Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@H:9]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[C@H:8](OS(C)(=O)=O)[CH:7]=1)=[O:5])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[C@H:8]([N:27]=[N+:28]=[N-:29])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](N=[N+]=[N-])[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Reaction time: 3 h

Procedure:
(3R,4S,5R)-3,4,5-tris-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester 43, product of the preceding experiment) was dissolved in DMSO. To the clear light yellow solution NaN3 was added at room temperature and the suspension was stirred for 3 hours. The orange solution was diluted with EtOAc and toluene and extracted 3 times with aqueous NaHCO3. The organic phase was separated, dried over Na2SO4, filtered and the combined filtrates evaporated in a rotary evaporator at 20° C./70-10 mbar. The remaining yellow oil was dissolved twice in toluene and evaporated in a rotary evaporator at 20° C./70-10 mbar to obtain the crude dry product (3R,4S,5R)-3-azido-4,5-bis-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (44), as yellow oil which was used in purification. A sample of 4 was obtained from crude 44 via a silica column chromatography using a 1:2 mixture of EtOAc and n-hexane. The combined fractions were evaporated and dried on a rotary evaporator to obtain 44 as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18](O)=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>CN(C=O)C>[CH2:40]([N:42]([CH2:43][CH3:44])[C:18](=[O:19])[C:11]1[CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([O:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:13]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:12]=1)[CH3:41]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 7, piretanide can be reacted with EDC, HOBt and diethylamine in DMF to yield N,N-diethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)-benzamide.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:33]4[CH2:34][CH2:35][N:30]([C:36]([NH2:38])=[O:37])[CH2:31][CH2:32]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: NC(=O)N1CCNCC1
Product: NC(=O)N1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-{5-[(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridin-2-yl}-piperazine-1-carboxylic acid amide was prepared starting from intermediate E and piperazine-1-carboxylic acid amide. MS calcd. for C27H25ClN6O3 [(M+H)+] 517.2, obsd. 517.0.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]([CH2:17][OH:18])=[CH:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:4]1[C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:6][CH2:7][C@H:2]([CH3:1])[CH:3]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methanol (10 mg) and triethylamine (17 ml) in dry dichloro-methane (0.5 ml) was added methanesulfonyl chloride (10 ml) at 0° C. The mixture was allowed to warm to room temperature, and stirred for 30 min. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methyl methanesulfonate (100 mg).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH2:31][CH2:32]Cl)C)=[CH:27][C:22]=2[O:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>CN(C=O)C>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH2:31][CH2:32][N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[C:8]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:7]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: CN(CCCl)Cc1ccc2c(c1)OCO2
Reactant: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
A solution of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine (2.1 g, 9.2 mmol) in DMF (15 mL) was added all at once to a stirred mixture of benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-amine hydrochloride salt (2.2 g, 8.1 mmol), DMF (10 mL) and diisopropylethylamine (2.5 mL) at ambient temperature under nitrogen. A catalytic amount of potassium iodide (340 mg, 2.0 mmol) is then added. The mixture is heated to 80° C. for 3 h. The solution is then cooled to room temperature, quenched into 200 mL of 1N dibasic potassium phosphate solution (pH 9), and extracted with ethyl acetate. The combined organics are dried over MgSO4, filtered and concentrated to a red residue. Purification via silica gel column chromatography (DCM to 4:1 DCM/MeOH) gave 2.0 g (52%) of benzo[1,3]dioxol-5-ylmethyl-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine as a red oil. [M+H]+ 421.30; 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.89 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 6.78 (s, 1H), 6.67 (m, 2 H), 5.88 (s, 2H), 3.52 (t, 1H, J=6.8 Hz), 3.6 (m, 3H), 2.77 (m, 1H), 2.2-2.6 (m, 8H), 1.62-1.95 (m, 3H). 13C-NMR (100 MHz, CDCl3) δ 175.7, 169.6, 154.0, 147.6, 146.5, 136.2, 132.8, 130.1, 121.9, 116.6, 115.0, 109.2, 107.8, 100.8, 69.8, 62.3, 56.0, 54.3, 53.1, 42.5, 33.2, 24.2, 23.4.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4C=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH:13]=2)[CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].CC1(C)OCC(C2C=CC3C(=CC=C(OC4C=CC(OCCCCC)=CC=4)C=3)C=2)(N)CO1>>[NH2:1][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=3)[CH:13]=2)[CH:8]=1)([CH2:3][OH:4])[CH2:5][OH:6]
Reactant: NC(CO)(CO)c1ccc2cc(Oc3ccc(Oc4ccccc4)cc3)ccc2c1
Agent: CCCCCOc1ccc(Oc2ccc3cc(C4(N)COC(C)(C)OC4)ccc3c2)cc1
Product: CCCCCOc1ccc(Oc2ccc3cc(C(N)(CO)CO)ccc3c2)cc1
Yield: 55 %

Procedure:
2-amino-2-(6-(4-(pentyloxy)phenoxy)naphthalen-2-yl)propane-1,3-diol was synthesized as per 2-amino-2-(6-(4-phenoxyphenoxy)naphthalen-2-yl)propane-1,3-diol (Example 245) in 55% yield using 2,2-dimethyl-5-(6-(4-(pentyloxy)phenoxy)naphthalen-2-yl)-1,3-dioxan-5-amine as starting material. MS: m/z=418.45 [M+Na+]. 1H NMR (MeOD) δ: 7.88-7.94 (m, 2H), 7.78 (d, J=8.8 Hz, 1H), 7.51 (dd, J=8.8, 2.0 Hz, 1H), 7.30 (dd, J=9.0, 2.5 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.01-7.07 (m, 2H), 6.94-7.01 (m, 2H), 4.05-4.12 (m, 2H), 3.96-4.02 (m, 4H), 1.70-1.85 (m, 2H), 1.37-1.54 (m, 4H), 0.92-1.01 (m, 3H)
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1nccnc1C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nccnc2F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-fluoro-3-(pyrrolidin-3-yl)pyrazine (0.2 g, 1.2 mmol) dissolved in DCM (2.4 mL) was added acetic anhydride (0.56 mL, 6.0 mmol) and sodium bicarbonate (0.502 g, 5.98 mmol). The reaction mixture was stirred at RT under N2 for 3 h. The reaction mixture was partitioned between 1N NaOH and DCM. The aqueous layer was back extracted with DCM (3×) and the combined DCM layer was washed with brine, dried (Na2SO4) and concentrated to provide 1-(3-(3-fluoropyrazin-2-yl)pyrrolidin-1-yl)ethanone as a yellow oil. MS (ESI, pos. ion) m/z: 210.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[Cl:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:16]2[C:17]([Cl:18])=[C:13]([CH3:12])[N:14]=[CH:15]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1nc[nH]c1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ncn(C(=O)Nc2cc(Cl)cc(Cl)c2)c1Cl
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Using a procedure similar to that described in Example 1, a solution of 47 g of 3,5-dichlorophenyl isocyanate in 100 ml of chloroform was added dropwise to 29 g of 4-methyl-5-chloroimidazole, likewise dissolved in 100 ml of chloroform. Refluxing was carried out for 2 hours, after which the solution was cooled and the residue was filtered off under suction, washed with chloroform and dried to give 60 g (78.8%) of 1-N-(3,5-dichlorophenylcarbamyl)-4-methyl-5-chloroimidazole of melting point 136.9°-138.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[NH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])=[CH:19]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([NH:17][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:19]=[C:20]2[CH2:28][CH2:29][C:30]([OH:32])([CH3:31])[CH3:33]
Reactant: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1cc(CCC(C)(C)O)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (300 mg, 1.38 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (325 mg, 1.38 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (380 mg, 1.38 mmol) and stirred at 50° C. for 2 h. The mixture is diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-7% MeOH in DCM to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (200 mg, 33%). MS: 435 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.26 (s, 1H), 9.09 (d, 2H), 7.70 (t, 1H), 7.29 (m, 2H), 7.22 (s, 1H), 7.01 (m, 1H), 2.90 (s, 3H), 2.82 (m, 2H), 1.91 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.C(OCC)(=O)C>[N+:15]([C:9]1[CH:10]=[CH:11][C:12]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:18]([OH:20])=[O:19])[CH:26]=2)=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:17])=[O:16]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccc(-c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)c1
Temperature: 100 °C
Yield: 84 %

Procedure:
To a solution of N-Phenyl-5-bromo-2-nitrobenzenamine (0.9 g, 3.2 mmol) and 3-carboxyphenylboronic acid (0.64 g, 3.92 mmol) in Toluene: EtOH: H2O (8:8:1) was added K2CO3 (1.4 g, 9.78 mmol). After stirring reaction for 15 min under argon tetrakis (triphenylphosphine) palladium (0.184 mg, 0.016 mol) was added, resulting mixture was then heated at 100° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and extracted three times with water. The aqueous layer was then acidified with 2M HCl to get 4′-nitro-3′-(phenylamino) biphenyl-3-carboxylic acid (0.8. g), 84% yield. 1H NMR (500 MHz, DMSO): δ 7.23 (m, 2H), 7.44 (m, 4H), 7.61 (t, J=7.7 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 8.00 (d, J=7.7 Hz 1H), 8.07 (s, 1H), 8.25 (d, J=9 Hz, 1H), 9.50 (s, 1H), 13.15 (bs, 1H). HRMS (ESI) calculated for C19H14N2NaO4: 357.0846, Found: 357.0816.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[O:23][CH2:24][C:25](O)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[O:23][CH2:24][C:25]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)=[O:26])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)COc1cccc(OCc2ccccc2)c1
Reactant: c1ccc(-c2cnco2)nc1
Product: O=C(COc1cccc(OCc2ccccc2)c1)c1ncc(-c2ccccn2)o1
Yield: 7 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 2-(3-(benzyloxy)phenoxy)acetic acid (Baker, B. R.; Neenan, J. P. J. Med. Chem. 1972, 15, 940-944) using General Procedure B. Column chromatography (SiO2, 2.5×6 cm, 20-40% EtOAc-hexanes gradient) followed by PTLC (SiO2, 50% EtOAc-hexanes) afforded 11d (26 mg, 0.07 mmol, 7%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.70 (app d, 1H, J=4.0 Hz), 8.03 (d, 1H, J=8.1 Hz), 7.86 (td, 1H, J=7.7, 1.5 Hz), 7.55-7.52 (m, 1H), 7.45-7.32 (m, 6H), 7.22 (t, 1H, J=8.2 Hz), 6.68 (dd, 1H, J=8.2, 2.4 Hz), 6.61 (t, 1H, J=2.2 Hz), 6.54 (dd, 1H, J=7.8, 2.5 Hz), 5.45 (s, 2H), 5.06 (s, 2H); 13C NMR (CDCl3, 100 MHz) 192.7, 169.7, 162.1 (2C), 158.3, 151.5, 149.2, 137.0, 136.7, 130.3, 128.6, 128.0, 127.5, 122.2, 106.9 (2C), 102.1, 70.1, 67.9; ESI-TOF m/z 387.1349 (C23H19N2O4+H+ requires 387.1345).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN(CC1SC(CSCCN)=CC=1)C.[CH3:26][N:27]([CH2:29][C:30]1[S:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44](OC)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28].[CH3:49][C:50]1[C:51]([CH2:55][S:56][CH2:57][CH2:58][NH2:59])=[N:52][O:53][N:54]=1>>[CH3:26][N:27]([CH2:29][C:30]1[S:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44]([NH:59][CH2:58][CH2:57][S:56][CH2:55][C:51]3[C:50]([CH3:49])=[N:54][O:53][N:52]=3)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)s1
Reactant: Cc1nonc1CSCCN
Agent: CN(C)Cc1ccc(CSCCN)s1
Agent: COC1=NS(=O)(=O)N=C1OC
Product: Cc1nonc1CSCCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)s1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine and the resultant 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with 2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared in Example 58, Step B], the title compound is thereby produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:16](=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)C=Cc2ccncc2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
44 G. of 3',4',5'-trimethoxyacetophenone and 440 ml. of water are heated at 70° C. with stirring and treated with 20.2 ml. of isonicotinaldehyde. Then, there are added, three times at intervals of 30 minutes, 4 ml. each time of a 6% sodium hydroxide solution in water/methaol (2:1). The resulting reaction mixture is kept overnight at 70° C., cooled in an ice-bath and the resulting crystals are filtered off then washed with ethanol and ether to result in a product with a melting point at 124°-127° C. After recrystallization from methanol/ether there are obtained crystals of melting ppont 128°-130° C. The mother liquors are evaporated under reduced pressure, taken up in ethyl acetic and the organic phase is washed twice with water. The washings are extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on a 30-fold amount of silica gel (ether/diethylamine 95:5) and after recrystallization from ethanol/ether, there are obtained 3',4',5'-trimethoxy-3-(4-pyridyl)-acrylophenone of melting point 127°-129° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN(C)C)c(C)c4)C3)o2)cc1
Yield: 74.6 %

Procedure:
Using a similar protocol as described in Example 16 employing 20C (0.16 g, 0.73 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.20 g, 0.80 mmol) as starting materials afforded 0.23 g (74%) of 20 as a solid. 1H NMR (600 MHz, CDCl3): δ 2.21 (s, 6H), 2.33 (s, 3H), 3.30 (s, 2H), 3.87 (s, 3H), 4.27-4.35 (m, 1H), 4.58-4.66 (m, 1H), 4.69-4.76 (m, 1H), 5.00-5.15 (m, 2H), 6.53 (d, 1H), 6.58 (s, 1H), 7.00 (d, 2H), 7.14 (d, 1H), 8.08 (d, 2H), MS (APCI+) m/z 423 [M+H]+, LC purity: 98%.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:23]>>[BrH:23].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CNCC2c1ccc(OC)c(OC)c1
Agent: Br
Product: Oc1ccc2c(c1)CNCC2c1ccc(O)c(O)c1

Procedure:
640 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 13 ml of 48% aqueous hydrogen bromide, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and crystals which separated out were collected, affording 580 mg of 7-hydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li]CCCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[OH:19][C:15]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC2)cc1
Temperature: -100 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a solution of 4-Bromo-benzonitrile (2.0 grams, 10.99 mmole) in tetrahydrofuran (30 ml) at −100° C. was added dropwise 2.5 M nBuLi (4.8 ml) and stirred at −100° C. for 15 minutes. Cyclobutanone (0.965 grams, 13.19 mmole) was added dropwise and stirred for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 40% ethyl acetate/hexane as eluent to give a clear oil (1.5 g). MW 173.23; MS (m/e) 173 (M+).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:3]1[C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:11][C:9]1[CH:10]=[CH:4][CH:5]=[CH:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(SCc3ccccc3)n(Cc3ccccc3)c2c1
Temperature: 6 °C
Yield: 166.9 %

Procedure:
To a flask were added 2.0 g 2-mercapto-5-methylbenzimidazole, 4.2 g potassium carbonate, 30 ml N,N-dimethylformamide and 3.9 g benzyl chloride. The reaction mixture was heated to 6° C. for 16 hours, then cooled to 50 C and quenched with 60 ml water and cooled to 5 C. The solid was filtered and washed with water and then recrystallized by dissolving in 50 ml hot acetonitrile and adding 10 ml of water. After cooling to 5 C, the product was filtered, washed and dried resulting in 3.5 g white solid as a mixture of the 5-methyl and 6-methyl isomers.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[N:16]=1.[N:28]([C@@H:31]1[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](N2C=C(C)C(=O)NC2=O)[CH2:32]1)=[N+:29]=[N-:30]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:33]2[O:34][C@H:35]([CH2:36][OH:37])[C@@H:31]([N:28]=[N+:29]=[N-:30])[CH2:32]2)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[N:16]=1
Reactant: CC(C)Oc1nc(N)nc2nc[nH]c12
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CC(C)Oc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C
Yield: 28 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c. was added 2-amino-6-isopropoxypurine (0.159 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.159 g, 0.8 mmol, of 2-amino-6-isopropoxypurine was added to the reaction. Fifteen days after the reaction was started, another 0.159 g, 0.8 mmol, of 2-amino-6-isopropoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. Twenty-seven days after the reaction was started, 0.159 g, 0.58 mmoles, of 2-amino-6-isopropoxypurine was added to the reaction. The reaction was stopped after thirty-three days. The reaction was heated at 80° C. to precipitate the enzyme and filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (95:5, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as a foam (28% yield). mp=195°-197° C.