Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol (3.1 g, 5.3 mmol) in dry dichloromethane (25 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.2 g, 7.54 mmol; Dess-Martin periodinane) and the reaction mixture stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (125 mL) followed by dichloromethane (50 mL). The mixture was stirred for 10 minutes and the phases separated. The aqueous phase was extracted with further dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a pale yellow foam (2.20 g). The product was further purified by preparative Hplc (C-18 column eluting with 80% aqueous methanol) to give (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl) methanone as a white solid (1.10 g). LCMS (Method D, ESI): RT 5.61 min, m+H=583.0; 1H NMR (400 MHz, CDCl3): δ 8.62 (ddd, J=4.8, 1.7, 1.0 Hz, 1H); 7.85-7.86 (m, 1 H); 7.80-7.81 (m, 3 H); 7.70 (d, J=8.3 Hz, 2 H); 7.44-7.45 (m, 3 H); 7.27 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49 (d, J=2.2 Hz, 1 H); 5.56 (dd, J=12.3, 2.1 Hz, 1 H); 4.26 (d, J=16.9 Hz, 1 H); 3.86-3.89 (m, 1 H); 2.83-2.84 (m, 3 H); 2.54-2.56 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>O>[N:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COc1cccc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc(N2CCNCC2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-methoxypyridine (20 g) and piperazine (32.9 g) with potassium carbonate (20.1 g) in water (50 ml) is stirred at 100° for 24 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is dissolved in ether. The organic phase is extracted with hydrochloric acid (10%). The aqueous phase is washed with ether, neutralized with sodium hydroxide (10%) and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated to give 2-piperazino-6-methoxypyridine. This material is stirred in acetonitrile (100 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (3.01 g) and potassium carbonate (1.3 g) at 20°-25° for 16 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed over silica gel (2% methanol in methylene chloride to 4%) to give the free base of the title compound which is 92% pure by HPLC. This material is dissolved in ethyl acetate and treated with methane sulfonic acid (0.606 g). The salt is filtered and recrystallized from methanol and ethyl acetate to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17](=O)[CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:38].[H][H]>[Pd].C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([NH2:38])[CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CCCC(=O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: [NH4+]
Agent: [Pd]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(CCC(N)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 125 °C

Procedure:
In a 1-gallon stirred autoclave were placed 113 gm. (0.229 mole) of 1,5-bis(3',5'-di-t-butyl-4'-hydroxyphenyl)pentanone, 35 ml. of ammonium hydroxide (58%), 1200 ml. of isopropanol and 13 gm. of 5% palladium on carbon (Pd/C). The mixture was heated for 2 hours at 125° C and 765 PSIG of hydrogen. 0.247 mole of hydrogen was absorbed.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([C:27]4[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=4)=O)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[NH3:37].[C:38]([O:42]C)(=O)[C:39]#[CH:40]>CO>[CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:40]=[CH:39][C:38](=[O:42])[NH:37][C:25]=4[C:27]4[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3]
Reactant: C#CC(=O)OC
Reactant: N
Reactant: CC(C)(c1cc(-c2cccc(CC(=O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CO
Product: CC(C)(c1cc(-c2cccc(-c3ccc(=O)[nH]c3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 150 °C

Procedure:
To a suspension of ketone from EXAMPLE 1, step 3 in MeOH (0.15M) at 0° C. was condensed NH3 (30% volume) and added methyl propiolate (6 eq). The reaction mixture was heated in a pressure tube at 150° C. for 5 h, cooled to rt and concentrated to dryness. The residue was purified by flash chromatography (EtOH:EtOAc, 12:88) to afforded the title compound.
Reaction SMILES: CNN.[CH2:4]([O:10][N:11]1C(=O)C2=CC=CC=C2C1=O)[C:5]#[C:6][CH2:7][C:8]#[CH:9].[Cl:22]CCl>>[ClH:22].[CH2:4]([O:10][NH2:11])[C:5]#[C:6][CH2:7][C:8]#[CH:9]
Reactant: C#CCC#CCON1C(=O)c2ccccc2C1=O
Reactant: ClCCl
Agent: CNN
Product: C#CCC#CCON
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl hydrazine (2 mL, 37.6 mmol) was added dropwise to a solution of N-(2,5-hexadiynyl)oxyphthalimide (9 g, 37.6 mmol) in 75 mL of dichloromethane and stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate diluted to 400 mL with diethyl ether. Anhydrous hydrogen chloride gas was bubbled into the dilute solution to give a precipitate of the hydrochloride salt of the title product, 3.96 g, m.p. 141°-143° C.
Reaction SMILES: [P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])(O)([OH:3])=[O:2].C(O)(C)(C)C.C1([N:36]=C=NC2CCCCC2)CCCCC1>O.N.C(N)=O>[P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])([NH2:36])(=[O:2])[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: NC=O
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(N)(=O)O)[C@H]2O)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Three millimoles of guanosine-3'-monophosphate were dissolved in a mixture of 7.5 ml of 2 N ammonia water and 5 ml of formamide, the solution was combined with 20 ml of tertiary butanol that contained 15 millimoles of dicyclohexyl carbodiimide, and the resulting mixture was heated at 80° C. for a period of 9 to 10 hours with care taken to prevent evaporation of the solvent. After the reaction, the mixture was left to stand overnight at room temperature, the precipitate was filtered off, the filtrate was concentrated under vacuum to remove the tertiary butanol, and the residue was extracted with ether. The aqueous layer was recovered, concentrated under vacuum, and the residue was treated with acetone to give a crystal of guanosine-3'-monophosphoramidate in a yield of about 50%. The crystal was heated under vacuum at 100° C. for a period of 3 to 4 hours until it was dehydrated thoroughly.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([O:22][C:19]2[CH:20]=[CH:21][C:16]([N:11]3[C:10]([C:8](=[O:9])[NH:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:14][C:13]([CH3:15])=[N:12]3)=[CH:17][CH:18]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(O)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-hydroxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid cyclohexylamide (300 mg, 1.00 mmol) and triphenylphosphine (291 mg, 1.11 mmol) in tetrahydrofuran (5 mL) was added 1-tert-butoxycarbonyl-4-hydroxypiperidine (221 mg, 1.10 mmol) followed by dropwise addition of diisopropylazodicarboxylate (216 μL, 1.10 mmol). The solution was stirred at room temperature overnight, concentrated and dissolved in ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4) and concentrated to give the crude product in quantitative yield. LC-MS (C27H38N4O4 calculated 482) m/z 483 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[C:18]1([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)[CH:3]=3)[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=2)[CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: C1=C(c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)CCC1
Yield: 61 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were reacted. The product was reacted with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of Example 10 and the mixture was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 106 mg (61%) of 3-Cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine over two steps. ESI MS m/z 347.3 (M+1).
Reaction SMILES: B(F)(F)F.CCOCC.C[N:11]([C:13](F)(F)[CH:14]([F:16])[F:15])C.[F:19][C:20]([F:30])([F:29])[C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[F-].[K+].[CH3:33][NH:34]N>ClCCl.C(#N)C>[CH2:26]([O:25][C:23]([C:22]1[C:13]([CH:14]([F:16])[F:15])=[N:11][N:34]([CH3:33])[C:21]=1[C:20]([F:30])([F:29])[F:19])=[O:24])[CH3:27]
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CN(C)C(F)(F)C(F)F
Agent: FB(F)F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
BF3.OEt2 (0.62 ml, 5.0 mmol) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in dry dichloromethane (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (5 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluoride (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.99 g, 3.64 mmol, 73%) was obtained as a yellow oil.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][OH:29])[CH3:25]
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NO)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. Hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Further, hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were then added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (10 mg, yield 31%).
Reaction SMILES: [C:1]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH2:7][C:8]([C:11]1[CH:12]=[C:13]([NH2:32])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:48]([O:50][CH2:51][C:52]([Cl:55])([Cl:54])[Cl:53])=[O:49]>CCOC(C)=O.O>[Cl:53][C:52]([Cl:55])([Cl:54])[CH2:51][O:50][C:48](=[O:49])[NH:32][C:13]1[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Yield: 126.7 %

Procedure:
A solution of Intermediate 153e (0.41 g, 0.67 mmol) in EtOAc (3.6 mL) was treated with aqueous 1N NaOH (1.2 mL, 1.2 mmol) then 2,2,2-trichloroethyl chloroformate (0.10 mL, 0.74 mmol) and the mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red oil (0.67 g). The oil was purified by FCC, using 0-25% EtOAc in cyclohexane to give the title compound as a pale golden gum (0.38 g, 72%). LCMS (Method 3): Rt 5.86 min, m/z 788.3, 790.3 [MH+].
Reaction SMILES: Br[CH:2]([CH2:16][CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:16]([C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)[CH3:17]
Reactant: Nc1ccccn1
Reactant: CCC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Product: CCc1c(-c2ccc3sc(=O)n(C)c3c2)nc2ccccn12

Procedure:
5-(3-Ethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (1.47) was prepared in substantially the same manner as that of Example 14 from 5-(2-bromobutyryl)-3-methyl-2-benzothiazolinone (4.71 g) and 2-aminopyridine (3.53 g). mp. 273°-274° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:21][CH:22]([CH3:24])[CH3:23])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH:5]=O.[CH3:25]/[C:26](/[NH2:30])=[CH:27]\[C:28]#[N:29].[CH2:31]([CH:34]1[CH2:39][C:38](=[O:40])[CH2:37][C:36](=O)[CH2:35]1)[CH2:32][CH3:33]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:37]3[C:38](=[O:40])[CH2:39][CH:34]([CH2:31][CH2:32][CH3:33])[CH2:35][C:36]=3[NH:30][C:26]([CH3:25])=[C:27]2[C:28]#[N:29])[CH:7]=[C:8]([O:21][CH:22]([CH3:24])[CH3:23])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)Oc1cc(C=O)cc(Br)c1OCc1ccc([N+](=O)[O-])cc1
Reactant: C/C(N)=C\C#N
Reactant: CCCC1CC(=O)CC(=O)C1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2ccc([N+](=O)[O-])cc2)c(OC(C)C)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of step b (1.06 g), 3-aminocrotonitrile (221 mg) and 5-propylcyclohexane-1,3-dione (415 mg) in ethanol (20 ml) was stirred at 80° C. for 17 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel in heptane/EtOAc=1/1 (v/v) as eluent. Yield: 750 mg. MS-ESI: [M+H]+=594.4/596.4
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1.[CH3:20][I:21]>C(O)C>[I-:21].[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N+:5]=1[CH3:20]
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Reactant: CI
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C(CO)CO)=[N+](C)CC2
Product: [I-]
Reaction time: 6 h
Yield: 71 %

Procedure:
0.03 mole (7.96 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 40 ml of absolute ethanol. 0.045 mole (6.39 g) of methyl iodide is added to the solution and the reaction mixture is kept at 30° to 40° C. for 6 hours. The precipitated crystals are filtered off and recrystallized from ethanol. The aimed compound is obtained with a melting point of 189° to 193° C.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: CCCCCCCOc1ccc(N=C=O)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (16 mg, 0.10 mmol) and diisopropylethylamine (52 uL, 0.30 mmol) in MeOH (2 mL) was added 1-(heptyloxy)-4-isocyanatobenzene (46 uL, 0.20 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (9 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 7.24 (d, 2H, J=9.2 Hz), 6.84 (d, 2H, J=8.8 Hz), 4.71-4.69 (m, 1H), 3.93 (t, 2H, J=6.4 Hz), 3.77-3.53 (m, 2H), 3.25 (s, 9H), 2.74-2.70 (m, 2H), 1.77-1.72 (m, 2H), 1.49-1.34 (m, 8H), 0.92 (t, 3H, J=6.8 Hz); MS ESI 394.3 [M+H]+, calcd for [C21H35N3O4+H]+ 394.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>O1CCOCC1.CS(C)=O>[CH2:28]([O:27][C:25](=[O:26])[NH:23][C:19]1[N:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:10]3=[N:11][O:12][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][N:20]=1)[CH3:29]
Reactant: Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a stirring solution of 4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine (75 mg; 0.205 mmol) in 1 mL of p-dioxane and 0.5 mL of DMSO, was added 40 μL (45.6 mg, 0.42 mmol) of ethyl chloroformate followed by 73 μL (54.3 mg, 0.42 mmol) of diisopropylethylamine. The reaction was stirred at 50° C., in a sealed vessel, for 8 hours. The solvents were removed under vacuo and the crude material was purified via HPLC with acetonitrile/water/TFA as the eluent. The material was isolated as a yellow powder (30 mg, 32% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.5 (br s,1H), 8.9 (s, 1H), 8.75 (d, 1H), 8.35 (m, 3H), 8.3(s, 1H), 8.0 (d, 1H), 7.89 (t, 2H), 7.65 (t, 1H), 4.2 (q, 2H), 1.26 (t, 3H) in ppm. LC-MS (ES+) m/e=439/441 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:23])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(C)(=O)=O)c1

Procedure:
The mixture of 4-chloro-3-methylsulfonyl-5-nitrobenzoic acid (10.0 g) and conc. sulfuric acid (5.0 ml) in methanol (100.0 ml) was heated under reflux for 10 hours and the mixture was evaporated in vacuo. To the residue was added water and the mixture was adjusted to pH 8 with potassium carbonate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 4-chloro-3-methylsulfonyl-5-nitrobenzoate (10.23 g).