Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[K+].I[CH:14]([CH3:16])[CH3:15]>CCO>[CH:14]([O:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: Cc1ccc(C#N)c(O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C#N)c(OC(C)C)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a stirred solution of 2-hydroxy-6-methyl-nicotinonitrile (10.1 g, 75.3 mmol) in 150 mL of absolute EtOH as added KOH (4.97 g, 75.3 mmol). The resulting mixture was heated at 80° C. for 2 h before it was cooled to ambient temperature. The solvent was removed in vacuo and the resulting residue was dried in a vacuum oven for over night. A suspension of the hydroxy pyridine potassium salt in 75 mL of anhydrous DMF was heated at 120° C. while 2-iodopropane (6.0 mL, 90.3 mmol) was added in portions. After 90 min at 120° C., TLC indicated the complete consumption of the starting material. Cooled and 100 mL of water was added to the mixture. The yellow solid was collected through filtration, washed with cold water and dried in vacuum oven to provide the titled compound as a light yellow solid (10.2 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:15](=[O:16])[N:14]([CH2:17][C:18](O)=[O:19])[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[S:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26].[ClH:33].C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[ClH:33].[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH:30][C:18](=[O:19])[CH2:17][N:14]1[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[S:11][CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:15]1=[O:16])[CH3:26]
Reactant: COc1ccc(C2CSc3ccccc3N(CC(=O)O)C2=O)cc1
Reactant: CCN(CC)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)CN1C(=O)C(c2ccc(OC)cc2)CSc2ccccc21
Yield: 67.2 %

Procedure:
1.71 g of (±) 2,3-dihydro-3-(4-methoxyphenyl)-4-oxo-1,5-benzothiazepin-5-(4H)-acetic acid of Step B of Example 14, 17 ml of methylene chloride, 1.74 g of N,N-diethylethylene diamine and 3.82 g of 1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride were stirred for 90 minutes and the solution was poured over 50 ml of water. 10 ml of a saturated aqueous solution of sodium bicarbonate were added, and extraction was done with methylene chloride. The extracts were washed with water, dried and the solvent was eliminated under reduced pressure to obtain 3.6 g of crude product which was chromatographed on silica (eluant: methylene chloride-methanol 8-2) to obtain 1.6 g of the expected product in the form of a base. The base was dissolved in 5 ml of isopropanol and a solution of hydrochloric acid in ethyl acetate was added to obtain 1.5 g of the expected hydrochloride which was crystallized from isopropanol to obtain 525 mg of pure product melting at 160° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](O)=[C:16]3[CH:15]=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:8]3[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][N:9]=3)[N:14]=[CH:15][C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1cnn2-c1ncccc1Cl
Product: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Phosphoryl trichloride (235 mL, 2455.17 mmol) was added to 1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol B15b (30.4 g, 122.76 mmol). The resulting solution was stirred at 100° C. for 4 hours. The mixture was concentrated in vacuo and to the residue was added an ice/water mixture. The resulting mixture was stirred for 1 hour during which time a solid precipitated. The solid was collected by filtration and washed with water (3×75 mL). The crude product was dissolved in EtOAc (500 mL) and dried over MgSO4, filtered and evaporated to afford 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (28.7 g). 1H NMR (400 MHz, DMSO-d6) δ 7.78 (1H, dd), 8.37 (1H, dd), 8.69 (1H, dd), 8.83 (1H, s), 8.92 (1H, s), m/z (ESI+) (M+H)+=266; HPLC tR=1.72 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>C(#N)C>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[N:4]=[CH:3]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: C1CSCCN1
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)N2CCSCC2)c1
Reaction time: 6 h

Procedure:
2 g (11 mmol) of 1-methyl-4-imidazolesulfonyl chloride from Example C-1, dissolved in 20 ml of acetonitrile, are added dropwise with stirring at room temperature to a solution of 1.51 ml (15 mmol) of thiomorpholine in 50 ml of acetonitrile. The reaction mixture is subsequently stirred for 6 hours, filtered and evaporated in vacuo. The residue remaining is recrystallized from isopropanol in order to give the title compound of melting point 154°-155° C.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.CCN(CC)CC.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][NH:29][CH2:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C1Sc2ccccc2NC1=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 2-methylene-4H-benzo[1,4]thiazin-3-one (5.14 mmol) in 10 mL of anhydrous DMF, Et3N (25.7 mmol) is added followed by O-benzylhydroxylamine hydrochloride (25.7 mmol). The mixture is stirred at 100° C. for 12 hours and then the solvent is evaporated. The crude is purified by column chromatography (hexane/EtOAc) to give 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one. Yield 58%. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.13 (m, 9H), 6.1 (bs, 1H), 4.64 (s, 2H), 3.86 (m, 1H), 3.3 (m, 1H), 2.9 (m, 1H). MS: (ES+): 301.2 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]2[C:6]([C:20]([O:22][CH3:23])=[O:21])=[C:7]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[N:8]([CH3:13])[C:9]=2[C:10](=[O:12])[CH:11]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)C>[OH:24][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([OH:12])=[C:9]2[C:5]=1[C:6]([C:20]([O:22][CH3:23])=[O:21])=[C:7]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[N:8]2[CH3:13]
Reactant: COC(=O)C=Cc1c(C(=O)OC)c2c(n1C)C(=O)C=C(OC)C2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)C=Cc1c(C(=O)OC)c2c(O)c(OC)cc(O)c2n1C

Procedure:
Methyl 5-methoxy-3-methoxycarbonyl-N-methyl-4,7-dioxo-2-indoleacrylate (18) (6.64 g, 20 mmol) was dissolved in a mixture of chloroform (600 ml) and ethanol (215 ml). The reduction was carried out on stirring with an aqueous solution (260 ml) of Na2S2O4 (42 g) at room temperature for 30 minutes.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(N(CC)C1C=CC=CC=1)C.B.[Br:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=1)=[O:37]>CC(OC)(C)C>[Br:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[C:40]([F:48])[CH:39]=1)[OH:37]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.83 mL, 1.4 mmol) and borane diethylaniline (2.5 mL, 14 mmol) in MTBE (25 mL) prepared at RT and heated to 40° C. A solution of 2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanone (143a, 4.0 g, 14 mmol, CASRN 54429-22-3) and MTBE (30 mL) was added dropwise to the above solution and the reaction was stirred at 40° C. for 30 min. The reaction was quenched by adding MeOH followed by 1M HCl and the reaction mixture was then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (9:1) to afford 3.2 g (79%) of (R)-2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanol (258).
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)=[O:11]>CN(C)C=O>[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:1])=[O:11]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(=O)N(C)C)C2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
84 mg of sodium bicarbonate and 41 μl of methyl iodide were added, whilst ice-cooling, to a solution of 163 mg of (2S, 4S)-2-(N,N-dimethylcarbamoyl)-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (4) above] dissolved in 1.5 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by chromatography using a Lobar column (Merck, LiChroprep Si60, size A). 45 mg of the title compound were obtained, as an oil, from the fractions eluted with a 3:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CSCCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Product: CSCCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 79 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyimino)-methyl]-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop oxyamino)-methyl]-benzamide (26.54 mg, 79%).
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(OCC)C>[C:15]1([C@@H:7]2[CH2:8][CH2:9][N:24]([CH2:21][CH2:22][CH3:23])[CH2:6]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCN
Reactant: CS(=O)(=O)OCC[C@H](COS(C)(=O)=O)c1ccccc1
Solvent: CCOCC
Product: CCCN1CC[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.5 %

Procedure:
2.0 g of methanesulfonic acid (S)-4-methanesulfonyloxy-3-phenyl-butyl ester (5.51 mmol) were dissolved in 5 ml of n-propylamine (60.82 mmol). The reaction mixture was stirred for 15 h at room temperature, diethyl ether added, the organic phase washed twice with water. The aqueous phase was reextracted once with diethylether, the organic layers combined, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 1.09 g of the product. ESI-MS: 190.1 [M+H]+
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:25][C@@H:26]([CH3:38])[CH2:27][C@H:28]([CH3:37])[O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.N1(C2C=CN=CC=2)CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:25][C@@H:26]([CH3:38])[CH2:27][C@H:28]([CH3:37])[O:29][C:30]1[CH:35]=[CH:34][C:33]([O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)=[CH:32][CH:31]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.36 g of 4-(4'-n-octyloxyphenyl)benzoic acid, 0.21 g of (S,S)-4-(3'-chloro-1'-methylbutoxy)phenol, 0.02 g of 4-pyrrolidinopyridine, 0.21 g of dicyclohexylcarbodiimide and 10 ml of methylene chloride were stirred together at room temperature for four hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (9:1) as a developing solvent to thereby give the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[F-].[K+].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1>[O:28]1[CH2:29][C@H:27]1[CH2:26][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Temperature: 22 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (10 g, 0.15 mol) in THF (100 mL) at 0° C. was added KF (22 g, 0.3 mmol). After 1 h, (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.4 g, 0.17 mmol) was added and the resulting solution was stirred at 22° C. for 16 h. The solid was removed by filtration and washed with THF. The solution was concentrated and the crude compound was used for next step without further purification (15 g, Yield 53%). LCMS (m/z): 190.1 (M+1).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:8]([F:11])([F:10])[F:9])(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.O>[N:23]([CH2:6][CH:7]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([F:11])([F:10])[F:9])=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate (213 g, 625 mmol) in DMF (2500 mL) was added sodium azide (91.1 g, 1.40 mol). The reaction mixture was heated to 80° C. After 16 hours, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (3×500 mL). The organics were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to afford benzyl (3-azido-1,1,1-trifluoropropan-2-yl)carbamate.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=O)C.C[O-].[Na+]>CO>[CH2:10]([C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[OH:4])[CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCC[C@@H]1CCC[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCCC[C@@H]1CCC[C@H]1O
Temperature: 20 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
A stirred solution of (1R,2R)-2-pent-4-en-1-ylcyclopentyl acetate (3.79 g, 19.3 mmol) in MeOH (320 ml) was treated with methanolic NaOMe (25%, 8.1 ml, 35.4 mmol) and stirred for 15 hours at 20° C. DOWEX 50WX8-100 ion-exchange resin (washed with MeOH) was added portionwise until the pH was neutral, then the mixture was filtered through CELITE. The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, and dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (2.61 g, 88%) as a liquid that was used directly in the subsequent reactions. [α]D −37.3 (c=0.65, CHCl3).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20]C(=O)C)=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:47]([C:50]1[N:51]=[CH:52][NH:53][CH:54]=1)([O-:49])=[O:48]>CN1CCCC1=O.C(OCC)(=O)C>[C:35]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][NH:26][C:4]2[N:3]=[C:2]([N:53]3[CH:54]=[C:50]([N+:47]([O-:49])=[O:48])[N:51]=[CH:52]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH2:19][OH:20])[C@@H:13]([OH:24])[C@H:12]2[OH:25])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O
Temperature: 150 °C

Procedure:
The title compound is prepared by dissolving acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in N-methyl-2-pyrrolidinone, followed by potassium carbonate (5 equivalents) and 4-nitro-1H-imidazole (10 equivalents). The mixture is heated by microwave irradiation to 150° C. for two hours, then diluted with ethyl acetate and washed consecutively with water (×2) and brine, before drying over magnesium sulfate. Filtration, removal of the volatile components under reduced pressure and purification by flash column chromatography/crystallisation affords the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>ClCCCl>[N+:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])([O-:12])=[O:11]
Reactant: O=C(O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
61 g of benzoic acid were suspended in 200 ml of 1,2-dichloroethane. The suspension was heated to 40° C. following the addition of 38.6 g (0.60 mol) of 98% nitric acid. 63.5 g of 100% sulphuric acid were then added dropwise over a period of 2 hours at that temperature, followed by stirring for another 3 hours. After cooling to 20° C., the deposit was filtered off. The filter residue was washed four times with 4 × 25 ml of 1,2-dichloroethane and then with water, followed by drying at 90° C. 32.6 g (39% of the theoretical yield) of 3-nitrobenzoic acid were obtained in this way.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[C:4]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH2:18](I)[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Br:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:7](=[O:14])[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[S:5][CH:6]=1
Reactant: CCI
Reactant: O=C(c1ccncc1)c1scc(Br)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of 4-bromo-2-isonicotinoylthiophene-3-carboxylic acid (311 mg, 1 mmol), ethyl iodide (234 mg, 1.5 mmol), Cs2CO3 (652 mg, 2 mmol) in CH3CN (50 mL) was stirred at 30° C. overnight. After completion of the reaction the solution was filtered and the volatile components removed under reduced pressure to give the title compound (305 mg, 90% yield) as yellow oil. The product was directly used for the next step without further purification. LC-MS (Method A): m/z 340 (M+H)+, Rt: 1.95 min.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C:25]2([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: C#CC1(N2CCCCC2)CCCCC1
Product: CO[C@@H]1CN(c2ccc(C#CC3(N4CCCCC4)CCCCC3)c(Cc3ccccc3)n2)C[C@H]1O

Procedure:
This was synthesized in the same manner as in Example 6 except that 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 1-(1-ethynylcyclohexyl)piperidine (Production Example 18) were used.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(C(=O)CCc3ccc4c(c3)OCO4)sc3ncccc23)c1Cl
Yield: 94.3 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4 -chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[3-(3,4-methylenedioxyphenyl)propionyl]thieno[2,3-b]pyridine-3-sulfonamide (0.26 g, 0.44 mmoles), methanol (7 ml) and 4N HCl (1.5 ml), giving 0.21 g (97%) of the title compound as a yellow foamy solid, m.p. 40-45° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:1][C:2]3[C:3]([CH3:12])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][N:8]=[CH:7][CH:6]=4)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1nc2ccncc2cc1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
3-Hydroxy-2-methyl-[1,6]naphthyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and 4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (597 mg, yield 56%).