Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:15]1(=O)[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1>CO.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Using oven dried glassware and under an atmosphere of nitrogen, anhydrous zinc chloride (25 g, 183 mmol) was stirred in anhydrous methanol (60 mL) then heated to a 75° C. internal temperature. Methyl 4-fluorobenzoylacetate (39.6 g, 202 mmol) was added as a single portion followed by dropwise addition of a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous diethyl ether (500 mL) over 4 hours. This was performed with a simultaneous distillation of ether from the reaction mixture such that the reaction volume remained approximately constant (a bath temperature of 140° C. maintained an internal temperature initially at 75° C. then gradually increasing to a maximum of 115° C.). 2.5 hours after the start of the benzoquinone addition, more methanol (20 mL) was added to facilitate stirring. After addition of benzoquinone was complete, heating of the reaction mixture at 100° C. (internal) continued for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (800 mL). The insoluble solids were removed from the biphasic solution by filtration and the organic layer was then separated, dried (Na2SO4), filtered and evaporated under vacuum. The brown residue was slurried in warm dichloromethane (˜225 mL) and the mixture was left to stand in a refrigerator for 18 hours. The resulting solids were filtered from the dark brown solution, washed with a small volume of dichloromethane then dried under vacuum to give Methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=285 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]=[O:11].Cl>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]=[O:11])=[C:4]([OH:8])[C:3]=1[CH3:9]
Reactant: Cc1c(O)cccc1F
Reactant: C=O
Agent: Cl
Solvent: CC#N
Product: Cc1c(F)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To 2.19 g (17.36 mmol) of 3-fluoro-2-methylphenol in 87 mL of anhydrous acetonitrile was added 12.1 g (126.73 mmol) of MgCI2 portionwise followed by addition of 9.0 mL (64.93 mmol) of TEA to afford a pinkish reaction mixture. To this mixture was added 3.8 g (126.73 mmol) of paraformaldehyde and the resulting yellow colored mixture was heated to relux for 4 hours. After cooling to room temperature, to the mixture was added 5% HCl slowly. The reaction was extracted with EtOAc (3×), washed with satd NaCl (3×), dried over MgSO4, filtered, and concd to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9) to afford 2.02 g (75%) of a pale tan oil which later solidified: 1H NMR (CDCl3/400 MHz) 2.14 (d, 3H, J=1.6 Hz), 6.68 (t, 1 H, J=8.8 Hz), 7.37 (dd, 1H, J=6.4, 8.4 Hz), 9.78 (s, 1H), 11.59 (d, 1H, J=2.0 Hz); HRMS (EI+) m/z calcd for (C8H7FO2) 154.0430, found 154.0428.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:23]=[CH:22][C:16]3[N:17]([CH3:21])[C:18]([CH3:20])=[N:19][C:15]=3[CH:14]=2)[OH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([C:13]2[CH:23]=[CH:22][C:16]3[N:17]([CH3:21])[C:18]([CH3:20])=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(O)c2ccc3c(c2)nc(C)n3C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc3c(c2)nc(C)n3C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.2 %

Procedure:
A suspension of (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazol-5-yl)-methanol (2.1 g, 6.7 mmol) and MnO2 (2.9 g, 33.6 mmol) in CH2Cl2 (300 mL) was stirred at room temperature for 17 h. The mixture was filtered through celite and solvent was removed. The crude product was slurried with ether to afford (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazol-5-yl)-methanone (2.0 g, 99%) as an off white solid: 1H NMR (DMSO-d6) δ 7.90 (s, 1H), 7.71-7.62 (m, 2H), 6.80 (s, 3H), 3.80 (s, 3H), 3.35 (s, 3H), 2.58 (s, 3H); 13C NMR (DMSO-d6) δ 195.28, 160.17, 154.83, 141.54, 140.27, 139.15, 130.15, 123.50, 120.73, 109.70, 107.19, 103.62, 55.47, 29.96, 13.52.
Reaction SMILES: CSC1OC([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=C(C2C=CC=CC=2)N=1.OOS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O.C(O)C>[C:17]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: CSc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Agent: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1
Yield: 132.5 %

Procedure:
4-[2-Methylthio-4-phenyl-5-oxazolyl]benzenesulfonamide (Example 50) (0.5 g, 1.44 mmol), ethanol (100 mL), water (50 mL), and Oxone® (potassium peroxymonosulfate, 0.88 g, 1.44 mmol) were stirred at room temperature for 16.0 hours. Sodium metabisulfite (5 g) and water (50 mL) were added and the resulting mixture stirred for 0.25 hours before the addition of ethyl acetate (200 mL). The organic layer was separated and washed with brine and water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate:hexanes (1:3). The first material collected was concentrated and recrystallized to yield 4-[2 -methylsulfonyl)-4-phenyl-5-oxzolyk]benzenesulfonamide as a white solid (0.3 g, 55%): mp 186-188° C. 1H NMR (DMSO-d6) 300 MHz δ 7.92 (d, J=8.5 Hz, 2H) 7.81 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.3 (s, 3H). Anal. Calc'd. for C16H14N2O5S2 : C, 50.78; H, 3.73; N, 7.40. Found: C, 50.79; H, 3.72; N, 7.38. The second material collected was concentrated and recrystallized to yield 4-[2-methylsulfinyl)-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.16 g, 31%): mp 174-176° C. 1H NMR (DMSO-d6) 300 MHz δ 7.9 (d, J=8.5 Hz, 2H) 7.8 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.2 (s, 3H). Anal. Calc'd. for C16H14N2O4S2 : C, 53.03; H, 3.89; N, 7.73. Found: C, 53.08; H, 3.85; N, 7.66.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4])#[N:2].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClCCl.CN(C=O)C>[CH2:14]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([CH:3]([C:1]#[N:2])[CH3:4])[CH:6]=1)[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cccc(C(C)C#N)c1
Reaction time: 1 h

Procedure:
To a solution of 700 mg 3-(1-Cyano-ethyl)-benzoic acid in 20 ml dichloromethane were added dropwise 610 mg oxalyl chloride and 2 drops of DMF at RT. After stirring for 1 hr, 10 ml ethanol were added and stirring was continued for another hr. The solvents were evaporated, the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution. The dichloromethane phase was dried, evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]2[O:16][CH:15]=[N:14][C:13]=2[C:17]=1[F:18].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[Br:29][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9]2[C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (12.31 g, 40.14 mmol) in DMF (100 mL) was added NBS (7.86 g, 44.15 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by water and the precipitate was filtered. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product (pale brown solid, 10.82 g, 69.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.42 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 7.82 (d, J=12.0 Hz, 1H), 7.37 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:12]([N:14]=C=O)=[O:13].N>C(#N)C.CO>[NH2:14][C:12]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:13]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: NC(=O)Nc1sccc1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-3-thiophenecarboxamide (0.44 g) was suspended in acetonitrile (25 ml) and trichloroacetylisocyanate (0.2 ml) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a solution of ammonia in methanol (10 ml of a 2M solution) was added and stirring continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. Trituration with ether gave the title urea (0.2 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1N>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Reactant: Nc1ccccc1F
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccccc2F)C[C@@H]1C
Yield: 52.8 %

Procedure:
A compound was produced in the same manner as in Example 12, using 100 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 2-fluoroaniline, and thus 77 mg (53%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:7][N:8]=1
Reactant: COc1ccc(C=O)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(F)(F)F)cn1
Yield: 93.5 %

Procedure:
According to Reference Example 8-12, by use of 6-methoxy-3-pyridinecarboxaldehyde (300 mg, 2.19 mmol), (trifluoromethyl)trimethylsilane (388 μL, 2.63 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 220 μL, 0.220 mmol) and tetrahydrofuran (6.0 mL), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=4/1) was performed to give 2-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CT) (424 mg, yield: 93%).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@@H:14]1O[C@@H](P(OCC)(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a stirring suspension of thymine (551 mg, 3.32 mmol) in dry DMF (3 mL) was added sodium hydride (60% oil dispersion, 133 mg, 3.32 mmol). After stirring the mixture for 30 min at room temperature, a solution of cis-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (500 mg, 1.66 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 15 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1-ethyl thymine (102 mg, 40%) and then the title compound as an oil (126 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.C([O-])(=O)C.[Na+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of 5-bromo-2-nitropyridine (2.0 g, 9.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 9.7 mmol), Pd(dppf)Cl2 (792 mg, 0.97 mmol), K3PO4.3H2O (5.2 g, 19.4 mmol), and sodium acetate (1.59 g, 19.4 mmol) in acetonitrile (100 mL) and water (5 mL) was evacuated and then refilled with N2. The reaction mixture was heated at 80° C. for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 1:5 ethyl acetate/petroleum ether to afford 200a as a yellow solid (2.2 g, 74%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([CH2:18][CH2:19][CH3:20])[N:3]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([O:8][CH2:9][CH2:10][OH:15])[N:5]=[C:4]([CH2:18][CH2:19][CH3:20])[N:3]=2)(=[O:32])=[O:33])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCCc1nc(Cl)c(Oc2ccccc2OC)c(Cl)n1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1

Procedure:
By reacting 4,6-dichloro-5-(o-methoxyphenoxy)-2-propylpyrimidine with p-tert-butylphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:10]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)CCN(C)C.C([Li])CCC.CN([CH:39]=[O:40])C>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([F:18])=[C:11]([CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)[CH:39]=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl-(5-ethoxy-2-fluoro-phenoxy)-dimethyl-silane described in example 1.2 in 160 ml THF was treated with 66.9 ml pentamethyl diethylentriamine and cooled to −78° C. 200 ml of 1.6 M n-butyllithium solution in hexanes were added dropwise. The light brown, viscous suspension was stirred at −50° C. to −60° C. for 5 hrs, then treated with 24.7 ml DMF within 20 min. The clear yellow solution was warmed up to r.t. overnight. The reaction was quenched with ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and evaporated to give 51.4 g 3-(tert-butyl-dimethyl-silanyloxy)-5-ethoxy-2-fluoro-benzaldehyde as a brown liquid which was used for the next step without further purification.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]#[N:8])[CH2:5][S:4][CH2:3]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>C(O)(=O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:16][C:2]1[CH2:3][S:4][CH2:5][C:6]=1[C:7]#[N:8]
Reactant: N#CC1CSCC1=O
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: N#CC1=C(Nc2ccccc2N)CSC1
Reaction time: 24 h

Procedure:
3-Keto-4-cyanotetrahydrothiophene (80 g, 0.629 mol) and o-phenylenediamine (68 g, 0.629 mol) were dissolved by heating in 1.5 liters of industrial methylated spirit. To the solution, glacial acetic acid (3 ml) was added, the solution then being heated under reflux with mechanical stirring for 24 hours. The solution was then chilled and filtered to give the title product as a solid, m.p. 163° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O:47][C:48]([CH2:50]CCCCOS(C1C=CC(C)=CC=1)(=O)=O)=[O:49])(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:50][C:48]([OH:49])=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of fine-powder sodium hydroxide in 300 ml of tetrahydrofuran is cooled to 0° C. At 0° C., 78 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid-tert-butyl ester, dissolved in 40 ml of tetrahydrofuran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for 3 hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of methanol. 50 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for one hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1>[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: Cc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1nc(N2CCCC2)ccc1N
Yield: 72.4 %

Procedure:
The process is carried out according to the method described in step 5.2, using 0.55 g (2.65 mmol) of 2-methyl-6-(pyrrolidin-1-yl)-3-nitropyridine, prepared in step 9.1, and 0.1 g of 10% palladium-on-charcoal. 0.34 g of the expected product is thus obtained, which product will be used as it is in the rest of the synthesis.
Reaction SMILES: Cl.N1C=CC=CC=1.C([O:10][C:11]1[C:16]2[S:17][C:18]3[C:23]([C:24]4([CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)C.[OH-].[Na+]>O>[OH:10][C:11]1[C:16]2[S:17][C:18]3[C:23]([C:24]4([CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: CCOc1cccc2c1Sc1ccccc1C21CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CN1CCC2(CC1)c1ccccc1Sc1c(O)cccc12
Temperature: 210 °C

Procedure:
To a melt of pyridine hydrochloride (19 g.) at 160° C. is added 4-ethoxy-1'-methylthioxanthene-9-spiro-4'-piperidine (1.3 g.). The stirred mixture is heated to 210° C. for 30 minutes and then cooled, diluted with water and made alkaline with aqueous sodium hydroxide solution. A small amount of solid material is removed by filtration and the filtrate is acidified with concentrated hydrochloric acid followed by neutralisation with sodium bicarbonate and extraction with chloroform. The chloroform extract is evaporated to dryness and the residual yellow gum crystallised from aqueous ethanol to give 4-hydroxy-1'-methylthioxanthene-9-spiro-4'-piperidine, m.p. 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-methoxy-4-nitro-methanesulfonylaminobenzene (1 g) in methanol (20 ml) containing palladium on carbon (10%, 100 mg) was stirred at RT under hydrogen for 48 h. The mixture was filtered through celite then evaporated to give 2-methoxy-4-amino-methanesulfonylaminobenzene as a brown gum. This was used without purification in the following reaction.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH2:20][OH:21])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:22](O)(=O)/[CH:23]=[CH:24]/[C:25](O)=O.C(O)CCCCCO.[PH2](O)=O.C(OP(OCC)OCC)C.[P]>>[CH2:7]([O:6][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH:20]([OH:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCOC(=O)C(CC(=O)OCCO)P(=O)(OCC)OCC
Agent: CCOP(OCC)OCC
Agent: O=[PH2]O
Agent: OCCCCCCO
Product: CCCCC(O)COC(=O)CC(C(=O)OCC)P(=O)(OCC)OCC

Procedure:
The procedures according to Example 1 were repeated using similar apparatus and under essentially similar conditions allowing for the differences in quantities of materials employed. In this example, for the materials of Example 1, 1 mol fumaric acid, 1 mol of 1,6-hexane diol, 0.1% of hypophosphorous acid and 1 mol of triethylphosphite were employed. The product of the reaction had analytical values for acid value, hydroxyl, free triethylphosphite and phosphorus content comparable to those reported in Example 1.