Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([F:21])[C:18]=1[O:19]C)[CH2:9][N:10]1[CH:14]=[N:13][N:12]=[C:11]1[SH:15]>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([F:21])[C:18]=1[OH:19])[CH2:9][N:10]1[CH:14]=[N:13][N:12]=[C:11]1[SH:15]
Reactant: COc1c(F)cc(Cn2cnnc2S)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1c(F)cc(Cn2cnnc2S)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Boron tribromide (25.6 ml, 0.0408 mole) (40% BBr3 in methylene chloride) was added dropwise over 10 minutes to a suspension of 4-(3',5'-difluoro-4'-methoxybenzyl)-1,2,4-triazole-3-thiol, prepared as in Example 4, (3.3 g) in 50 ml methylene chloride and stirred overnight at 25° C. The reaction mixture was poured into a mixture of ice-ethyl acetate, separated, and extracted two additional times with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with sodium sulfate, filtered, and evaporated to an oil. The oil was dissolved in methylene chloride:methanol (90:10) and purified on a flash silica column eluted with methylene chloride:methanol (90:10) to produce a solid which was recrystallized from ethanol-hexane to yield 0.8 g (23% ) of 4-(3',5'-difluoro-4'-hydroxybenzyl)-1,2,4-triazole-3-thiol, m.p.: 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:8](=[O:10])[C:6]2[CH:5]=[C:4]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1cc(Oc2cncnc2)cc(C(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(Oc2cncnc2)cc(C(=O)Nc2ccc(F)cn2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
6-methyl-4-(pyrimidin-5-yloxy)picolinic acid (610 mg, 2.64 mmol, 1 eq) and 5-fluoro-2-aminopyridine (296 mg, 2.64 mmol, 1 eq) were dissolved in pyridine (40 mL) in a flame-dried round-bottom flask. The reaction was cooled to −15° C. and phosphorus oxychloride (270 μL, 2.90 mmol, 1.1 eq) was added dropwise while keeping the temperature below −15° C. After stirring for 30 minutes at −15° C. and the reaction was quenched with ice-water and neutralized with 10% K2CO3. The mixture was extracted with EtOAc (3×) and the combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 310 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J=3.0 Hz, 1H), 8.27 (dd, J=9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J=8.6, 3.1 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 2.58 (s, 3H); ES-MS [M+1]+: 326.2.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O.[OH-].[NH4+:22]>>[NH2:22][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(c1ccccc1)c1cccc(C(F)(F)F)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Temperature: 140 °C
Yield: 90 %

Procedure:
A suspension of (2-fluoro-3-trifluoromethyl-phenyl)-phenyl-methanone (0.5 g, 1.87 mmol) in 10 ml of ammonium hydroxide (28%) was sealed in a heavy-welled Pyrex tube. The sealed tube was heated at 140° C. overnight. The reaction was poured into water/saturated ammonium chloride solution and extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated to give (2-amino-3-trifluoromethyl-phenyl)-phenyl-methanone as an oil (0.45 g, 90%). MS ESI (m/z) 266 ([M+H]+);
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:26]=[C:22]([CH3:21])[CH2:23][C:24]([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:25]
Reactant: C=C(C)C(=O)OCC(C)(C)CO
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(C)(C)COC(=O)CC(C)=O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To a 2-L flask was charged neopentyl glycol (208.3 g, 2.0 moles), toluene (250 mL), hydroquinone (0.5 g) and sodium methoxide (25% in methanol, 8 g). The mixture was heated to 60-65° C. and methyl methacrylate (120 g, 1.2 moles) was added dropwise over 1 hour. The reaction was held at 70° C. for one hour under moderate vacuum to remove methanol and low boilers. Reaction was worked up by washing with 2×250 mL water and 1×100 mL saturated sodium chloride solution at 70° C. Toluene was evaporated and the resulting crude product (166 g) distilled to provide 3-hydroxy-2,2-dimethylpropyl methacrylate of 97% GC assay. To a 300 mL flask was charged 3-hydroxy-2,2-dimethylpropyl methacrylate (11.5 g, 0.064 moles), methylene chloride (20 g), DMAP (0.01 g), hydroquinone (0.05 g) and the mixture cooled to 0-5° C. To this was added dropwise diketene (5.4 g) at <3° C. Reaction allowed to warm to room temperature and stir overnight. Reaction cooled to 0-5° C. and additional diketene (2 g) added to complete reaction. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 92.6% assay with 1.6% starting material remaining (GC assay).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:17][CH2:16]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].I[C:30]1[CH:42]=[CH:41][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=1.CNC1CCCCC1NC>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:30]3[CH:31]=[CH:32][C:33]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:41][CH:42]=3)[CH:13]=[C:12]([CH:15]3[CH2:16][CH2:17][CH:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:19][CH2:20]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Ic1ccc(CN2CCOCC2)cc1
Reactant: CCCCNc1ncc2[nH]cc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2n1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCNc1ncc2c(n1)c(C1CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(CN2CCOCC2)cc1
Temperature: 195 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (59 mg, 0.14653 mmol) and 4-iodobenzyl morpholine (67 mg, 0.22 mmol) in NMP (1 mL) was added CuI (3 mg, 0.022 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (2 mg, 0.044 mmol). The reaction mixture was stirred under microwave irradiation at 195° C. for 30 min. Then the reaction was diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (85 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.17 (s, 1H), 4.86 (s, 1H), 3.71-3.52 (m, 4H), 3.44-3.38 (m, 4H), 3.32-3.17 (m, 1H), 2.81-2.71 (m, 2H), 2.45-2.33 (m, 4H), 2.15-2.04 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.29 (m, 8H), 0.94-0.75 (m, 12H), 0.00 (s, 6H). MS m/z 578.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.ClCCl.CCCCCC>ClCCl>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(C)=O)c(O)c1Br
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(Br)c1O
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Stir 1-(3-bromo-2-hydroxy-4-methoxy-phenyl)-ethanone (20 g, 82 mmol) in dichloromethane (500 mL) at −30° C. under a nitrogen atmosphere. Treat with boron tribromide (30 mL, 318 mmol) and stir over night at room temperature. Pour mixture into cracked ice and stir for 1 hr. Extract twice with dichloromethane, wash organic layers with water, saturated aqueous sodium chloride solution, dry with magnesium sulfate, filter, and evaporate filtrate. Chromatograph residue on silica gel eluting with 2:1 dichloromethane/hexane to provide the title compound (13.8 g, 74% yield) as an off white powder. 1H NMR (CDCl3) δ 13.5 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.20 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C3CCCCO3)[N:15]=[C:14]4[C:26]3[N:31]=[C:30]([O:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]4)[CH:29]=[N:28][CH:27]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[C:14]4[C:26]3[CH:27]=[N:28][CH:29]=[C:30]([O:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]4)[N:31]=3)[CH:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(NC6CC6)n5)cc34)n2)C1
Agent: Cl
Product: c1cc(-c2ccc3[nH]nc(-c4cncc(O[C@@H]5CCCNC5)n4)c3c2)nc(NC2CC2)n1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of (3R)-tert-butyl 3-(6-(5-(2-(cyclopropylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (116 mg, 0.19 mmol) and HCl (5-6 M in IPA, 3.8 mL, 18.9 mmol) was heated at 80° C. for 1 h. The reaction was cooled to RT and concentrated to a yellow solid that was slurried with a 1\1 mixture of DCM/MeOH (2 mL) and applied to a pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The column was washed with MeOH (10 mL). The compound was released with 10 mL of 2 M NH3 in MeOH to afford the title compound (75 mg, 0.18 mmol, 92% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 429.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (br. s., 1H), 8.96 (s, 1H), 8.40 (d, J=5.28 Hz, 1H), 8.16-8.26 (m, 2H), 7.74 (d, J=8.80 Hz, 1H), 7.36 (d, J=5.09 Hz, 1H), 5.25-5.35 (m, 1H), 3.36-3.44 (m, 1H), 2.86-2.93 (m, 1H), 2.75-2.82 (m, 1H), 2.67-2.75 (m, 1H), 2.52-2.58 (m, 2H), 2.21-2.32 (m, 1H), 1.55-1.76 (m, 2H), 0.67-0.76 (m, 2H), 0.45-0.59 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:5]([S:2]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)(=[O:4])=[O:3])[CH:6]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCS(=O)(=O)CC2)c1

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1 g, 3.3 mmol, Buttpark Ltd.) and DIPEA (641 mg, 866 μL, 4.96 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of thiomorpholine 1,1-dioxide (447 mg, 3.3 mmol, CAS RN 39093-93-1) in CH2Cl2 (4.00 mL). After 90 minutes the suspension was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 80:20). Light brown solid (0.99 g; 74%). MS (ESI): m/z=419.05 [M+NH4]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].OC1C=C(O)C=C(O)C=1.[C:16]([O:19][CH:20]=[CH2:21])(=O)[CH3:17].OC1C=C(OC=C)C=C(O)C=1.OC1[CH:39]=[C:38]([O:40][CH:41]=[CH2:42])[CH:37]=[C:36]([O:43][CH:44]=[CH2:45])C=1>C1(C)C=CC=CC=1>[CH:20]([O:19][C:16]1[CH:17]=[C:36]([O:43][CH:44]=[CH2:45])[CH:37]=[C:38]([O:40][CH:41]=[CH2:42])[CH:39]=1)=[CH2:21]
Reactant: C=COc1cc(O)cc(OC=C)c1
Reactant: C=COC(C)=O
Agent: C=COc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: Oc1cc(O)cc(O)c1
Solvent: Cc1ccccc1
Product: C=COc1cc(OC=C)cc(OC=C)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added 1,3,5-trihydroxybenzene (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1,3-dihydroxy-5-vinyloxybenzene, 1-hydroxy-3,5-bis(vinyloxy)benzene, and 1,3,5-tris(vinyloxy)benzene were formed in yields of 5%, 4%, and 18%, respectively, with a conversion from 1,3,5-trihydroxybenzene of 29%.
Reaction SMILES: [CH3:1][N:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].O.C>C(O)(=O)C.[Fe]>[CH3:1][N:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1N
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
To a solution of 88.9 g of the product of Example 33 in 565 ml of 90% aqueous acetic acid was added 83 g of iron powder at 80°-90° in several portions. Water (60 ml) was then added and heating continued for 20 minutes. Charcoal (10 g) was added and the solution filtered through Celite® and concentrated in-vacuo. The residue was made strongly alkaline with 20% NaOH solution, then extracted with methylene chloride. The extract was dried and concentrated in-vacuo to give 29.3 g of N-methyl-N-(phenylmethoxy)-2-aminobenzenesulfonamide as a yellow oil. [NMR: δ 5.1 (broad singlet, 2H, NH2)].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1)=[O:9].[CH3:34][N:35]([CH3:49])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46]C=O)=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:49][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:16][CH2:17]2)=[O:9])=[CH:44][CH:45]=1
Reactant: CN(C)CCCOc1ccc(CC=O)cc1
Reactant: NCCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CCCOc1ccc(CNCCCCCNC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Biphenyl-2-ylcarbamic acid 1-[2-(5-aminopentylcarbamoyl)ethyl]piperidin-4-yl ester (45.2 mg, 0.1 mmol; prepared as described in Preparation 4) was dissolved in 1 mL of MeOH. To the solution was added [4-(3-dimethylaminopropoxy)phenyl]acetaldehyde (0.1 mmol) at room temperature. The reaction was stirred at room temperature for 30 minutes before it was treated with Na(OAc)3BH (64 mg, 0.3 mmol). Stirring was continued for an additional 1 hour. The reaction mixture was concentrated, then dissolved in 1 mL of 1:1 HOAc/H2O solution and purified on reverse phase HPLC. The title compound was obtained as a tri(trifluoroacetate) salt. MS m/z: [M+H+] calcd for C38H53N5O4, 644.42; found, 644.3.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14](F)=[O:15].[OH-].[K+]>>[CH3:12][N:13]([S:17][S:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN(SSC1CCCCC1)C(=O)F
Reactant: CN1C(=O)C(C)(C)SC1=NO
Agent: [K+]
Agent: [OH-]
Product: CN(SSC1CCCCC1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(cyclohexylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example X by reacting 3.48 g (0.02 m) of 3,5,5-trimethyl-2-oximino thiazolidin-4-one with 4.47 g (0.02 m) of N-methyl-N-(cyclohexylthiosulfenyl) carbamoyl fluoride and 1.32 g (0.02 m) of potassium hydroxide. Weight of 2-[[O-[N-methyl-N-(cyclohexylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one produced was 3.1 g. m.p. 86°-88° C.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[C:40](=[N:41][O:42][CH3:43])[CH2:39][CH2:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:44][O:45]C(=O)C)[CH2:7][O:8]2)(=O)C.C1COCC1.O.O[Li].O>CO>[CH3:43][O:42][N:41]=[C:40]1[CH2:39][CH2:38][CH:37]=[C:36]1[O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@@:9]34[O:20][C@@:6]([CH2:44][OH:45])([CH2:7][O:8]3)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]4[OH:16])[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:30][CH:31]=1
Reactant: CON=C1CCC=C1Oc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CON=C1CCC=C1Oc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of compound (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-((5-(methoxyimino)cyclopent-1-en-1-yl)oxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (110 mg, 0.16 mmol) in MeOH:THF:H2O (0.48 mL, 0.36 mL, 0.12 mL), LiOH.H2O (10.3 mg, 0.24 mmol) was added at 0° C. The reaction mixture was stirred for 1 h at r.t. After completion of the reaction as confirmed by TLC, the solvent was evaporated in vacuo. The crude compound obtained was purified by column chromatography (silica gel, 0.4:9.6 MeOH:DCM) to provide title compound (75 mg, 90.5%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH3:16]
Reactant: CCc1ccc(-c2csc(N)n2)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2scc(-c3ccc(CC)cc3)n12
Reaction time: 8 h

Procedure:
10 g of 2-amino-4-(4'-ethylphenyl)-thiazole are dissolved in 50 ml of ethanol and 8.4 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. After standing overnight, the mixture is concentrated by evaporation in vacuo to dryness at a bath temperature of 40° to 50° C. 50 ml of chlorobenzene are added to the residue, followed by heating unter reflux for 1 hour. After concentration by evaporation in vacuo, the residue is dissolved in ether, treated with carbon, filtered and petroleum ether subsequently added. The product precipitating is washed with a little ether and dried. 3-(4'-ethylphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 142°-144° C. is thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1.F[B-](F)(F)F.[O:25]=[N+:26]=[O:27]>C(#N)C>[CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([N+:26]([O-:27])=[O:25])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: O=[N+]=O
Reactant: Cc1cccnc1C1CC(C)(C)Oc2ccccc21
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1cccnc1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 46.4 %

Procedure:
685 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of acetonitrile at room temperature and 360 mg of nitronium tetrafluoroborate were added. After 30 minutes the solvent was removed by evaporation and ethyl acetate and water were added. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 374 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-6-nitro-2H-1-benzopyran in the form of a solid of melting point 164°-165° C. after recrystallization from t-butyl methyl ether.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:26]1([C:22]2[CH:21]=[C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:5]4[CH:4]=[C:3]([OH:2])[N:7]([C:8]5[N:9]=[CH:10][CH:11]=[CH:12][N:13]=5)[N:6]=4)=[CH:19][CH:18]=3)[CH:25]=[CH:24][CH:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3cccc(-c4ccccc4)c3)cc2)nn1-c1ncccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3cccc(-c4ccccc4)c3)cc2)nn1-c1ncccn1
Yield: 93 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 50 of Example C-24 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:9]
Reactant: BrBr
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1c(Cl)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.8 %

Procedure:
To a solution of 2,4-dichlorophenol (4 g, 24.5 mmol) and sodium acetate (2 g, 24.5 mmol) in acetic acid (40 ml) was added bromine (1.3 ml, 24.5 mmol) and the reaction stirred at room temperature for 14 hours. The reaction was poured into 600 ml ice and filtered. The product was extracted into dichloromethane (200 ml) dried over sodium sulphate and concentrated in vacuo to furnish 5.5 g of the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][O:32][CH2:33][B-](F)(F)F.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd+2]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH2:31][O:32][CH3:33])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Under Argon, the solution of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (52 mg, 0.100 mmol), potassium methoxymethyltrifluoroborate (16.66 mg, 0.110 mmol), palladium(II) acetate (0.671 mg, 2.99 μmol), (2-DICYCLOHEXYLPHOSPHINO-2′,6′-DIISOPROPYL-1,1′-BIPHENYL)[2-(2-AMINOETHYL)PHENYL)]PALLADIUM(II) (4.36 mg, 5.98 μmol and cesium carbonate (0.024 ml, 0.299 mmol) in 1,4-Dioxane (0.9 ml) and Water (0.1 ml) was allowed to stir at 100° C. for 24 h. LC-MS showed the desired product's mass. EtOAc was added into the mixture and the organic layer was washed by water and brine. After drying over Na2SO4 the organic layer was evaporated under reduced pressure yielding 6-chloro-3-(methoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine, 52a. The intermediate was taken to the next reaction without further purification. MS ESI Calc'd for C27H22ClN3O [M+H]+ 440, found 440.