Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]([CH2:15][CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F-].[K+].Br[CH2:32][CH2:33]Br.O>CN(C)C=O>[CH2:32]1[CH2:33][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[N:14]([CH2:15][CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11](=[N:19][C:20]4[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=4[CH3:28])[CH:10]=3)=[CH:3][C:2]=2[O:1]1
Reactant: BrCCBr
Reactant: CCn1c(-c2ccc(O)c(O)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc3c(c2)OCCO3)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dihydroxyphenyl)--ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (1.0 g) in dimethylformamide (30 ml) were added spray-dried potassium fluoride (0.77 g) and 1,2-dibromoethane (0.25 ml). The mixture was stirred at 110° C. for 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel and eluted with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure to give 3,4-dihydro-6-(3,4-ethylenedioxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.3 g).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12]([O:17]CC)(=[O:16])[C:13]([CH3:15])=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]([CH3:15])[C:12]([OH:17])=[O:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)CC1CCCC(=O)C1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
The process according to claim 8, by which 3-isobutyl-cyclohexanone and ethyl pyruvate are condensed without solvent and the condensate formed is heated at 220°-230° C. to give p-isobutyl-hydratropic acid.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O>[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:1])[N:5]=1
Reactant: Oc1cccnc1Cl
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Oc1ccc(I)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (2.38 mL, 46.3 mmol) was added to a solution of 2-chloro-3-pyridinol (5.00 g, 38.6 mmol) in water (60 mL) containing potassium carbonate (18.7 g, 135 mmol). The resulting solution was allowed to stir for 2 h at room temperature. The mixture was treated with sodium thiosulfate, acidified to pH 2 using 12M aqueous HCl, and extracted with EtOAc. The organic phase was dried over MgSO4 and evaporated. Purification by flash chromatography using EtOAc/hexanes gave 2-chloro-6-iodopyridin-3-ol. 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (d, J=8.2 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H). MS (ESI) m/z: Calculated; 254.9 Observed: 255.8 (M++1).
Reaction SMILES: C([N:8]1[C:12]2[C:13]([N:19]([CH3:21])[CH3:20])=[N:14][N:15]([CH3:18])[C:16](=[O:17])[C:11]=2[N:10]=[C:9]1[N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)C1C=CC=CC=1.N.[Li].[Cl-].[NH4+]>O1CCCC1>[CH3:21][N:19]([CH3:20])[C:13]1[C:12]2[NH:8][C:9]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]3)=[N:10][C:11]=2[C:16](=[O:17])[N:15]([CH3:18])[N:14]=1
Reactant: CN(C)c1nn(C)c(=O)c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(Cc3ccccc3)c12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: CN(C)c1nn(C)c(=O)c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c12
Yield: 7.4 %

Procedure:
A 5 ml tetrahydrofuran solution of 0.117 g of t-butyl 4-[1-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate was added to 15 ml of liquid ammonia, and 0.009 g of lithium was added to the mixture under reflux. 1 ml of a 5% aqueous ammonium chloride solution was added to the solution, and the solvent was evaporated off. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.007 g of the title compound.
Reaction SMILES: CC1(C)N=NN=N1.C(=O)=O.CC(C)=O.C([Li])CCC.[CH3:20][N:21]1[C:25]([CH3:26])=[N:24][N:23]=[N:22]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.Cl>[CH3:20][N:21]1[C:25]([CH2:26][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][N:23]=[N:22]1
Reactant: CCOC(=O)Cl
Reactant: Cc1nnnn1C
Agent: CC1(C)N=NN=N1
Agent: Cl
Agent: O=C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nnnn1C
Reaction time: 0.67 h

Procedure:
To a solution of 1,5-=dimethyltetrazole (10 g) in 100 mL of dry tetrahydrofuran and 20 mL of hexamethylphosphoramide at -78° C. (dry ice-acetone) under an argon atmosphere was added dropwise 50 mL (1.2 equivalent) of n-butyllithium (2.5M in hexane). The deprotonation of 1,5-dimethyltetrazole was allowed to proceed at -78° C. for 40 minutes, then at -20° C. for 30 minutes. The anion solution was rechilled to -78° C. and transferred via a cannula over a period of 45 minutes into a cold (-78° C.) solution containing 12 mL of ethyl chloroformate in 50 mL of tetrahydrofuran. The reaction mixture was diluted with aqueous 2N HCl and saturate aqueous solution of sodium chloride and then extracted with ethyl acetate. The residue from the organic extract was purified by silica gel flash chromatography. The appropriate fractions were combined and evaporated to give 4 g of product. The product was further purified by crystallization from ethyl acetate-hexanes to yield 3.52 g (21%) of the title compound; m.p.=64°-66° C.
Reaction SMILES: C([O:10][C:11](=[O:48])[C@H:12]([C@@H:21]([CH3:47])[O:22][C:23](=[O:46])[C@H:24]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[N:25]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH3:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C(C1C=CC=CC=1)=O>CC(O)=O.[Zn]>[CH2:30]([O:29][C:27]([N:25]([CH3:26])[C@H:24]([C:23]([O:22][C@H:21]([CH3:47])[C@@H:12]([C:11]([OH:48])=[O:10])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:46])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)OCc2ccccc2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)N(C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a homogeneous solution of D2 (24.49 g, 38.4 mmol) in aq AcOH (211 ml, 90%) at 0° C., powdered Zn was added (18.65 g, 288.3 mmol). The resulting mixture was stirred at 0° C. for 3 h until disappearance of the starting material (followed by TLC), The reaction mixture was filtered over celite and washing with EtOAc (200 ml). The filtrate was concentrated at reduced pressure and the residue was chased with Et2O (200 ml) and filtered. The filtrate was successively partitioned between aq KHSO4(100 ml, 10%) and brine (100 ml). The organic phase was dried (Na2SO4) and concentrated to give an oil which was purified by flash LC (Lichroprep RPC18, ACN:H2O 1:1 (800 ml, then 7.3 (600 ml)] to yield D1 (15.53 g, 74%) as a white solid. [α]D24 −27.6 (c 2.187, DCM); lit [α]D −20.5 (c 2, DCM), JOC, 62, 2, 1997. Rf=0.58 [ACN/H2O (7:3)].
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:10])[CH3:11])[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: CC(C)(C)c1nc(C=O)c(Cl)c(N)c1F
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)c1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-6-(tert-butyl)-3-chloro-5-fluoropicolinaldehyde (316 mg, 1.370 mmol) and t-butanol (6.85 mL). The mixture was treated with H2O (2.283 mL), 2-methylbut-2-ene (1.1 mL, 1.370 mmol), sodium hydrogenphosphate (389 mg, 2.74 mmol). Finally, sodium chlorite (372 mg, 4.11 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream colored solid. The crude material was stirred with Et2O (˜5 mL). After stiffing for ˜3 h the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, >99%) was isolated as a white solid: mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.97 (s, 2H), 1.41 (d, J=1.5 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −132.92; 13C NMR (101 MHz, CDCl3) δ 161.62, 151.12, 149.21, 146.63, 141.58, 117.18, 36.69, 28.37.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][CH:7]=[CH:6]2.C1(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.O1CCOCC1>[N:36]([CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][CH:7]=[CH:6]2)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1nccc2cc(CO)ccc12)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: [N-]=[N+]=NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1

Procedure:
To 6.3 g of N-[6-(hydroxymethyl)-1-isoquinolinyl]benzamide (1 g) in 40 mL of toluene and 40 mL of dioxane at 0° C. 7.8 mL of diphenylphosphoryl azide (DDPA) and 5.4 mL of 1,8-diazabicyclo(5.4.0)undec-7ene (DBU) were added. After 24 hours the reaction mixture was poured into water (pH 7) and extracted with ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated. Trituration with diethyl ether gave 6.4 g of the title compound. Mp. 125-129° C. MS (m/e)=303.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH:17]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][C:40](=O)[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=3[CH:49]=2)=[CH:12][CH:11]=1)=O.B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[O:4][CH2:5][CH2:6][NH:7][CH2:8][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][CH:17]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=3[CH:49]=2)=[CH:12][CH:11]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)NCCOc4cc(F)ccc4F)cc3)cc21
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: NCCO
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CNCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
The solution of 0.440 g of benzyl 4-{4-[2-(2,5-difluorophenoxy)ethylcarbamoyl]phenyl}-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 2.0 ml of tetrahydrofuran is admixed with 13.6 ml of 9-BBN (0.5M in tetrahydrofuran) and stirred at reflux over 18 hours. The reaction mixture is cooled, admixed with 0.412 ml of ethanolamine and concentrated by evaporation. The residue is stirred at 0° C. in 40 ml of EtOAc-heptane (1:1) overnight and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (1:3 EtOAc-heptane); Rt=4.76.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>CC(O)C>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: CC(C)O
Product: O=C[O-]
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
To a mechanically stirred suspension of O-desmethylvenlafaxine (200.0 g, 0.759 mol in 2-propanol (1000 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (40 ml, d=1.22, 46.85 g, 1.018 mol., 1.34 molar excess) over a period of 1 hour. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL). The filtrate and washings (temperature 48–49° C.) were stirred slowly under a nitrogen atmosphere and allowed to cool to 45° C. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool at a rate of about 1° C. per 4 minutes. The solution became cloudy at 40.5° C. The stirred, cloudy solution was allowed to cool to 34–35° C., then maintained at that temperature for a period of 1.5 hours. Most of the product crystallized during this period. The stirred slurry of crystals was allowed to cool to 25° C. over a period of 1 hour and then cooled in an ice bath over a period of 1 hour to 5–10° C. The slurry was chilled to −10° C. in 40 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (0 to −10° C.) acetone (3×400 mL). Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours) furnished 203.1 g (86%) of the product, O-desmethylvenlafaxine formate. The product had a mp=145–147° C. and residue on ignition 0.1% (as sulfated ash). It was characterized by DSC (sharp endotherm at 151.8° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:10]1([S:16]([O:1][CH2:2][C:3]([CH2:8][O:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])([CH2:6][O:7][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH2:4][O:5][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC(CO)(CO)CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(OCC(COS(=O)(=O)c1ccccc1)(COS(=O)(=O)c1ccccc1)COS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 3 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
2.27 g (16.7 mmol) of pentaerythritol and 32.6 g of pyridine were placed in a 100 ml reaction vessel and 17.7 g (100 mmol) of benzenesulfonyl chloride was dropped over 0.7 hour while stirring at a temperature of 2 to 4° C. in a nitrogen atmosphere. After dropping, the temperature was raised to 15° C. and reaction was conducted for 4 hours. In a separate 300 ml reaction vessel, the reaction solution was dropped in an 11.3% by weight aqueous solution of hydrochloric acid while stirring at a temperature of 10 to 23° C. After dropping, the water phase was separated. The crystal precipitated by dissolving the oily matter by heating in 48 g of a mixed solution of acetone:methanol (weight ratio 3:1) and then concentrating was separated by filtration, washed and dried under reduced pressure to obtain 9.08 g of 2,2-bis(benzenesulfonyloxymethyl)-1,3-propanediol dibenzenesulfonate (yield: 78.0% [based on pentaerythritol]).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)C=O.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=1>C(OCC)(=O)C>[N+:31]([C:23]1[CH:22]=[C:21]([CH2:20][S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])([O-:33])=[O:32]
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
1.01 g of potassium carbonate and 0.39 mL of thiophenol were added to 10 mL of N,N-dimethylformamide solution containing 1.00 g of methyl 4-(bromomethyl)-2-nitrobenzoate at room temperature and stirred at the same temperature for 7 hours. Ethyl acetate was added to the reaction mixture and insoluble were removed by filtration and water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to obtain 0.70 g of methyl 2-nitro-4-((phenylthio)methyl)benzoate as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([S:12]([NH2:13])(=[O:14])=[O:15])=[C:9]([F:11])[CH:10]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)c(Cl)cc1F
Reaction time: 12 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-sulfamoylbenzoic acid (3.2 g, 12.65 mmol) in THF (10 mL) was added 1M BH3 THF (38 mL, 38.0 mmol). After stirring 12 h, the reaction mixture was quenched with MeOH and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc-Hex) to afford 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.9 g). To a suspension of 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.78 g, 7.43 mmol) in DCM (10 mL) was added PBr3 (2.21 g, 8.17 mmol). The reaction was stirred for 24 h when it was determined to be complete by GCMS. The reaction was carefully quenched with H2O and then partitioned between THF and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (1.98 g) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.08 (d, J=7.8 Hz, 1H), 7.84 (s, 2H), 7.80 (d, J=9.9 Hz, 1H), 4.83 (s, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:26])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:26][C:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: COc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2cc(C3(O)CCNCC3)ccc2c1
Yield: 85.8 %

Procedure:
A mixture of 1.0 gm (2.9 mMol) 1-benzyl-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine and 5% palladium on carbon in 20 mL methanol was stirred at room temperature under about 1 atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through a bed of CELITE and the filtrate was concentrated under reduced pressure to provide 0.64 gm (86%) of the desired compound as a white foam. A portion of the material was converted to the oxalate salt for analysis.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].OS(O)(=O)=O>C(O)CCCCC>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:8][CH2:7][CH2:6][CH2:14][CH2:13][CH3:12])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 75 °C
Yield: 181.7 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are dissolved in 40 ml of n-hexanol, 108 mg (1.05 mmol) of concentrated H2SO4 are added and the mixture is heated at 75° C. for 2 hours. The reaction mixture is cooled to room temperature and the product is filtered off with suction. Washing with hexanol and drying gives 5.8 g (19.8 mmol; 91%) of carbohexoxymethylene-4-chloro-anthranilic acid as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:19]([O:1][CH2:2][C@H:3]1[C@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1OCC=C[C@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@H]1O
Temperature: 0 °C

Procedure:
To a 0° C., stirred solution of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (OA g, 2.84 mmol) in CH2Cl2 (40 ml) under an Argon atmosphere was added imidazole (0.231 g, 3.4 mmol) followed by TBSCl (0.428 g, 3.4 mmol). The resulting mixture was stirred for 1H at 0° C. The reaction mixture was washed with water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4 The solvent was removed in vacuo and the crude product purified by flash chromatography (25-40% EtOAc in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)Cc3ccccc3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(Cc4ccccc4)n3n2)cc1
Yield: 52.1 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylacetamide (Intermediate 66) (90 mg, 0.25 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(phenylmethyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 346 (M+1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:10][CH:11]1[CH:15]([CH3:16])[C:14](=[O:17])[O:13][S:12]1(=[O:19])=[O:18]>>[C:1]([O:6][CH2:7][CH2:8][O:9][C:14](=[O:17])[CH:15]([CH3:16])[CH:11]([S:12]([OH:19])(=[O:18])=[O:13])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1C(=O)OS(=O)(=O)C1C
Reactant: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OCCOC(=O)C(C)C(C)S(=O)(=O)O
Yield: 70 %

Procedure:
By procedure 9)a) above, β-hydroxyethyl methacrylate is reacted with an equimolar amount of 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide. There is obtained a 70% yield of methacryloxyethyl-2-methyl-3-sulfo-butyrate.