Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([S:47][S:48][C:49]([N:51]([CH3:66])[C@@H:52]([CH2:59][S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:53](OCC#N)=[O:54])=[O:50])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)C(O)=O>O.O1CCCC1>[C:43]([S:47][S:48][C:49]([N:51]([CH3:66])[C@@H:52]([CH2:59][S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:53]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:54])=[O:50])([CH3:46])([CH3:45])[CH3:44]
Reactant: CN(C(=O)SSC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C(=O)SSC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.2 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (77 mg, 0.121 mmol) in water (2.40 ml) and a solution of (R)-cyanomethyl 2-((tert-butyldisulfanecarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-G) (198 mg, 0.483 mmol) in tetrahydrofuran (1.21 ml) were added to buffer A (46 ml), and the mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (0.967 ml) was then added, after which the mixture was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butyldisulfanecarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-G) (3.8 mg, 3%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=[O:17])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:17])[NH:8]1
Reactant: C[Mg]Br
Reactant: O=c1nc(-c2ccccc2)c2ccccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Phenyl-1H-quinazolin-2-one (5.0 g, 4.5 mmol) in THF (50 ml) is added methylmagnesium bromide (15.0 ml) dropwise at −78° C. under nitrogen. The mixture is stirred overnight at room temperature. The mixture is poured into an aqueous solution of NH4Cl and then extracted with EtOAc. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is purified on silica gel to give product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3(OCC(C)(C)C[O:14]3)[CH2:11]2)[CH2:7]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10](=[O:14])[CH2:11]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CC2CC3(CC2C1)OCC(C)(C)CO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1CC2CC(=O)CC2C1
Yield: 13.4 %

Procedure:
A solution of the product of Step 3 (400 mg, 1.350 mmol) in acetone (8.0 mL) and water (8.00 mL) was stirred at room temperature 16 hrs with p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol). The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography (10 to 60% EtOAc in hexanes) afforded ethyl[5-oxooctahydropentalen-2-yl]acetate (38 mg, 0.181 mmol, 13.4% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.14-4.09 (m, 2H), 2.73-2.71 (m, 2H), 2.53-2.47 (m, 2H), 2.37-2.32 (m, 3H), 2.29-2.25 (m, 2H), 2.08-2.02 (m, 2H), 1.27-1.24 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCCCC

Procedure:
The procedure of Example 1 is repeated using 11.92 grams of 2,6-di-tert-butyl-4-mercaptophenol, 11.41 grams of di-n-butyl maleate, and 0.5 gram of triethylamine. The product is purified by dry column chromatography to give a clear syrup.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[C:11]([F:21])[C:10]=1[F:22].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[C:12]([F:20])=[C:13]([F:19])[C:14]=1[S:15]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:17])=[O:16]
Reactant: COC(C)CCO
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
To a solution of 3-methoxybutane-1-ol (0.78 g, 7.5 mmol) and TEA (0.388 g, 3.8 mmol), in CH2Cl2 (15 mL) was added pentafluorobenzenesulfonyl chloride (0.79 g, 3.0 mmol). The solution was stirred at rt for 4 h. Saturated aqueous NaHCO3 (10 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (30 mL) and washed with 0.5 M HCl (2×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (15% ethyl acetate in hexanes) yielded the desired product (0.39 g, 36%). 1H NMR (400 MHz CDCl3) δ 4.40 (m, 2H), 3.45 (m, 1H), 3.26 (s, 3H), 1.87 (m, 2H), 1.15 (d, 3H, J=6.1 Hz). Anal. Calcd. For C11H11F5O4S: C, 39.53; H, 3.32. Found: C, 39.83; H, 3.45.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nccs1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nccs1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a room temperature solution of thiazol-2-ylmethanol (1.00 g, 8.684 mmol) in CH2Cl2 was added imidazole (1.18 g, 17.4 mmol) followed by tert-butyldimethylsilyl chloride (1.70 g, 11.3 mmol). After 30 minutes, the mixture was quenched with 2 mL of MeOH and passed through a pad of silica gel eluting with CH2Cl2 (700 mL) and concentrated in vacuo to afford 2.01 g (100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>C(Cl)Cl.O1CCCC1>[NH2:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc(-c2ccccc2C#N)cc1Br)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NCc1ccccc1-c1ccc(CO)c(Br)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 136 mg (0.258 mmol) of 3'-bromo-4'-t-butyldiphenylsilyloxymethyl-1,1'-biphenyl-2-nitrile (Step G) in 3 mL of dry methylene chloride under a nitrogen atmosphere was added 199 mg (0.775 mmol) of tetra-n-butylammonium borohydride. The reaction mixture was heated at reflux for 8 hours, cooled to room temperature, poured into 25 mL of water and extracted with ethyl acetate (3×35 mL). The combined organic extracts were washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was dissolved in 3 mL of tetrahydrofuran and treated with 1 mL of 6 N aqueous hydrochloric acid. The resulting solution was heated at reflux for 4 hours, cooled in an ice bath and quenched with 10 mL of 1 N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3×35 mL). The organic extracts were washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with chloroformB 10% ammonium hydroxide (33%) in methanol (9:1), to afford 43 mg (57%) of the product as an off-white solid. 1H NMR (200 MHz, CD3OD): δ 3.69 (s, 2H), 4.68 (s, 2H), 7.16 (dd; 7, 6 Hz; 1H), 7.21-7.41 (m, 4H), 7.47 (dd; 9, 8 Hz; 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated for C14H14BrNO 292; found 292, 293 (50%).
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[S:20])=[C:14]([OH:29])[C:13]=1[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].[Si:36](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].N1C=CN=C1>>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:30]([N:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])[C:14]=1[O:29][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: Cc1ccccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Yield: 57.4 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-Chloro-2-hydroxy-3-[N″,N″-dimethylaminosulfonyl]phenyl]-N′-(2-methylphenyl)thiourea (557 mg, 1.39 mmol), tert-butyldimethylsilyl chloride (1.04 mg, 6.95 mmol) and imidazole (189 mg, 2.78 mmol) were reacted to form the desired product (410 mg, 57%). EI-MS m/z 514.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: O=C(O)Cc1c(Cl)cccc1I
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(Cl)cccc1I
Temperature: 25 °C

Procedure:
A mixture of 2-(2-chloro-6-iodophenyl)acetic acid (10 g, 34 mmol) in 100 mL EtOH was treated with 2 mL concentrated H2SO4, and refluxed for 15 hours. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL EtOAc, washed with water (3×50 mL), saturated NaCl (20 mL), dried over sodium sulfate and concentrated. The crude mixture was purified by column chromatography (10-20% EtOAc/hexane) to give 9.5 g of pale yellow oil. MS m/e: (M+H)+ 324.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][N:4]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1)[CH2:17][C:18]([F:19])([F:20])[F:21])(=[O:32])=[O:31]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.104 g, 0.333 mmol) in CH2Cl2 (3 mL) at 0° C. was added Et3N (0.07 mL, 0.5 mmol), followed by MsCl (0.03 mL, 0.37 mmol). The resulting mixture was stirred 12 h, gradually warming to rt. The mixture was poured into 10% v/v HCl and the layers were separated. The organic layer was washed (sat'd NaHCO3, water, brine), dried over Na2SO4, filtered and concentrated to a colorless film (0.122 g), which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7, 2.7 Hz, 1H), 4.43 (t, J=5.7 Hz, 2H), 4.10 (q, J=8.5 Hz, 2H), 3.95 (t, J=5.7 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:18][C:16]([C:14]1[CH:15]=[N:11][N:12]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=2)[CH:13]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of (4-Chloromethyl-phenyl)-methanol (600 mg, 3.8 mmol), ethyl 1H-pyrazole-4-carboxylate (537 mg, 3.8 mmol) and potassium carbonate (2.6 g, 19 mmol) in 30 mL acetone was stirred at 50° C. for 3 h. The mixture was filtrated and concentrated in vacuo. The crude was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min) to yield the title compound. LCMS (method A) RtA=1.403 min; [M+H]+=261.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[NH2:10][O:11][S:12]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])(=[O:14])=[O:13].CCOCC>ClCCl>[NH2:10][O:11][S:12]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])(=[O:13])=[O:14].[CH3:21][C:20]1[CH:19]=[C:18]([CH3:22])[CH:17]=[C:16]([CH3:23])[C:15]=1[S:12]([O-:14])(=[O:13])=[O:11].[NH2:10][N+:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cncc(Br)c1
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(Br)c[n+](N)c1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(Adapted from: Miki, Y. et. al.; Heterocycles 1996, 43, 2249-2256; 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene was prepared using the procedure described in Krause, J. G. Synthesis, 1972, 3, 140). A solution of 3-bromo-5-methoxypyridine (8.72 g, 46.4 mmol) in dichloromethane (93 ml) was cooled to 0° C. A solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (13.31 g, 46.4 mmol) in dichloromethane (93 ml) was added in a steady stream via canula and the mixture was allowed to stir for 1 h at 0° C. At this time, 460 mL of ether was added dropwise via addition funnel over 5 minutes. The precipitated solid was collected via filtration, and washed with cold ether. The solid was placed under vacuum for 30 minutes to afford 1-amino-3-bromo-5-methoxypyridinium 2,4,6-trimethylbenzenesulfonate as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cn(-c2cccc(F)c2C#N)cn1

Procedure:
As described for example 84a, 2,6-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) the title compound was obtained as an off-white solid (yield: 29%). 1H-NMR (300 MHz, DMSO): δ=2.19 (d, J=0.8 Hz, 3H), 7.39 (s with fine splitting, 1H), 7.56-7.64 (m, 2H), 7.92 (mc, 1H), 8.04 (d, J=1.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:14]2[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[N:16][N:15]=2)[NH2:13])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25].[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][C:43]2=[O:52])[CH2:38][CH2:37]1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:13][C:24]([N:36]2[CH2:37][CH2:38][CH:39]([N:42]3[CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[NH:44][C:43]3=[O:52])[CH2:40][CH2:41]2)=[O:25])[C:14]2[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[N:16][N:15]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(N)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 2-(7-methyl-1H-indazol-5-yl)-1-(1-neopentyl-1H-tetrazol-5-yl)ethanamine (20.0 mg, 0.06 mmol) in dimethylformamide (1.0 mL) at 0° C. was treated with carbonyl diimidazole (11.0 mg, 1.1 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (15.0 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 22.0 mg (64%). 1H-NMR (CD3OD, 500 MHz) δ 0.90 (s, 9H), 1.35-1.60 (m, 4H), 2.53 (s, 3H), 2.71-2.85 (m, 2H), 3.41-3.52 (m, 2H), 3.98-4.14 (m, 5H), 4.24 (d, J=14.3, 1H), 4.34 (m, 1H), 6.77 (d, J=7.9, 1H), 6.94 (dd, J=7.6, 7.3, 1H), 7.06-7.17 (m, 3H), 7.45 (s, 1H), 7.88 (s, 1H), 7.98 (s, 1H). Mass spec.: 571.28 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH:16](OCC)=[O:17].CCO.O>CCOCC>[O:17]=[CH:16][CH:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cc1cc(C)cc(OC)c1
Reactant: CCOC=O
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(C=O)c1cc(C)cc(OC)c1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
To a solution of ethyl 3-methoxy-5-methylphenylacetate (3.0 g; 14 mmol; is from step (iv) above) and ethyl formate (1.9 g; 26 mmol) in ether (75 mL) was added Na (0.39 g; 17 mmol) in small lumps. The solution was cooled to 0° C. and EtOH (abs.; 0.24 mL) was then added. To the resulting slurry was added ether (100 μL), EtOH (5 mL) and water until the slurry was dissolved. The aqueous phase was collected, acidified to pH 2 (HCl/aq) and extracted with ether. The organic phase was washed with NaHCO3/aq, dried (Na2SO4), and evaporated to yield 2 g (59%) of the sub-title compound.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>CO>[C:1]([C@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C#CC1(O)CN2CCC1CC2
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Product: C#C[C@@]1(O)CN2CCC1CC2
Yield: 13.7 %

Procedure:
15.1 g of 3-ethynyl-3-quinuclidinol and 15 g of L-(+)-tartaric acid were dissolved under heating in 300 ml of methanol. After standing to cool, the resulting crystals were collected by filtration and recrystallized from methanol for three times, to give 2.07 g of the title compound.
Reaction SMILES: [Si]([N:8]1[C@H:11]([CH2:12][C:13](SC)(SC)SC)[C@@H:10]([C@H](O)C)[C:9]1=[O:23])(C(C)(C)C)(C)C.[C:24](=O)(O)[O-:25].[Na+].C[OH:30]>>[C:13]([CH2:12][CH:11]1[NH:8][C:9](=[O:23])[CH2:10]1)([O:25][CH3:24])=[O:30]
Reactant: O=C([O-])O
Reactant: CSC(C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Reactant: CO
Agent: [Na+]
Product: COC(=O)CC1CC(=O)N1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Mercuric chloride (12.37 g, 45.6 mmol) is added in one portion to a solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)-ethyl]azetidin-2-one (6.0 g, 15.2 mmol) in 250 ml of absolute methanol at 0° C. The resulting mixture (heavy white precipitate) is stirred at 0° C. for 3 min., then quenched by addition of sodium bicarbonate (8.99 g, 107 mmol). This mixture is then filtered and the solid residue is washed with additional methanol. The combined filtrate and washings are concentrated in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase is separated, washed with saturated aqueous ammonium chloride solution, water and brine and dried over magnesium sulfate. Removal of solvents in vacuo gives an oil which is chromatographed on a silica gel column (3:2 cyclohexane:ethyl acetate) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl)]-4-carbomethoxymethyl azetidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:15]([O-:17])=[O:16].C(O)C.CN(C)C(=N)N(C)C.[CH2:30](I)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O>[N+:15]([C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]([O:14][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:18])([O-:17])=[O:16]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
To a solution of 19.5 g. of dimethyl-5-hydroxy-2-nitroisophthalate in 150 ml. of dry ethanol are added 8.8 g. of tetramethylguanidine, followed by 29.1 g. of octadecyliodide. The mixture is refluxed for 16 hr., cooled, and poured into 700 ml. of water. The precipitate is collected and washed well with water. The dried crude product is triturated with methanol. The insoluble solid is collected, giving 32.6 g. of product, m.p. 65°-68° C., which is used without further purification.