Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C@@:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1>CO>[CH3:26][N:10]1[C@:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Solvent: CO
Product: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl (6R)-1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (10.0 g, 25.3 mmol) in MeOH (100 mL) at ambient temperature was added ceric ammonium nitrate (27.7 g, 50.6 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The resulting mixture was partitioned between H2O (500 mL) and EtOAc (1 L) and the organic layer was discarded. The aqueous layer was adjusted to pH=7-8 by addition of 1 N aqueous NaOH and extracted further with EtOAc (2×500 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 90:10, to give the title compound. MS: m/z=276.1 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1cccc2[nH]nc(I)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
A mixture of 3-iodo-1H-indazole-4-carbonitrile (3.0 g, 11.1 mmol), dihydropyran (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) under nitrogen in THF (40 mL) was heated at 85° C. overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (3.31 g, 84.0%). MS (ESI): m/z=354 [M+1]+.
Reaction SMILES: O1CCCC1.[NH2:6][CH:7]1[C:28](=[O:29])[N:9]2[C:10]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])=[C:11]([Cl:14])[CH2:12][S:13][C@H:8]12.Cl>[Fe].O>[NH2:6][CH:7]1[C:28](=[O:29])[N:9]2[C:10]([C:15]([OH:17])=[O:16])=[C:11]([Cl:14])[CH2:12][S:13][C@H:8]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h

Procedure:
To a mixture of tetrahydrofuran (120 ml) and water (25 ml), p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (10 gm) was added. Iron powder (10 gm) was charged at 30° C., followed by the addition of concentrated HCl (12.5 ml) in a tetrahydrofuran (10 ml) and water (2.5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring for 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried. Yield 4.17 gm (72.3%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Cl)[CH:16]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Product: COC(=O)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-pyrrolidine-2-carboxylic acid methyl ester has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as light yellow oil. MS: 299.2, 301.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S@:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:7]1[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=[C:8]1[S@:10]([CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1)=[O:11])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution (10 mL) of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.34 g) synthesized by the method described in Synthetic Example 1 of Japanese Patent Application under PCT laid-open under kohyo No. 10-504290 in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at 60° C. for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.C1COCC1.[OH-].[K+:29]>CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@H]32)O1.C1COCC1>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[K+:29]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1

Procedure:
A 20 mL scintillation vial was loaded with 556.8 mg (1.641 mmols) of topiramate (Cheminor Drugs Ltd., Hyderabad, India, Batch TP001.J00) and 1 mL THF (Sigma, St. Louis, Mo. USA, 99.0+%, Lot 50k1485), and all of the topiramate dissolved. 89.9 mg (1.602 mmols) of solid KOH (Spectrum, Lot PN0690) was dissolved in the topiramate/THF solution. The solution was allowed to evaporate overnight at room temperature leaving an amorphous solid. The solid was further dried by placing it in a vacuum desiccator I white brittle solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26].CO.O.O.[OH-].[Li+]>CCCCCC.C(OCC)(=O)C>[F:26][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure J and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid methyl ester (Compound 14, 0.18 g, 0.48 mmol), methanol (4 mL), tetrahydroluran (8 mL), water (2 mL) and lithium hydroxide monohydrate (0.2 g, 4.76 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 50-100% ethyl acetate in hexane as the eluent, the title compound was obtained as a dirty white solid (0.068 g, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCc1ccccc1
Reactant: COc1cc(C)cc(OC)c1
Product: COc1cc(C)cc(OC)c1CCCCc1ccccc1
Yield: 1347.9 %

Procedure:
3,5-Dimethoxytoluene (2.93 mL, 20 mmol) and 4-phenylbutylbromide (4.13 mL, 1.2 mmol) were reacted as described under General Procedure H and the crude product was purified by flash chromatography (silica-gel, petroleum ether/EtOAc 200:1) to afford the product as a clear oil (4.6 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.13-7.22 (m, 5H), 6.34 (s, 2H), 3.76 (s, 6H), 2.60-2.64 (m, 4H), 2.31 (s, 3H), 1.53-1.67 (m, 4H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11]>C(O)(=O)C>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: Oc1c(F)cccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
Bromine (13.54 g, 0.0846 mol) dissolved in acetic acid (40 mL) was added drop by drop to a cooled solution of 2,6-difluorophenol (20 g, 0.153 mol) in acetic acid (80 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bisulfite solution and then extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 4-bromo-2,6-difluorophenol (21 g) as a yellow liquid. This was employed directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[CH3:30][C@@H:26]1[N:27]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH2:25]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (350 mL) were added K2CO3 (14 g, 104 mmol) and (3S)-tert-butyl-3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol). The mixture was stirred at 65° C. overnight and then after cooling to room temperature, poured into water (700 mL). The solid precipitate was collected and dried under vacuum. It was further purified on a flash column eluting with 20:1 petroleum ether/ethyl acetate and then with CH2Cl2 to give 105a as a yellow solid (8.05 g, 50%). LCMS: [M+H]+ 323
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Na+:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+:31]
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1

Procedure:
Ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (204.7 g) was dissolved in ethanol (1.5 L) and stirred under nitrogen at reflux until all the starting material is in solution. 2M Sodium hydroxide (355 ml) was added and the solution heated under reflux for 1 hr 10 minutes. HPLC showed that there was no residual starting material. The solution was filtered and the filter washed with a ˜1:1 mixture of hot ethanol (515 ml) and water (520 ml). The combined filtrate and wash were re-heated to reflux, and water (1.5 L) was added slowly over 5 minutes. The solution was then cooled to 20+/−5° C. over 2 hours and stirred for 1 hour. The product was then filtered off and washed with ethanol:water (1:1, 1030 ml), then ethanol:water (˜1:3; 385 ml ethanol:1.15 L water). The resulting solid was dried to a constant weight at 60° C. under vacuum, to give the title compound. (186 g).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1.Cl.[Cl-].[Na+]>CO.C(OCC)(=O)C>[F:16][CH:4]([F:3])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2 N sodium hydroxide solution (3.74 mL) was added to a solution of methyl 5-difluoromethoxypyridine-2-carboxylate obtained in Preparation Example 49-(1) (760 mg) in methanol (15 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was made acidic with hydrochloric acid. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (482 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([Br:26])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Temperature: 85 °C

Procedure:
200 mg of 4-(3-Chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (178) were dissolved in 5 ml of CH3CN and heated to 85° C. Then a mixture of 148 mg of N-bromosuccinimide and 9 mg of AIBN was added as solid and the resulting mixture was heated to reflux for 1 h. The solvent was removed in vacuo and the residue subjected to flash column chromatography. The yield of the isolated product was 41%
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=3F)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:35][CH2:36][O:37][C:19]2=[CH:18][CH:17]=1.O>C1COCC1.[Cl-].[Na+].O>[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=3[O:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:35][CH2:36][O:37][C:19]2=[CH:18][CH:17]=1
Reactant: OC1CCOCC1
Reactant: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of potassium tert-butoxide (5.42 g) and THF (30 ml) was added to a solution of 4-hydroxytetrahydropyran (1.53 ml) in THF (30 ml) and the resultant mixture was stirred for 20 minutes. A slurry of 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (6 g) in THF (30 ml) was added and the resultant mixture was heated to reflux for 1.75 hours. A second portion (1.81 g) of potassium tert-butoxide was added and the mixture was heated to reflux for an additional 2 hours. A second portion (0.15 ml) of 4-hydroxytetrahydropyran and a third portion (0.45 g) of potassium tert-butoxide were added and the mixture was heated to reflux for 0.5 hours. A fourth portion (0.9 g) of potassium tert-butoxide was added and the mixture was heated to reflux for a further 20 minutes. The resultant reaction mixture was allowed to cool to 50° C. and brine (60 ml) and water (30 ml) were added in turn. The layers were separated and the aqueous solution was extracted in turn with THF (30 ml) and with isopropyl acetate (30 ml). The organic extracts were combined and washed with brine (30 ml). The organic solution was evaporated. The residual solid was stirred for 1 hour under a mixture of methyl tert-butyl ether (24 ml) and isohexane (12 ml). The solid was isolated, washed with a 1:1 mixture of methyl tert-butyl ether and isohexane and dried in vacuo overnight at 40° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (5.02 g, 93% HPLC purity using Method A, retention time 4.61 minutes). A portion (3 g) of the material so obtained was dissolved in hot ethyl acetate (54 ml). The hot solution was filtered. The filtrate was allowed to cool to ambient temperature and was stirred for 3 hours. The resultant solid was isolated by filtration, and dried in vacuo at ambient temperature. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (1.61 g, 99.2% HPLC purity using Method A, retention time 4.51 minutes); NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].C(O)(=O)CC.[C:10](#[N:12])[CH3:11]>>[NH2:12][C:10]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH3:11]
Reactant: CC#N
Reactant: OP(O)O
Solvent: CCC(=O)O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Yield: 85 %

Procedure:
Into a reactor similar to the above were charged 174 g phosphorous acid and 92 g propionic acid. 41.5 g acetonitrile was introduced slowly for 72 minutes at 135°-140° C. into the agitated mixture which was maintained for an additional 10 hours at that temperature. The 1-aminoethane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the same manner as described in Example 1. The yield was 85% of the theory calculated on the acetonitrile employed.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].Cl[C:8](=[CH2:11])[C:9]#[N:10].CC([O-])=O.[Na+]>C(O)C>[C:1]([N:5]1[CH:11]=[CH:8][C:9]([NH2:10])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ccc(N)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
A mixture of tert-butylhydrazine (2.4 g, 27 mmol), 2-chloroacrylonitrile (2.9 g, 33 mmol), NaOAc (3.17 g, 38 mmol) and ethanol (30 mL) was heated to 80° C. with stirring for 12 h. The solvent was removed in vacuo and the resulting mixture was treated with saturated NaHCO3 solution (200 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were dried over NaSO4, concentrated in vacuo, purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1 to 1:2) to give 1-tert-butyl-1H-pyrazol-3-amine (1.39 g, 37%) as a brown oil. LC-MS: [M+H]+, 140.2, tR=0.696 min.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
100 g of crude methyl cinnamate and 926.8 g of 2.8% caustic soda were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. Furthermore, 1 g of powdery active carbon (trade name PMSX, made by Toyo Calgon Inc.) was added, and the solution was stirred for 30 minutes and then filtered at 80° C. by the use of Nutsche. The resultant filtrate was placed in a 2-liter flask equipped with a thermometer and a stirrer and then maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 86.0 g of cinnamic acid. The purity of cinnamic acid was 98.8%, and the content of each of palladium, copper and manganese was 5 ppm or less. The recovered active carbon was dried, and metallic components were then measured. As a result, the contents of palladium, copper and manganese were 990 ppm, 8.5% and 5.7%, respectively. In the filtrate and the washing solution with which cinnamic acid had been washed, metallic components of palladium, copper and manganese were each contained in an amount of 5 ppm or less.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1O)[C:20]([O:22][CH3:23])=[O:21]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5.5 ml of trifluoromethanesulphonic anhydride (33 mmol) are slowly added dropwise to a solution of 5.49 g methyl 3-chloro-4-hydroxy-benzoate (29.4 mmol) in 15 ml of pyridine at 0° C. After the reaction mixture has been stirred at 0° C. for 5 minutes and at room temperature for 4 hours, it is partitioned between water and ether. The organic phase is washed in succession with water, dilute hydrochloric acid, water and saturated sodium chloride. solution, dried over sodium sulphate and concentrated and the residue is chromatographed over silica gel using methylene chloride to give 8.93 g of a pale yellow thinly mobile oil [95.2% of theory, Rf 0.63 (hexane:ethyl acetate=3:1)].