Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][CH:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)C(N)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)C(N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A suspension of 2-amino-3-methyl-3-sulfanylbutanoic acid (D-penicillamine) (5.0 g, 34 mmol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 min. Then 2,4,6-trimethoxy-benzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. Stirring was continued for 1 hour at 0° C. and then for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2/MeOH/EtOAc to give the title compound (10.5 g, 95%) as a white solid. 1H-NMR (300 MHz, CDCl3) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40–4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH+).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[Br-:18].[Br-].[Br-].P>C1(C)C=CC=CC=1>[Br:18][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1ccc(-c2ccccc2C#N)cc1
Reactant: [Br-]
Agent: P
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution (15 mL) of 4′-(1-hydroxyethyl)biphenyl-2-carbonitrile (3.52 g) in toluene was added phosphine tribromide (5.00 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (3.93 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)=[CH:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Product: COc1ccc(COC(=Cn2ncnn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone with 4-methoxybenzyl chloride there was obtained 2-[2-(2,4-dichloro-phenyl)-2-(4-methoxy-benzyloxy)-vinyl]-2H-tetrazole as a colourless oil. [M+H]+ =376.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]C)=[O:12].[C:16]1([N:22]=[N+:23]=[N-:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=[N:24][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: COCCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of sodium hydride (60% in oil, 2 g) in DMF (50 ml) was cooled to 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (9.4 g) was added, and the mixture was stirred at 0° C.-5° C. for 30 min. Phenyl azide (6 g) was added, and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure, and methanol (100 ml) was added to the residue and 4N aqueous sodium hydroxide solution (20 ml) was further added. The mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (100 ml) was added to the residue. 6N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (100 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (7.2 g) as a white powder.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:16][C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:22])=[O:21]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc2ccccc2c1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc2ccccc2c1Nc1ccccc1C(=O)O

Procedure:
In Monatsh, 71, pages 122-127 (1937), W. Knap reports that when 1-bromo-2-methylnaphthalene and anthranilic acid were heated in the presence of copper powder and potassium carbonate in nitrobenzene (boiling at 210° C.) to the boiling point of nitrobenzene, N-(2-methyl-1-naphthyl)-anthranilic acid was obtained in the form of a grayish yellow crystal having a melting point of 215°-216° C.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+:6].Cl[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10].[Na]>C(O)C>[S:1]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10])([OH:4])(=[O:3])=[O:2].[Na:5][Na:6]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: O=S([O-])[O-]
Reactant: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C(O)C(c1ccc(-c2ccccc2Cl)cc1)S(=O)(=O)O
Product: [Na][Na]
Reaction time: 15 h

Procedure:
To a solution of 250 ml. of anhydrous ethanol and 0.12 moles of sodium sulfite is added 29 g. (0.1 moles) of α, 2'-dichloro-4-biphenylylacetic acid, sodium salt. The reaction mixture is stirred for 15 hours, filtered and the residue worked with ethanol. The filtrate is evaporated to dryness to obtain α-sulfo-2'-chloro-4-biphenylylacetic acid, disodium salt.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][NH2:7])[CH:2]=[CH2:3].[CH3:8][O:9][SiH:10]([O:13][CH3:14])[O:11][CH3:12].C(N(CC)CC)C.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[CH3:22][Si:23]([CH3:26])([CH3:25])[N:7]([Si:23]([CH3:26])([CH3:25])[CH3:22])[CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:10]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:8]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCCN
Reactant: C[Si](C)(C)Cl
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CO[Si](CCCOCCN([Si](C)(C)C)[Si](C)(C)C)(OC)OC
Reaction time: 24 h
Yield: 85.9 %

Procedure:
After adding toluene (200 mL) to a round-bottom flask containing 2-(allyloxy)ethanamine (0.398 mol) and dissolving trimethoxysilane (0.398 mol), a commercially available platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane solution was added and the mixture was stirred for 24 hours. Upon completion of reaction, after removing the solvent through distillation under reduced pressure and extracting with water and diethyl ether, the product was dissolved in dichloromethane (200 mL). After adding triethylamine (1.0 mol) and trimethylchlorosilane (0.8 mol), the mixture was stirred for a day at room temperature. Upon completion of reaction, after removing the solvent through distillation under reduced pressure, 0.342 mol (yield: 86%) of the target compound was obtained by extracting with water and diethyl ether. 1H and 13C NMR spectroscopic data of the purified N,N-bis(trimethylsilyl)-2-(3-(trimethoxysilyl)propoxy)ethanamine are as follows.
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.[Cl:33][CH2:34]Cl.[CH2:36]([OH:38])C>O>[ClH:33].[CH3:36][O:38][C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:34])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1=CCCN(CCOC=C(c2cccc(F)c2)c2cccc(F)c2)C1
Reactant: ClCCl
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C(=COCCN2CCC=C(C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1, 2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (1.15 g, 0.0027 mol) (prepared as described in Method D) was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.5 ml) was introduced. After stirring the solution at room temperature for 4 h, ice (30 g) was added, and the pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added, and the pH was further adjusted to ca. 1 with 37% hydrochloric acid solution. Water was added until the solid material was dissolved, and the dichloromethane phase was dried (Na2SO4) and evaporated to an oil, which was co-evaporated three times with acetone. The residue was triturated with diethyl ether to give the title compound (0.60 g, 52%), which gave HPLC retention times of 17.1 and 17.6 min. for the geometric isomers (gradient elution, water/20-80% acetonitrile, both containing 0.1% TFA).
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:15]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=N1.[C:35]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=O)(=[O:37])[CH3:36].NCC1C=CC=CN=1>ClCCl>[C:35]([O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:41]([C:42]([NH:17][CH2:18][C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][N:15]=2)=[O:44])[CH:40]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)NCc2ccccn2)c1
Reaction time: 0.17 h

Procedure:
93 ml (0.66 mol) of triethylamine and 160 g (0.36 mol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) are added, at ambient temperature under argon, to 65.0 g (0.36 mol) of 3-acetoxybenzoic acid in solution in 600 ml of dichloromethane. After 10 minutes, 32.5 g (0.30 mol) of 2-(aminomethyl)pyridine in solution in 200 ml of dichloromethane are added dropwise at 0° C. The reaction medium is allowed to return to ambient temperature and then stirred for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 23.1 %

Procedure:
The title compound (D165) (17 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-((3-(trifluoromethyl)phenyl)amino)azetidin-1-yl)nicotinic acid (D115) (50 mg, 0.135 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (30.62 mg, 0.135 mmol).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].ICCCCCCCCCC=C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:36]([O:38][P:39]([O:43]CC)[O:40][CH2:41][CH3:42])[CH3:37]>>[CH2:36]([O:38][P:39]([O:40][CH2:41][CH3:42])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[O:43])[CH3:37]
Reactant: C=CCCCCCCCCCO
Reactant: CCOP(OCC)OCC
Agent: C=CCCCCCCCCCI
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C=CCCCCCCCCCP(=O)(OCC)OCC

Procedure:
10-undecen-1-ol (1)(numbering from Scheme 1) was converted to iodinated compound 3 through a tosylate intermediate (2). Reaction of 3 with excess triethylphosphite under reflux conditions afforded the diethoxy phosphonate 4, which was converted to the ethoxyhydroxy phosphonate 5 by treatment with trimethylsilylbromide (TMSBr). The double bond of 6 was oxidatively cleaved with ruthenium trichloride and sodium periodate (Carlsen, et al. (1981) J. Org. Chem. 46, 3k936-3938) to yield the terminal carboxylic acid product 6. Treatment of 6 with excess diethylaminosulfur trifluoride (DAST) and N-hydoxysuccinimide (NHS) afforded an N-succinyl fluorophosphonate intermediate which was reacted with 5-(biotinamido) pentylamine (NH2-biotin) to generate FP-biotin (7). This synthetic route also allowed for the facile coupling of 6 to other reporter groups, including fluorescein cadaverine, which generated a fluorescent fluorophosphonate, FP-fluorescein [8; MALDI-FTMS (DHB) m/z 778.2671 (C38H47FN3O8PS+Na+ requires 778.2703)].
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([S:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][C:18]4[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])=[CH:10][CH:11]=[CH:12][C:13]3=4)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)OC(C)(C)C)cccc43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)O)cccc43)cc2)cc1
Yield: 9.5 %

Procedure:
The crude [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was treated with 10% trifluoroacetic acid (0.02 mL) in dichloromethane (1 mL) at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (Pursuit C-18, 20×150 mm, water/acetonitrile/0.05% trifluoroacetic acid) to give [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid (4.3 mg, 9.5% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (br. s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.78-8.00 (m, 4H), 7.68 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 4.62 (s, 2H), 4.29-4.44 (m, 1H), 2.42-2.62 (m, 2H), 2.37 (s, 3H), 1.79 (br. s, 1H), 1.56 (d, 3H); MS cald. for C25H25NO5S 451, obsd. 452 [(M+H)+].
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.CCCCCC.C(=O)(O)[O-].[Na+]>C1COCC1>[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]#[CH:2])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of the compound of step 1b above (27.1 g, 76.3 mmol) and THF (550 mL) was cooled to -75° C. Under a nitrogen atmosphere, a 2.5 M solution of n-butyllithium in hexane (62.6 mL, 156 mmol) was added dropwise over a 15 minute period. After stirring for 1 hour, saturated aqueous sodium bicarbonate was added dropwise to the reaction flask. The dry ice bath was removed and an additional portion of saturated aqueous sodium bicarbonate was added. The mixture was extracted with EtOAc (3×) and the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with Et2O/hexane (1:6 to 1:5) to give 11.5 g (77% yield) of the title compound (1c) as an oil: [α]D≤ -92.1 (c 2.20, MeC)H); 1H NMR (CDCl3, 300 MHz) δ 4.45 (m, 1H), 3.53-3.24 (m, 2H), 2.25-1.85 (m, 5H), 1.48 (s, 9H); MS (CI) m/e 196 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=3)[C:16](=[S:32])[NH:15][C:14]=2[N:33]=1)(C(C)(C)C)(C)C.[F-].[CH2:35]([N+](CCCC)(CCCC)CCCC)[CH2:36]CC.O>O1CCCC1>[CH2:35]([S:32][C:16]1[N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:24][CH:25]=2)[C:18](=[O:19])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[N:33][C:14]=2[N:15]=1)[CH3:36]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1nc2nc(CO)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (498 mg) was suspended in tetrahydrofuran (15 ml), a tetrahydrofuran solution (1M, 3 ml) of tetrabutylammonium fluoride was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (15 ml), iodoethane (0.24 ml) and 1M aqueous sodium hydrogen carbonate solution (1 ml) were added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1M hydrochloric acid and water, and the precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (373 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.N1C=CC=CC=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28].CCCP(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC1CCCO1.CCOC(C)=O>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1)=[O:28]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: N#Cc1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
To a solution of 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 400 mg, 2.17 mmol) in 2-methyltetrahydrofuran (12 mL) was added pyridine (524 uL, 6.51 mmol) and 5-bromo-2-chlorobenzoic acid (768 mg, 3.26 mmol). The mixture was heated to 85° C. and propylphosphonic anhydride (50% w/w in EtOAc, 3.10 mL, 4.34 mmol), was added dropwise. The reaction was heated at 85° C. for 16 hours, then stirred for 48 hours at room temperature. The reaction was quenched by the addition of 10% aqueous potassium carbonate solution (24 mL, 17.4 mmol) with stirring at room temperature for 1 hour. The reaction was diluted to 150 mL with EtOAc and washed with 10% aqueous solution of potassium carbonate (100 mL) followed by 2M aqueous HCl (100 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-1% methanol in dichloromethane to afford the title compound (640 mg, 74%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](Cl)=[O:6].Cl.[CH3:16][O:17][NH:18][CH3:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:19][N:18]([O:17][CH3:16])[C:5](=[O:6])[C:4]1[CH:8]=[C:9]2[O:12][CH2:13][O:14][C:3]=1[C:2]([F:1])=[C:10]2[F:11]
Reactant: CNOC
Reactant: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A solution of 14.4 grams (0.065 mole) of 3,4-difluoromethylenedioxybenzoyl chloride in 150 mL of methylene chloride was stirred and cooled to 0° C. To this was added 6.4 grams (0.066 mole) of O,N-dimethylhydroxylamine hydrochloride, followed by the dropwise addition of 11.0 mL (0.136 mole) of pyridine. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was washed with two portions of aqueous 10% hydrochloric acid, two portions of aqueous IN sodium hydroxide, and two portions of an aqueous saturated solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 15.1 grams of N-methyl-N-methoxy-3,4-difluoromethylenedioxybenzamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=1)[CH2:10][NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS([C:30]1[S:34][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)=[N:32][N:31]=1)(=O)=O.CS(C1SC(C2C=C3C(=CC=2)C=NC=C3)=NN=1)=O>CC(N(C)C)=O>[Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH:13]=1)[CH2:10][NH:11][C:30]1[S:34][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)=[N:32][N:31]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnccc3c2)s1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(CN)O[Si](C)(C)C(C)(C)C)c1
Agent: CS(=O)c1nnc(-c2ccc3cnccc3c2)s1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(CNc2nnc(-c3ccc4cnccc4c3)s2)O[Si](C)(C)C(C)(C)C)c1

Procedure:
(±)-2-(tert-Butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)phenyl)ethanamine and 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)isoquinoline and 6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)isoquinoline (prepared as in Scheme 7) was heated at 80-100° C. for 3 hours in DMA (0.3 M) to provide (±)-N-(2-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)phenyl)ethyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine. This intermediate was dissolved in THF and TBAF (1M in THF, 1.24 mmol) was added. After 16 hours, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica (eluting with DCM/MeOH gradients) to provide (±)-3-(1-hydroxy-2-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)ethyl)phenol (20 mg, 8%). LCMS (M+H) 365 calc. for C19H17N4O2S 365.1. 1H NMR (300 MHz, DMSO-d6): δ ppm 9.33 (s, 1H+OH), 8.56 (d, J=5.8 Hz, 1H), 8.27 (m, 2H), 8.18 (m, 2H), 7.92 (d, J=5.8 Hz, 1H), 7.14 (t, J=7.6, 1H), 6.84 (m, 2H), 6.65 (m, 1H), 5.58 (d, J=4.0 Hz, OH), 4.80 (m, 1H), 3.60 (m, 1H). 1H missing, covered by water signal.