500 mL) and THF (200 mL) was cooled to 0° C. and sodium borohydride (1.7 g, 45.0 mmol, 1.54 eq) was add portionwise within 1 h. The reaction mixture was allowed to warm up room temperature and stirred for 3.5 h. The reaction was quenched with saturated aqueous ammonium chloride (20 mL). The solvents were removed under vacuum and the residue was partitioned between ice-cold 1N hydrochloric acid (200 mL) and ethyl acetate (500 mL). The organic layer was separated and washed successively with saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified on a silica column eluted with 20-50% ethyl acetate in hexanes, affording 7.1 g of 11a (71% yield). 1H NMR (CDCl3): 1.01 (q, J=7.5 Hz, 6H), 1.46 (s, 3H), 1.50 (s, 3H), 1.61 (m, 2H), 1.88 (m, 2H), 2.78 (m, 1H), 2.89 (m, 1H), 4.96 (d, J=3.5 Hz, 1H), 5.54 (d, J=10.0 Hz, m, 2H), 5.78 (s, 1H), 6.69 (d, J=10.0 Hz, 1H), 10.18 (s, 1H); 13C NMR (CDCl3): 9.57, 14.04, 23.10, 27.47, 28.08, 29.78, 38.59, 70.73, 77.58, 102.85, 107.15, 107.62, 109.12, 116.54, 126.76, 150.89, 151.28, 156.08, 159.70, 162.01; IR: 1683 cm−1; MS (ACPI+): 345 (M+1); Anal. Calcd. for C20H24O5: C 69.75, H 7.02; Found: C 69.90, H 7.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][C:7]2=[O:30].[BH4-].[Na+]>CO.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[OH:30]
Reactant: O=C1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CC(O)c1cccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.9 %

Procedure:
To a stirred solution of (E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indene-1,4′-piperidin]-3(2H)-one (20 mg, 0.042 mmol) in MeOH (2 mL) and THF (2 mL) was added solid NaBH4 (12 mg). The mixture was stirred at rt for 3 h. The mixture was diluted with 10% aq citric acid and extracted with ether (2×30 mL). The combined ether extracts were dried over MgSO4 and concentrated. The residue was purified by prep HPLC to afford (±)-(E)-1-(7-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (1.8 mg, 9%) as a solid. LC-MS Method 1 tR=1.83, min, m/z=480, 482; 1H NMR (CDCl3) 1.39 (m, 2H), 1.63 (m, 1H), 2.12 (m, 1H), 2.5-3.0 (4H), 3.36 (m, 1H), 4.16 (m, 1H), 4.82 (m, 1H), 5.23 (br s, 1H), 6.86 (d, 1H), 7.18 (m, 1H), 7.3-7.8 (6H), 7.95 (d, 1H).
Reaction SMILES: [CH2:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17](C)[C:18](OC(C)(C)C)=O)[CH:2]=[CH2:3].[ClH:47]>>[ClH:47].[ClH:47].[ClH:47].[ClH:47].[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: C=CCNCCCNC/C=C/CNCCCNC

Procedure:
A mixture of 0.6 g (0,916 mmol) of (E)-1-allyl-14-methyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 9 ml of 3N methanolic hydrochloric acid is reacted analogously to Example 8. The resulting title compound melts at >260° C. 1H-NMR (D2O): δ2.07-2.17(m,4H); 2.73(s,3H); 3.12-3.19(m,8H); 3.69(d,2H); 3.77(d,4H); 5.48-5.55(m,2H); 5.83-5.98(m, 1H); 6.04-6.07 (m,2H).
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].N1C=CC=CC=1>CN(C)C=O>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:21][N:20]=[N:19][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C
Yield: 27.6 %

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][CH:16]([CH3:20])[CH2:17][CH2:18]Br>>[CH3:15][CH:16]([CH3:20])[CH2:17][CH2:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCCCCCCCCCBr
Reactant: CC(C)CCBr
Product: CC(C)CCCCCCCCCCCCCCO

Procedure:
15-methylhexadecan-1-ol was prepared from 12-bromo-1-dodecanol and 3-methylbutylbromide. The 1H NMR was identical to that reported by Masuda et al. ((2002) Biosci. Biotech. Biochem. 66:1531-1537).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[O:29]1[CH2:32][C:31](=O)[CH2:30]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([CH:31]4[CH2:32][O:29][CH2:30]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1COC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2COC2)C3)cc1

Procedure:
Compound fo was prepared according to the procedure described in Example 8 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with oxetan-3-one. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:29]=[CH:28][C:16]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[O:30][CH3:31].[Na].[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[C:37]2=[O:44].ClC1C=C2C(=CC=1)NC(=O)C2=O.[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[C:37]2([OH:44])[C:13]1[CH:29]=[CH:28][C:16]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[O:30][CH3:31]
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of n-butyllithium in hexane (1.6 m, 19.6 ml, 31.4 mmol) was slowly added dropwise to a solution of (4-bromo-3-methoxyphenoxy)triisopropylsilane (8.67 g, 24.1 mmol) in THF (100 ml) at −15° C. After 15 min, a solution of 5-chloroisatin sodium salt [prepared by treating a solution of 5-chloroisatin (3.65 g, 20.1 mmol) in THF with one equivalent of sodium hydride at 0° C. for one h] was added dropwise to the solution of the organolithium species. The reaction mixture was allowed to warm to room temperature and was stirred for a further hour. Aqueous ammonium chloride solution was added to the reaction solution while stirring, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (mobile phase 10-30% gradient of ethyl acetate in dichloromethane) afforded 3.8 g (41%) of the desired adduct.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Oc1ncnc2cc(F)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
7-Fluoroquinazolin-4-ol (1 g, 6.0 mmol) was dissolved in concentrated H2SO4 (3 mL) at 0° C. Concentrated HNO3 (3 mL) was added dropwise with stirring in 15 min. The mixture was stirred at 100° C. for 3 h and cooled to room temperature. The mixture was poured into ice-water with stirring. The precipitate was filtered and recrystallized in HOAc to give 0.60 g of 7-fluoro-6-nitroquinazolin-4-ol (38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: COc1ccc2ncc(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cnc3ccc(OC)cc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (316 mg, 1.3 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 3-(chloromethyl)-6-methoxyquinoline hydrochloride SLA 47088B (265 mg, 1.1 mmol) and a 2 N aq. LiOH solution (1.3 mL, 2.6 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was then removed at 40° C. under vacuum and the residue was then taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 89 mg of 6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (3.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 84 as a brown solid (93 mg, 17% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:48])([CH3:49])[CH3:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C(C)C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (248 mg, 357 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (4.29 ml, 4.29 mmol, Eq: 12.0). The reaction mixture heated at 60° C. for 18 h. The solution was cooled to room temperature, and then diluted with saturated NaHCO3 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, and then dried over Na2SO4. Concentrated in vacuo. The solid was triturated with Et2O and dried under vacuum to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (202 mg, 87%). LC/MS-ESI observed [M+H]+ 652. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.42 Hz, 6H) 1.43 (s, 9H) 1.84 (br. m., 5H) 2.28 (br. m., 2H) 2.50 (br. m., 1H) 2.79 (br. s., 1H) 3.03 (d, J=10.20 Hz, 2H) 3.90 (s, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.92 (s, 1H) 7.40-7.73 (m, 6H) 8.17-8.32 (m, 4H) 8.60 (s, 2H)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([O:33]C)=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([OH:33])=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)OC)cc3)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)O)cc3)c2)c(C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixed solution of methyl 2-(4-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}phenyl)cyclopropanecarboxylate (1.33 g, 2.80 mmol) in methanol (6 mL) and tetrahydrofuran (12 mL) was added 2 M aqueous sodium hydroxide solution (3 and the mixture was stirred at 50° C. for 2 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30) to give the title compound (1.29 g, quantitative) as a colorless oil.
Reaction SMILES: CO.Cl.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:14]([NH:17][C:18]2[CH:38]=[CH:37][C:21]([C:22]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH:7]=[CH:6][CH:5]=1>>[N:24]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][S:14]([C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[N:4]=[CH:5][CH:6]=[CH:7]4)(=[O:16])=[O:15])=[CH:38][CH:37]=2)=[O:23])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4cccnc34)cc2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1)N1CCNCC1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of MeOH.HCl, Boc protected amine 138 (2 gm, 4.03 mmol) was added and the resulting mixture was stirred for 1 hr. After completion of reaction, solvent was removed under reduced pressure, washed with water followed by addition of NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to afford product 139 (1.5 gm, 94.30% yield).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH2:10]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH2:11][CH2:12][CH3:13]>ClCCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:16]1[CH:17]=[CH:18][N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]=1
Reactant: C[O+](C)C
Reactant: CCCCn1ccnc1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCCCn1cc[n+](C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure of Example 2 was followed. 3 g of trimethyloxonium tetrafluoroborate in suspension in 10 ml of 1,2-dichloroethane was added to 2.7 ml of N-butylimidazole in 10 ml of 1,2-dichloroethane. The mixture was stirred for 4 hours at room temperature. The remaining solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: CCOC(=O)CCc1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1csc(CCC(=O)O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoate (220 mg, 0.53 mmol) in EtOH (5 mL) was added NaOH (42 mg, 1.06 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, neutralized to pH=4-5, extracted with EtOAc, and concentrated to give 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid (Scheme II, 12, X1=4-hydroxyphenyl, X2=4-chloro-2-methoxyphenyl) (127.42 mg, yield 62%). 1H NMR (DMSO-d6 400 MHz): δ 9.36 (br, 1H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.91-6.88 (m, 2H), 6.79 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.40 (s, 3H), 2.92 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H); MS (ESI): m/z [M+1]+=389.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1C
Temperature: 70 °C
Yield: 23 %

Procedure:
To 3-amino-2-methylbenzoic acid (500 mg, 3.3 mmol) in methanol (20 ml) was added sulfuric acid (500 μl) and heated to 70° C. for 22 h, at which point the volume was reduced by rotary evaporation. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The resultant organic layer was dried over sodium sulfate, filtered, and then concentrated to afford a tan oil (125 mg, 23%) of methyl 3-amino-2-methylbenzoate, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.99-6.93 (m, 1H), 6.89-6.86 (d, 1H), 6.81-6.78 (d, 1H), 5.12-5.07 (br. s, 2H), 3.78 (s, 3H), 2.16 (s, 3H). MS (EI) for C9H11NO2: 166 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].O>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To an ice cooled solution of 2,4-dinitrofluorobenzene (9.3 g, 50 mmol) and K2CO3 (6.9 g, 50 mmol) in 40 ml NMP was added dropwise dipropylamine (6.07 g, 60 mmol) in 10 ml NMP. After stirring for 1 hr, the reaction mixture was poured into a separatory funnel containing 100 ml water and extracted 3×100 mls with ether. The combined organics were washed with 3×100 ml water, 100 ml brine, dried with anhydrous MgSO4 and concentrated, giving 13.1 g crude product. This material was pure enough to carry on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:24])[N:9]=1)=[CH:17][C:16]([O:22]C)=[CH:15][CH:14]=3.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:24])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3
Reactant: COc1ccc2c(c1)nc(C)c1c(C)nc(-c3ccccc3Cl)n12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Temperature: 0 °C

Procedure:
5 g 1-(2-Chlorophenyl)-3,4-dimethyl-7-methoxy-imidazo(1,5-a)quinoxaline, 100 mL dichloromethane and 12 mL BBr3 were heated in a closed vessel for 3 hours at 110° C. After cooling the suspension was given in 600 mL ice-cooled aqueous potassium carbonate solution. After stirring for 30 min at pH 7-9 the precipitate was filtered off, washed with water and dried.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[Br:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(CBr)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (60% dispersion in mineral oil. 40 mg, 1.0 mmol) was added to a solution of pyrrole (67 mg, 1.0 mmol) in THF (2.0 mL) and the mixture was stirred at room temperature for 5 min. Then 4-(bromomethyl)benzenesulfonyl chloride (269 mg, 1.0 mmol) was added to the mixture. After stirring at room temperature for additional 10 min, brine (15 mL) was added and the mixture was extracted with AcOEt (40 mL×2). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 10% AcOEt/hexane) to give 1-[4-(bromomethyl)benzenesulfonyl]pyrrole: 46 mg, 15% yield, colorless oil. The purity was determined by GC/MS (>95%), m/e 299 (M+, C11H10NO2BrS).