Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][N:28]=1)[CH3:26])(=O)=O>O1CCCC1.CS(C)=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=3)[CH3:26])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (263 mg, 1.1 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (44.2 mg, 60 wt % in mineral oil, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. A solution of the crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate prepared above in DMSO (6 mL) was added. The mixture was heated to 60° C. for 48 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1-(4′-(trifluoromethyl) biphenyl-4-yloxy)ethyl)nicotinic acid (60 mg). 1H NMR (400 MHz, CD3OD, 5): 8.98 (m, 1H), 8.19-8.21 (m, 1H), 7.54-7.61 (m, 4H), 7.42-7.44 (m, 3H), 6.86-6.89 (m, 1H), 5.42-4.43 (q, 1H), 1.58 (d, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:27]1[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.1 %

Procedure:
A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (1 g, 3.35 mmol) in N,N-dimethylacetamide (30 mL) was treated with 4-hydroxypiperidine (396 mg, 3.92 mmol) and triethylamine (1 mL, 7.17 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (1.77 g, 4.67 mmol) was added and the resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture was then poured into water (300 mL) and extracted with dichloromethane (2×200 mL). Combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford the desired compound as a pale yellow gum (1.24 g, 97% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.42-1.54 (1H, m), 1.55-1.67 (2H, m), 1.76-1.84 (1H, m), 1.92-2.01 (1H, m), 3.05-3.15 (1H, m), 3.38-3.55 (2H, m), 3.94-3.99 (1H, m), 4.14-4.22 (1H, m), 4.27 (2H, s), 7.02 (1H, t), 7.26-7.32 (2H, m), 7.70-7.79 (3H, m), 8.44-8.48 (1H, m), 10.07 (1H, s); m/z (LC-MS, ESI+), RT=1.44 (M+H 382.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Yield: 86.5 %

Procedure:
To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.69 g, 19.1 mmol), phenol (1.98 g, 21.0 mmol) and PPh3 (5.51 g, 21.0 mmol) in THF (80 ml) was added DIAD (4.13 ml, 21.0 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)], to give methyl (2S, 4S)-1tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylate (5.31 g, 86%) as a colorless oil. 1H-NMR (CDCl3) δ 1.43 (br, 9H, one of isomers), 1.48 (br, 9H, one of isomers), 2.48 (m, 1H), 3.75 (br, 3H), 4.42–4.96 (m, 2H), 6.88–7.35 (in, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Yield: 77.8 %

Procedure:
To a well stirred solution of (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (1.11 g, 3.4 mmol) and 4-(N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in CH2Cl2 (200 mL) was added powdered 4-nitrophenyl chloroformate (0.891 g, 4.42 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using CHCl3/EtOAc (20%-50%) as the eluent to give (+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (1.30 g, 78%) as a viscous oil. [α]D=+262.2 (c=2.3 g in 100 mL CHCl3).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:4][CH2:3]1.C1C(O)=CC=CC=1C.[CH3:23][N:24]([CH3:27])[C:25]#[N:26].[OH-].[Na+]>O>[CH3:23][N:24]([CH3:27])[C:25]([NH2:26])=[N:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[N:5]1[CH2:4][CH2:3][O:2][CH2:7][CH2:6]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN(C)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1cccc(O)c1
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-morpholinoaniline hydrochloride (19.2 g), m-cresol (80 ml) and dimethylcyanamide (9.45 g) was heated at 100° C. for five hours, cooled and added to the mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid separated by filtration, washed with water and dissolved in dichloromethane. The solution was dried and the solvent removed to give a residue which wa recrystallised from hexane to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-143° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][CH2:16][CH2:15][N:14]=[C:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH2:12]1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(Cl)=[O:37]>C(Cl)CCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[CH:12]=[C:13]2[C:18]3[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=3[O:24][C:36](=[O:37])[N:14]2[CH2:15][CH2:16][S:17]1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C2C=C3c4c(cc(C)oc4=O)OC(=O)N3CCS2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (63 mg, 0.168 mmol), prepared as in Reference 5, was dissolved in ethylene dichloride (2 mL) and then 4-(dimethylamino)pyridine (0.020 g), di-iso-propylethylamine (0.5 mL) and phosgene (0.4 ml, 2 M in toluene) were added at room temperature. The reaction was monitored by analytical HPLC. After stirring at room temperature for 30 minutes, the solvent was removed in vacuo. Product was purified by HPLC (RPC18 column, 2-70% acetonitrile/water containing 0.1% HCl) to provide 10-(2,4-dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dione (20 mg) as an off-white powder. LCMS: M+ 401.0.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][CH:42]=[C:41]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)[CH:40]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1cccc(-c3ccccc3)c1)CC2(C)C
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
A mixture of Cu(OAc)2 (16 mg, 0.09 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), [1,1′-biphenyl]-3-ylboronic acid (17.9 mg, 0.09 mmol) and 34 mg molecular sieves. The resulting mixture was stirred, uncovered, at room temperature for 21 h. The mixture was adsorbed directly onto silica gel and purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (10 mg, 37% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.27-7.16 (m, 3H), 7.08-6.99 (m, 2H), 6.79-6.70 (m, 1H), 4.88 (s, 1H), 4.01 (d, J=15.6 Hz, 1H), 3.75 (d, J=15.9 Hz, 1H), 3.73 (s, 3H), 3.56 (dt, J=13.1, 6.6 Hz, 1H), 3.49-3.41 (m, 1H), 3.38-3.30 (m, 1H), 1.59 (s, 1H), 1.51 (d, J=4.0 Hz, 6H), 1.35 (s, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.02 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(O)C>N1C=CC=CC=1>[CH2:16]([O:18][N:19]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1)[CH3:17]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 92.6 %

Procedure:
3.0 Grams (11 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 2.2 g (22 mmol.) of O-ethylhydroxylamine hydrochloride were refluxed under heat in a mixed solvent containing 10 ml of ethanol and 10 ml of pyridine For 30 minutes. The solvents were distilled off under reduced pressure, and then the residue was treated with 5% hydrochloric acid and extracted with ethyl acetate. The so-obtained solution was consecutively washed with 5% aqueous potassium carbonate and with saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off to give 3.2 g of 4-ethoxyimino-5,8-dimethyl-6-bromothiochroman (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10]Cl>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Cl:10]
Reactant: ClCl
Reactant: Cc1ccc(Cl)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
1 Mol of 2,4-dichloro-methylbenzene and 322 g of carbon tetrachloride are heated to reflux. 0.8 g of azobisisobutyronitrile is added and chlorine gas is introduced in a slight excess. After 0.5 hours, 0.75 mol of product is obtained according to gas-chromatographic analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.O>CO>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (700 g, 2.1 mol) in methanol (14 L) was added Quinidine (617 g, 1.90 mol). The mixture was stirred at 90° C. under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6%.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C[SH-][C:15]([SH-]C)=[N:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.O>CN(C=O)C>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:16][C:15]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(Nc3nc4ccccc4s3)nc2c1
Temperature: 153 °C
Yield: 60.1 %

Procedure:
O-phenylenediamine (21.6 g (0.2 mol)) was dissolved in 944 g of DMF, and thereto was added dropwise a solution obtained by dissolving 50.9 g (0.20 mol) of S,S′-dimethyl-N-(2-benzothiazolyl)-carbonimidodithioate in 1258 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 13 hours, and then cooled to 0° C. Thereto was added dropwise 2000 g of water, and a precipitate was filtered off, washed with water, and dried to obtain 32.0 g of 2-(2-benzothiazolylamino)benzoimidazole (L8: see Table 1 below). The yield was 60.1% based on o-phenylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C#N)[CH:15]=2)[CH:5]=[C:6](F)[CH:7]=1.BrC1C=C(C(OCC)=O)OC=1C1C=CC([F:39])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:39])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Reactant: CCOC(=O)c1cc(Br)c(-c2ccc(F)cc2)o1
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(-c2ccc(F)cc2)o1

Procedure:
The synthesis of the title compound takes place in analogy to the synthesis of the compound from Example 11A starting with the compound from Example 7A. Extraction is carried out with dichloromethane and purification with the mobile phase cyclohexane/ethyl acetate (30:1). 4.12 g (41% of theory) of the title compound with a purity of 50% are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:23][C:24](=[O:44])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][Si](C(C)C)(C(C)C)C(C)C)=[CH:27][C:26]=1[Cl:43])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:23][C:24](=[O:44])[C:25]1[C:26]([Cl:43])=[CH:27][C:28]([OH:32])=[CH:29][C:30]=1[Cl:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-triisopropylsilanyloxy-benzoylamino)propionic acid methyl ester (6.76 g, 9.48 mmol) in THF (150 mL) was added a solution of TBAF (14.22 mL, 14.22 mmol, 1M) in THF at 0° C. The resulting solution was slowly warmed to room temperature and stirred for 15 h. Then, the reaction mixture was diluted with water and the organic compound was extracted into ethyl acetate (2×150 mL). The combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was dissolved in ethyl acetate in hot conditions and then diluted with hexanes. The resulting solids were collected by filtration and washed with hexanes. After drying in air, 5.23 g (99%) of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-hydroxy-benzoylamino)propionic acid methyl ester was obtained as a white solid. ES(+)-HRMS m/e calcd. for C24H18Cl4N2O5 (M−H)− 552.9897, obsd. 552.9897.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]C1)=[O:7])([CH3:4])[CH3:3].NC1(C(O)=O)CCC1.NC1(C(O)=O)CC1>>[CH3:4][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: NC1(C(=O)O)CC1
Agent: NC1(C(=O)O)CCC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC1

Procedure:
The title compound (998 mg) was made in a similar fashion to the preparation of Intermediate 100 replacing 1-aminocyclobutanecarboxylic acid with 1-aminocyclopropanecarboxylic acid (550 mg, 5.44 mmol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].Cl.[CH3:31][O:32][NH2:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2[NH:33][O:32][CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (3.71 mmol) in dry tetrahydrofuran (60ml) was mixed with O-methyl hydroxylamine hydrochloride (37.1 mmol) and triethylamine (6.2 mL). The mixture was stirred at room temperature for 96 hours under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue chromatographed on a flash silica gel column eluting with CHCl3—CH3OH (99:1), to give (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolan-3-yl acetate, a compound of formula (4), which was crystallized from a mixture of chloroform/hexanes (1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[C:17]([C:21]([O-])=O)[C:18]([O-])=[O:19])[O:14]CC)[CH3:11]>>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[N:7][C:6]=1[CH3:8])[N:1]=[CH:21][C:17]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:18]2[OH:19]
Reactant: Cc1nc(N)ccc1Br
Reactant: CCOC(OCC)=C(C(=O)[O-])C(=O)[O-]
Product: CCOC(=O)c1cnc2nc(C)c(Br)cc2c1O
Temperature: 250 °C
Yield: 34.6 %

Procedure:
A solution of 6-amino-3-bromo-2-methylpyridine (1.89 g, 10 mmol) and diethoxymethylenemalonate (2.16 g, 10 mmol) is heated at 110° C. for 30 min. The reaction is cooled and the residue is recrystallized from EtOH. To the resulting solid is dissolved in 45 mL of Ph2O. The mixture is heated to 250° C. for 3 h. The solution is then cooled to room temperature and the resulting precipitate is collected and dried. The crude product is chromatographed on silica (Biotage flash 40M, 2% MeOH/CH2Cl2 eluent). Fractions homogeneous by TLC are collected and concentrated to yield 1.075 g (35%) of the desired product as a yellow solid. Physical data are as follows: m.p. 270° C. (dec.); 1H NMR (DMSO-d6) δ12.73, 8.49, 8.47, 4.21, 2.67, 1.27.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[OH-].[Na+].Cl>O.CCO.O.CCO>[CH3:4][C:3]1[C:2]([OH:1])=[CH:13][C:12]2[CH:11]=[N:10][C:9]([S:15][CH3:16])=[N:8][C:7]=2[N:6]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: CC(=O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc2cc(O)c(C)nc2n1
Yield: 55.4 %

Procedure:
Add 1-hydroxypropan-2-one (24.3 mL, 355 mmol) and 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (50 g, 296 mmol) to a solution of sodium hydroxide (23.64 g, 591 mmol) and water (200 mL). Add EtOH (600 mL) to the suspension and stir at RT overnight. Slowly add a solution of concentrated HCl (50 mL) in water (350 mL). Add 1:1 EtOH/H2O (100 mL) and collect the solids by filtration. Wash the solids with 1:1 EtOH/H2O (250 mL), ice cold EtOH (4×25 mL) and hexanes (2×250 mL). Dry in the vacuum oven at 30-35° C. to provide the title compound as a tan solid (34 g, 56% yield). MS (m/z): 208.1 (M+1).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCCCCC2)nc2cc3c(cc21)CCC3
Yield: 53.8 %

Procedure:
2-(1-Azepanyl)ethylamine (289) (0.52 g, 3.6 mmol) was added to a stirred solution of chloride 21 (322 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 46 (264 mg, 56%) as a yellow solid: mp (MeOH) 121-123° C.; 1H NMR δ 8.08 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.93 (br s, 1H, NH), 3.47-3.52 (m, 2H, CH2N), 2.97-3.03 (m, 4H, H-6, H-8), 2.74 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.65-2.68 (m, 4H, 2×CH2N), 2.15 (p, J=7.4 Hz, 2H, H-7), 1.58-1.68 (m, 8H, 4×CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.1, 129.7, 120.5, 114.6, 55.9, 55.1 (2), 38.8, 33.1, 32.3, 28.4 (2), 26.9 (2), 25.7. Anal. calcd for C18H25N5O: C, 66.0; H, 7.7; N, 21.4. Found: C, 66.0; H, 7.6; N, 21.5%.