Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Clc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 2-chlorobenzothiazole (12.0 g, 70.7 mmol) in concentrated H2SO4 (60 mL) was added HNO3 (69% solution, 6 mL) dropwise at 0° C. for 20 min. The mixture was stirred at 5° C. for 3 h, poured into ice-water (150 mL). The precipitate was collected and washed with 5% sodium bicarbonate and water, dried in vacuo. 1H NMR analysis showed the mixture contained 78% 6-nitro-2-chlorobenzothiazole and 8% 5-nitro-2-chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72%). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150:15 mL), Iron powder was added in one portion. The mixture was refluxed for 1.5 h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10% NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was recrystallized from ethanol. Light purple crystals (2.5 g, 83%) were obtained. Mp 160-164° C.; TLC single spot at Rf 0.27 (30% EtOAc/hexane); 1HNMR (270 MHz, DMSO-d6) δ 7.58 (1H, d, J=9.0 Hz, 4-H), 7.03 (1H, d, J=2.0 Hz, 7-H), 6.77 (1H, dd, J=9.0, 2.0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the recrystallization of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-chlorobenzothiazol-5-yl-amine as yellow solid. Mp 146-149° C.; TLC single spot at Rf 0.52 (10% EtOAc/DCM); 1HNMR (270 MHz, DMSO-d6) δ 7.63 (1H, d, J=8.6 Hz, 7-H), 7.05 (1H, d, J=2.3 Hz, 4-H), 6.78 (1H, dd, J=8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:33]=[CH:32][C:13]([C:14]([C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:32]1[CH:33]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1
Reaction time: 8 h
Yield: 14 %

Procedure:
A mixture of m-aminophenol (0.64 g, 5.87 mmol), 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (2.0 g, 5.95 mmol), and anhydrous potassium carbonate (4.0 g) was stirred in dry dimethylsulfoxide (20 ml) at 120° C. under nitrogen for 48 hours. The cooled reaction mixture was poured into water and carefully neutralized with conc. hydrochloric acid to precipitate 2.58 g of a white solid. The crude product was digested in hot toluene, and the toluene solution (after decanting from a large quantity of gum) was allowed to stand overnight at 0° C. The crystals thus obtained were recrystallized to give 0.35 g of product, m.p. 144°-150° C. dec. (14%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:9]=[N:10][NH:8][C:7]=12
Reactant: O=N[O-]
Reactant: Cc1ccnc(Cl)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-chloro-4-methylpyridin-3-amine [133627-45-9] (3.0 g, 21.0 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.45 g, 21.0 mmol) in water (2.5 mL). The reaction mixture was stirred at rt for 15 min then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at rt for 3 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The insoluble solid was filtered off (dried under vacuum; batch 1) and the organic filtrate was washed with water and brine, then dried (Phase separator) and concentrated under vacuum (batch 2). The two batches were combined to give 7-chloro-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 153 [M+H]+, tR (HPLC conditions k): 0.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CO.C(O)C>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1

Procedure:
evaporation. The yield in that procedure is only 59% of crude product. Apart from the poor yield, the complicated aqueous work up is a disadvantage. In DE-OS (German Published Specification) 2,737,489, a procedure is described, according to which p-chlorobenzaldehyde is reacted with pinacolone in the presence of sodium hydroxide in methanol/ethanol at maximum temperatures of up to 25° C. 4,4-Dimethyl-1-(p-chlorophenyl)-1-penten-3-one is formed as a solid, has to be filtered off with suction and washed with further solvent. The required low temperature results in an inhomogeneous, partially solid reaction mixture, which can only be stirred with difficulty. Furthermore, molar amounts of sodium hydroxide have to be used. A further disadvantage is that the portions of the reaction product which remain in the mother liquor have to be isolated in an additional workup step. To hydrogenate the double bond, the pentenone is dissolved in ethyl acetate and reacted with about 26% by weight of Raney nickel and with hydrogen at atmospheric pressure and a reaction time of about 14 1/2 hours. The very large amount of catalyst and the very long reaction time are the crucial disadvantages of this process. In all known procedures, the condensation product of pinacolone and p-chlorobenzaldehyde has to be isolated and purified as a solid and is only then subjected to hydrogenation in a second separate operation.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.S(=O)(=O)(O)[OH:17]>O=[Mn]=O.O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:17])=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Agent: O=[Mn]=O
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 54 %

Procedure:
The procedure of Example 2 is used except that the 4,4'-difluorodiphenylmethane, water, and sulfuric acid are first mixed, then heated before the MnO2 is added. The yield is 54% 4,4'-difluorobenzophenone that is 95% pure.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(=O)([O-])[O-].[K+].[K+]>O>[N:12]1[NH:13][C:14](=[S:15])[N:16]=[C:2]2[C:4]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[NH:1]2
Reactant: NNC(N)=S
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: S=c1nc2[nH]c3ccccc3c2n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A mixture of 7.36 g (50.0 mmoles) of isatin, 250 ml of water, 5.01 g (55.0 mmoles) of thiosemicarbazide and 10.4 g (75.0 mmoles) of potassium carbonate was heated to reflux. After 30 minutes, a red solution resulted which was cooled to room temperature and filtered through celite. The pH was adjusted to 4.5 with glacial acetic acid and the resulting yellow solid was collected and washed with hot ethanol. After drying, 8.04 g of material was obtained. (J. Medicinal Chemistry, 15:277 (1972))
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
Amine preparation: a mixture of BOC-piperazine (1.87 g), ethyl 2-bromoisobutyrate (5.90 g) and potassium carbonate (1.53 g) in MeCN (20 mL) was heated in a sealed tube at 80° C. for 3 days. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.97 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2].[C:26](#[N:30])[CH2:27][C:28]#[N:29]>CCO.N1CCCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[C:27]([C:26]#[N:30])[C:28]#[N:29])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2]
Reactant: N#CCC#N
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1cc(C=C(C#N)C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D11a; 0.037 g, 0.104 mmol) in EtOH (10 mL) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred at room temp. for 2 h, then concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hex) to give 2-(2-ethyl-4-(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a yellow solid (0.012 g, 28%): mp 135-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:17]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butoxycarbonylpiperidin-4-ol (25 g, 0.124 mol) in 100 ml anhydrous THF was added to a suspension of sodium hydride (5.96 g, 0.15 mol, pentane washed) in 100 ml anhydrous THF at 0° C. The reaction was stirred at 0° C. for 1 hour, then treated with a solution of benzyl bromide (25.65 g, 0.15 mol) in 20 ml anhydrous THF. The reaction was allowed to stand for 20 h at room temperature, cooled to 0° C., and 50 ml water was added cautiously. The product was extracted using ethyl acetate, the combined organic extracts were washed with water, dried (MgSO4) and concentrated. Chromatography using petroleum ether→20% ethyl acetate-petroleum ether gave 4-benzyloxy-1-tert-butoxycarbonyl-piperidine as a colourless solid. δH (250 MHz, CDCl3) 1.45 (9H, s), 1.51-1.65 (2H, m), 1.80-1.94 (2H, m), 3.04-3.15 (2H, m), 3.51-3.61 (1H, m), 3.70-3.84 (2H, m), 4.56 (2H, m), 7.26-7.35 (5H, m). m/e (ES) 292.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[CH3:35].COC1C(S(C)CC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=CC(C)=C(C=1)OCC(O)=O>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[CH3:35])=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: COc1cc(OCC(=O)O)c(C)cc1[SH](C)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
Preparation of (3-Methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (compound 39A) The title compound was prepared in the manner analogous to Example 3A using (4-bromo-2-methyl-phenyl)-methanol and 4-(trifluoromethyl)benzeneboronic acid. MS m/z 249 (M-OH). Step 2. Preparation of 4chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (compound 39B) The title compound was prepared in the manner analogous to Example 3B using 39A. 400 MHz 1H NMR (DMSO-d6) δ 7.84 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.57 (s, 1H), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H). Step 3. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 39C) The title compound was prepared in the manner analogous to Example 1F using 1D and 39B. MS m/z 491 (M+1). Step 4. Preparation of [5-Methoxy-2-methyl-4-(methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 39) The title compound was prepared in the manner analogous to Example 1 using 39C. IR cm−1: 1740, 1322; 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8.1 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J=7.8 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.04 (s, 1H), 6.53 (s, 1H), 4.71 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+1). Anal. Calc'd for C25H23F3O4S.0.1 H2O; C, 62.78; H, 4.89; found: C, 62.57; H, 4.82.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 90.8 g (0.55 mol) of n-hexyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 125-128° C./0.5 Torr), yielding 100 g of 4-n-hexyloxyphenyl bromide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Si:36]([O:43][C@@H:44]1[CH2:49][C@@H:48]([OH:50])[CH2:47][N:46]([C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:45]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[C:61](O)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[C:61]([O:50][C@H:48]1[CH2:49][C@@H:44]([O:43][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:45][N:46]([C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:47]1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a stirring 0° C. solution of triphenylphosphine (1.2 equiv) in 23 mL of THF was added di-tert-butyl azodicarboxylate (1.2 equiv). The mixture was stirred at 0° C. for 10 minutes. Then a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (1.0 equiv) in 11 mL of THF was added and stirred for 20 minutes at 0° C. Benzoic acid (1.2 equiv) was then added and the reaction mixture was allowed to slowly warm to rt. After 16 hours the reaction mixture was concentrated in vacuo then diluted with EtOAc and washed with water then brine. The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:8) to yield (3S,5R)-benzyl 3-(benzoyloxy)-5-(tert-butyl-dimethylsilyloxy)piperidine-1-carboxylate (77%). LC/MS (m/z): 470.2 (MH+), HPLC Rt=6.05 min.
Reaction SMILES: [OH-:1].[Na+:2].CO.[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:17]([OH:20])([OH:19])=[O:18])([P:13]([OH:16])([OH:15])=[O:14])[OH:12])[CH:6]=1>O>[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:13]([O-:16])([OH:15])=[O:14])([P:17]([O-:19])([OH:20])=[O:18])[OH:12])[CH:6]=1.[OH2:1].[OH2:12].[OH2:12].[OH2:12].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac form 1) (38 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 19 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The solution was then evaporated to dryness to obtain 6.1 g (99%) of Zoledronate disodium crystal form XXV (LOD by TGA=7.4%). Purity by HPLC 99.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].N>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCN1
Agent: N
Solvent: CCOCC
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
20 g. of p-methoxybenzoyl chloride and 20 g. of 2-pyrrolidinone are boiled at reflux in 20 ml. of diethyl ether for 16 hours and then diethyl ether, ice and 2-N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)=[O:14]
Reactant: Brc1ccsc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sccc2Br)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
Treat a stirred, chilled (0° C.) solution of 3-bromothiophene (20 g, 0.123 mol) and dichloromethane (150 mL) with titanium tetrachloride in dichloromethane (184 mL, 1.0M) at such a rate as to maintain the temperature below 5° C. Add dropwise a solution of 4-methoxybenzoyl chloride (20.9 g, 0.123 mol) and dichloromethane (75 mL) at such a rate as to maintain the temperature below 5° C. Stir one hour at 0-5° C., then quench the reaction by addition of ice (100 mL) and 6N hydrochloric acid at such a rate that the internal temperature remains at or below 10° C. Add more water (100 mL), separate the organic phase, wash with water, dry (Na2SO4), filter and evaporate to an oil which solidifies. Recrystallize the solid from ether to afford the title compound as off-white crystals (19.7 g, 54%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a suspension of 24.9 g (100.4 mmol) of 4-iodobenzoic acid in 46.25 g (58.9 ml, 1.0 mol) of ethanol (100%) was added 3.0 ml of conc. sulfuric acid. The resulting mixture was refluxed for 60 minutes, and then distilled until a clear, homogeneous solution was obtained. The solution was allowed to cool to room temperature, partitioned between 250 ml of water and 250 ml of pentane, and the layers were separated. The aqueous phase was washed with 3×100 ml-portions of pentane. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to a dark yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil. PMR (CDCl3): d 1.39 (3H, t, J=7.2 Hz), 4.37 (2H, q, J=7.2 Hz), 7.73-7.82 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[Si:22]([O:29][NH2:30])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Si:22]([O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (31I, 366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588 mg, 4.0 mmol), Hg(OAC)2 (640 mg, 2.0 mmol) and toluene (5 mL) was heated at 100° C. for 2 h. The mixture was cooled to r.t. and filtered through celite. Filtrate concentrated and the resulting oily residue was triturated with dry methanol to afford a pale yellow solid. Filtered and dried to afford ((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (105a, 384 mg, 80%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s, 9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36, 4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td, J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C20H28BrFN5OSi, 480.12. found 480.30.
Reaction SMILES: N#N.[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCN(CC)CC>CN(C=O)C>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol) in dry DMF (25 mL) was added trimethylsilyl chloride (5.77 mL, 45.17 mmol) followed by Et3N (8.38 mL, 60.23 mmol) at rt. The reaction mixture was stirred at 80° C. for 24 h. The mixture was then cooled to rt, diluted with hexanes and washed with sat. aq. NaHCO3. The layers were separated and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 9:1) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil. Rf (Hexanes/EA, 9:1)=0.50.