Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: CCCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Product: CCCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-propyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-propyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]2[C:12](=[CH:13][C:14]=1[CH:15]([CH2:21][CH3:22])C(OCC)=O)[C:11]1([O:26][CH2:25][CH2:24][O:23]1)[CH2:10][CH2:9]2)(=[O:3])C.O.[OH-].[Li+]>CO>[CH2:21]([CH:15]1[C:14]2[CH:13]=[C:12]3[N:8]([CH2:9][CH2:10][C:11]43[O:23][CH2:24][CH2:25][O:26]4)[C:7](=[O:27])[C:6]=2[CH2:5][O:4][C:1]1=[O:3])[CH3:22]
Reactant: CCOC(=O)C(CC)c1cc2n(c(=O)c1COC(C)=O)CCC21OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1C(=O)OCc2c1cc1n(c2=O)CCC12OCCO2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Dissolved in 15 ml of methanol was 759 mg of ethyl 6-[(acetoxy)methyl]-α-ethyl-1,1-(ethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolizine-7-acetate (V), followed by an addition of 5 ml of water and a further addition of 420 mg of lithium hydroxide (monohydrate). The resultant mixture was stirred at room temperature for 2 hours. After removal of methanol by distillation, the residue was added first with about 10 ml of ice water and then with 1.5 ml of acetic acid, followed by stirring at room temperature for 22 hours.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:10]4[CH2:14][CH2:13][CH2:12][NH:11]4)=[CH:4][CH:3]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Ic1ccc(NC[C@@H]2CCCN2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NC[C@@H]4CCCN4)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from (4-iodophenyl)-(S)-1-pyrrolidin-2-ylmethylamine and 5-(4-chlorophenyl)-2-ethynylpyridine. The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). The eluates were evaporated down in vacuo and the residue was neutralized with sat. aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM, dried over magnesium sulfate and evaporated down in vacuo. Yield: 35 mg (11% of theoretical); C24H22ClN3 (M=387.904); calc.: molpeak (M+H)+:388/390 (Cl); found: molpeak (M+H)+:388/390 (Cl); HPLC-MS: 5.0 minutes (method B).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:47])[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]1[C:39]([CH2:40]O)=[C:38]([CH3:42])[N:37]=[C:36]1[CH2:43][N:44]([CH3:46])[CH3:45].[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[F:34][C:32]1[CH:31]=[CH:30][C:29]([N:35]2[C:39]([CH2:40][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])=[C:38]([CH3:42])[N:37]=[C:36]2[CH2:43][N:44]([CH3:45])[CH3:46])=[C:28]([C:27](=[O:47])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2ccccc2Cl)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-fluoro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-fluoro-2-(o-chlorobenzoyl)-phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]-methyl]phthalimide.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].O.[NH2:15][NH2:16].O>C(O)(=O)C.O>[Br:1][C:2]1[C:3](=[O:4])[NH:15][NH:16][C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 100 °C

Procedure:
A mixture of bromomaleic anhydride (50 g, 283 mmol) and sodium acetate (76.5 g, 562 mmol) in 40% acetic acid/water (750 ml) was treated with hydrazine monohydrate (16.5 ml, 339 mmol) at room temperature under nitrogen. The brown solution was stirred and heated at 100° C. for 18 h. Upon cooling the mixture was poured into water (1 l) and extracted with ethyl acetate (6×500 ml). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title pyridazile (20 g, 37%) as an orange solid. 1H NMR (250 MHz, d6-DMSO) 7.68 (br s). MS (ES30 ) 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(=O)C.[OH-].[NH4+]>CO.O.[Zn]>[CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCOc2ccc([N+](=O)[O-])cc2C1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)N1CCOc2ccc(N)cc2C1
Reaction time: 3 h

Procedure:
To 4-isopropyl-7-nitro-2,3,4,5-tetrahydro-1,4-benzoxazepine (17.46 g) in methanol (1.5 1) was added acetic acid (36 ml) and zinc dust (36 g) portionwise, and the mixture was stirred for 3 h. The mixture was diluted with water (1 1), basified with conc. ammonium hydroxide (250 ml), and extracted with ethyl acetate (5×250 ml). The extracts were dried with magnesium sulfate, filtered and concentrated to an oil (11.34 g, 74%) which was used immediately in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH3:4].[Mg].I[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1>O1CCCC1.C1C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[CH:7][C:8]([CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: [Mg]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 1414.8 %

Procedure:
A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise at room temperature at a rate such that a gentle reflux was maintained to a suspension of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. The cloudy suspension was stored at room temperature for an additional 30 minutes to produce a gray solution that was then added dropwise over 15 minutes to a mixture of 1-iodo-4-bromobenzene (3.0 g, 10.6 mmol) and tetrakis (triphenylphosphine) palladium (0) in 50 mL of dry benzene at room temperature. The mixture was stirred for 2 hours, diluted with 50 mL of water, the organic layer was separated and the aqueous layer was extracted with ether (2×50 mL). The combined organic extracts were dried and evaporated to yield 1.69 g (80%) of a light brown oil, and used in the next step without further purification.
Reaction SMILES: C(O)(=[O:3])C.Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C@@H:14]([OH:25])[CH2:13]2)[N:7]=1.C([O-])(=O)C.[Na+]>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[C@H:14]([OH:25])[CH2:13][N:12]([C:8]3[N:9]=[CH:10][NH:11][C:6](=[O:3])[N:7]=3)[CH2:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: O[C@H]1CN(c2ncnc(Cl)n2)CC=C1c1ccc(F)cc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)[C@H](O)C2)nc[nH]1

Procedure:
To an acetic acid (1.6 mL)-water (0.30 mL) solution of (R)-1-(4-chloro-1,3,5-triazin-2-yl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-ol (155 mg, 0.505 mmol) synthesized in Reference Synthesis Example 332a, sodium acetate (155 mg, 1.89 mmol) was added and the resultant mixture was stirred at 90° C. for 2 hours. After completion of the reaction, water was added to the reaction solution and the resultant mixture was cooled to 0° C. The precipitated solid was collected by filtration and the solid was washed with water to obtain a compound (122 mg, yield 77%) of Reference Synthesis Example 333a as the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O.O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Temperature: 67.5 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
3,4-Dinitrobenzoic acid (1.000 Kg, 4.71 mol, 1.0 wt), tetrahydrofuran (10.00 L, 10.0 vol), and dimethyl for amide (0.010 L, 0.01 vol) were charged to a flask under nitrogen. Thionyl chloride (0.450 L, 6.16 mol, 0.45 vol) was added at 20 to 30° C. and the reaction mixture was heated to 65 to 70° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically in 3 hours. The reaction mixture was cooled to 0 to 5° C. and triethylamine (1.25 L, 8.97 mol, 1.25 vol) was added at 0 to 10° C. Morpholine (0.62 L, 7.07 mol, 0.62 vol) was charged to the reaction mixture at 0 to 10° C. and the slurry was stirred for 30 minutes at 0 to 110° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The reaction mixture was warmed to 15 to 20° C. and water (4.00 L, 4.0 vol) was added. This mixture was then charged to a 40 L flange flask containing water (21.00 L, 21.0 vol) at 15 to 25° C. to precipitate the product. The flask contents were cooled to and aged at 0 to 5° C. for 1 hour and the solids were collected by filtration. The filter-cake was washed with water (4×5.00 L, 4×5.0 vol) and the pH of the final wash was found to be pH 7. The wet filter-cake was analysed by 1H NMR for the presence of triethylamine hydrochloride. The filter-cake was dried at 40 to 45° C. under vacuum until the water content by KF<0.2% w/w, to yield (3,4-dinitrophenyl)-morpholin-4-yl-methanone (1.286 Kg, 97.0%, KF 0.069% w/w) as a yellow solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1[C:26]2[C:17](=[CH:18][C:19]3[C:24]([C:25]=2[C:27](Cl)=[O:28])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=1>>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]3[C:26]([C:25]=2[C:27]([N:10]2[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]2)=[O:28])=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:20]=[CH:21][CH:22]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Product: O=C(c1c2ccccc2cc2ccccc12)N1CCC(N2CCCCC2)CC1

Procedure:
Anthracen-9-yl-[1,4′]bipiperidinyl-1′-yl-methanone was prepared as a pale yellow powder from 4-piperidinopiperidine and anthracene-9-carbonyl chloride (Intermediate 3) by a procedure analogous to that described above for the preparation of Example 127.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)O)[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[F:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH:12]=[CH:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:26][N:25]([CH3:27])[CH2:24][CH2:23][C:6]1=2
Reactant: COc1ccc(C(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C=Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 5 °C

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: Br[C:2]([CH3:24])([CH3:23])[C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[OH:8])=[O:4].[H-].[Na+].O>CN(C)C=O>[CH:18]1([O:17][C:11]2[CH:10]=[C:9]([CH:7]3[O:8][C:2]([CH3:24])([CH3:23])[C:3](=[O:4])[NH:5][CH2:6]3)[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C(O)CNC(=O)C(C)(C)Br)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CNC(=O)C(C)(C)O2)cc1OC1CCCC1
Yield: 21.1 %

Procedure:
A crude product (1.03 g) of 2-(2-bromo-2-methylpropionamido)-1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol and sodium hydride (60%) (0.23 g) were stirred in dry dimethylformamide (40 ml) at room temperature for one night. Water was added to the reaction solution obtained and the solution was extracted with ethyl acetate. Next, the extract was washed several times with water and was dried over anhydrous sodium sulfate, then the solvent was evaporated in vacuo to obtain a crude product. The crude product obtained was purified by flash chromatography (SiO2: eluted with gradient of range from 33% ethyl acetate/hexane to 75% ethyl acetate/hexane) to obtain the above-described compound 0.17 g (yield 21.1%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=3[C:16]#[N:17])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH:21]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-[2-bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-4-chloro-benzonitrile (Intermediate AB) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light brown solid. tR: 7.83 min (HPLC 2); ESI-MS: tR=1.32 min, [M+H]+ 516/518 (LC-MS 1); TLC: Rf=0.26 (1:4 EtOAc/hexanes).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:15][C@H:16]3[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH:25]=[CH2:26].[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34]([N:19]2[CH2:20][C@H:16]([O:15][C:8]3[C:7]4[C:12](=[CH:13][C:4]([O:3][CH3:2])=[C:5]([CH:25]=[CH2:26])[CH:6]=4)[NH:11][C:10](=[O:14])[CH:9]=3)[CH2:17][C@H:18]2[C:21]([O:23][CH3:24])=[O:22])=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(=O)[nH]c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2cc(=O)[nH]c3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC)C1CCCCC1
Reaction time: 0.25 h
Yield: 119.9 %

Procedure:
To a solution of the product from Step 4, methyl (4R)-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinate hydrochloride (0.84 g, 2.206 mmol) and linker B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (0.689 g, 2.316 mmol) in DMF (2 mL) was added DIPEA (1.156 mL, 6.62 mmol) and HATU (1.090 g, 2.87 mmol). After 15 min, the reaction was complete and 1 N HCl and EtOAc were added. The organic layer was washed with water and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified on silica (gradient elution, 0-5% MeOH/DCM) to yield 1.65 g of material which still contained HATU residue. This was removed by extracting the material with EtOAc and 1N HCl (4×), water (1×) and brine (1×). The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 1.13 g (82%) of the title compound. LRMS ESI+(M+H)+ 624.6.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-].[Na+:18].O>CO>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:18].[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water in Methanol]. The reaction mixture was heated to reflux temperature for 22 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2×50 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (84%) of Zoledronate trisodium crystal form XI in a mixture with crystal form IX (LOD by TGA=10.5%).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[Na]>C(OCC)(=O)C.C(O)C>[C:9]1([CH:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)C(Br)c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A solution of 25.4 g (0.1 mole) of 1-bromo-1-phenyl-3,3-dimethyl-butan-2-one in 50 ml of ethyl acetate was added dropwise, at the boil, to a solution of 12.85 g (0.1 mole) of 4-chlorophenol and 2.3 g (0.1 mole) of sodium in 100 ml of ethanol. After boiling for 12 hours under reflux, the sodium bromide which had separated out was filtered off hot. The filtrate was distilled in vacuo and the solid residue which remained was recrystallized from ligroin. 20.2 g (67% of theory) of 1-phenyl-1-(4'-chlorophenoxy)-3,3-dimethyl-butan-2-one of melting point 103° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@H:6]1[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]2[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=2)[CH2:10][O:9][CH2:8][C@@H:7]1[O:29][CH2:30][CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[CH2:45]([O:47][CH2:48][C:49]([O:51][CH2:52]Cl)=[O:50])[CH3:46]>CC(C)=O>[CH2:45]([O:47][CH2:48][C:49]([O:51][CH2:52][O:25][C:24]1[C:19]([C:18](=[O:28])[NH:17][C@H:11]2[CH2:10][O:9][CH2:8][C@H:7]([O:29][CH2:30][CH:31]([CH3:32])[CH3:33])[C@@H:6]([O:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[CH:3]=3)[C@H:14]([CH3:15])[O:13][C:12]2=[O:16])=[N:20][CH:21]=[CH:22][C:23]=1[O:26][CH3:27])=[O:50])[CH3:46]
Reactant: CCOCC(=O)OCCl
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](Oc3cccc(Cl)c3)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOCC(=O)OCOc1c(OC)ccnc1C(=O)N[C@H]1COC[C@H](OCC(C)C)[C@@H](Oc2cccc(Cl)c2)[C@H](C)OC1=O
Temperature: 45 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a solution of N-((3S,7S,8S,9S)-8-(3-chlorophenoxy)-7-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (85 mg, 0.163 mmol) in acetone (2.0 mL) was added Na2CO3 (34.5 mg, 0.325 mmol), NaI (4.87 mg, 0.033 mmol), and chloromethyl 2-ethoxyacetate (37.2 mg, 0.244 mmol). The reaction was warmed to 45° C. and stirred for 16 h. The reaction was then concentrated and the residue purified by flash chromatography (SiO2; EtOAc/Hexanes) to give the title compound as a white foam (72.2 mg, 69.5%): 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.4 Hz, 1H), 7.17 (t, J=8.2 Hz, 1H), 7.04 (t, J=2.2 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H), 6.95-6.87 (m, 2H), 5.82 (s, 2H), 5.23-5.06 (m, 2H), 4.25 (t, J=9.1 Hz, 1H), 4.10 (s, 2H), 3.91 (s, 4H), 3.82 (dd, J=11.8, 5.3 Hz, 1H), 3.71 (dd, J=11.1, 7.4 Hz, 1H), 3.59 (q, J=7.0 Hz, 2H), 3.37 (ddd, J=8.9, 7.4, 1.6 Hz, 1H), 3.29 (dd, J=8.8, 6.3 Hz, 1H), 3.15 (dd, J=8.8, 6.4 Hz, 1H), 1.67-1.51 (m, 2H), 1.39 (d, J=6.3 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 0.68 (dd, J=18.4, 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.88, 170.06, 163.23, 160.17, 145.87, 143.98, 141.92, 134.59, 129.98, 121.38, 116.68, 114.41, 109.87, 89.44, 83.42, 82.64, 78.00, 74.36, 74.08, 72.30, 67.80, 67.20, 56.25, 52.32, 28.62, 19.16, 19.06, 18.72, 15.01; HRMS-FAB (m/z) [M+H]+ calcd for C30H39ClN2O11, 639.2315; found, 639.2320.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:13][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of methyl-2-(4-fluorobenzoyl)benzoate (5.31 g, 21 mmol) in 23 mL of DMF is added dropwise to a solution of NaH (0.91 g, 23 mmol) and imidazole (1.43 g, 21 mmol) in 35 mL of DMF. The resulting mixture is heated at 120° C. for 20 hours under N2. After cooling, the product is poured onto ice and extracted with CHCl3 (4×30 mL). The combined extracts are dried (Na2SO4) and evaporated to give crude product. Chromatographic purification of the crude residue on silica gel (using EtOAc as the eluent) gives pure methyl-2-[4(1H-imidazol-1-yl)benzoyl]benzoate. M.P. 134.5°-136.5° C.