Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:15][O:14][C:10]([C:11]1[S:12][C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[C:8]=1[NH2:9])=[O:13]
Reactant: COC(=O)CS
Reactant: N#Cc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2cccnc2c1N

Procedure:
To a solution of compound 145-C (23.41 g, 169.0 mmol) in acetonitrile (170 mL) was added methyl thioglycolate (16.2 mL, 178 mmol) and K2CO3 (46.72 g, 338 mmol). The mixture was heated under reflux for 3 h then filtered hot and the filter cake rinsed with acetonitrile. The filter cake was suspended in refluxing acetonitrile, filtered hot, and rinsed with additional acetonitrile. The combined filtrates were evaporated in vacuo, the residue triturated with warm water (250 mL), filtered, and rinsed with water. The solid was dissolved in warm methanol (500 mL), treated with charcoal, filtered, and evaporated in vacuo. The residue was triturated with ethanol (25 mL), filtered, washed with ethanol (25 mL), and dried in vacuo to afford compound 145-D as a brown powder (21.65 g, 62%). 1H-NMR (DMSO-d6): δ 3.83 (s, 3H), 6.91 (s, 2H), 7.52-7.59 (m, 1H), 8.40 (dd, 1H), 8.69 (dd, 1H); MS: m/z 209.1 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].C(O)(=O)C>C(OC(=O)C)(=O)C>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(O)c1cccc2ccccc12

Procedure:
128 g (1 mole) of naphthalene are dissolved in 102 g (1 mole) of acetic anhydride in an apparatus with a stirrer and a means for the supply of sulphuric acid, a dephlegmator, cooler and vacuum-receiver. Then 98 g (1 mole) of a 100% sulphuric acid are added to the solution of naphthalene in acetic anhydride for 60 minutes at a temperature of 60° C. The removal of the forming acetic acid is effected under vacuum under a residual pressure of 1 to 10 mm Hg. After discontinuation of distillation of acetic acid, i.e. on completion of the reaction of naphthalene sulphonation, there are obtained 208 g (1 mole) of naphthalene-α-sulphonic acid and 118 g (2 moles) of glacial acetic acid. The resulting naphthalene-α-sulphonic acid is poured to 224 g (4 moles) of a preliminary prepared melt of potassium hydroxide having a temperature of 180° C. under vigorous stirring. Then the melt temperature is raised to 285° C. for 5 minutes and the melt is maintained at this temperature for 5 minutes to complete the fusion process. On expiration of 10 minutes, the melt is cooled to a temperature of 80° C., diluted with 200 g of water and the resulting aqueous solution containing potassium α-naphtholate and potassium sulphite is supplied into a mixer provided with a cooling jacket, whereinto a solution of 98 g (1 mole) of sulphuric acid in 400 g of water has been preliminarily charged. Then the resulting mixture is cooled to a temperature of 10° C. and the precipitated α-naphthol is separated from the aqueous solution of the mixture of potassium sulphite, potassium sulphate and non-precipitated α-naphthol and β-naphthol by filtration. The yield of α-naphthol with a purity of 99.5% is 115 g (0.8 mole) as calculated for the employed naphthalene which corresponds to 80% of the theoretical value. The filtrate is treated with an equal volume of carbon tetrachloride and, after separation of the aqueous layer and distilling-off carbon tetrachloride, there are obtained 25 g (0.17 mole) of α-naphthol with a purity of 95%. The total yield of α-naphthol is 97% of the theoretical as calculated for the employed naphthalene.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O.[Na+].[Cl-].CCCCCC.CC(C)=O>CN(C=O)C.CC(C)=O.C(Cl)Cl>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in DMF (15 mL) was added distilled water (18 L, 1.0 mmol, 6 equiv.) and NaCl (10 mg, 0.18 mmol, 1 equiv.). The mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 40 min the reaction was shown to have reached 99.6% completion by HPLC peak area and a faint baseline spot on TLC (5% acetone/methylene chloride). The solution was cooled to room temperature after 60 min of reflux and solvent removed under reduced pressure. The residue was precipitated from methylene chloride-methanol to give methyl pyropheophorbide-a (60 mg, 67%).
Reaction SMILES: [H-].[Na+].O.[F:4][C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) is suspended in dry DMF (10 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice:water. To above suspension is added dropwise over 15 minutes (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 4 hours. The reaction mixture is poured into 300 ml of ice:water. The resultant solid is isolated by suction filtration, washed with water (500 ml), and air dried to yield 5.5 g (20 mmol, 83%) of the clean desired material as an yellow powder.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH2:5][CH2:4][C@H:2]2[OH:3]>ClCCl>[CH2:8]1[O:9][C@@H:1]2[O:7][C@H:6]1[CH:5]=[CH:4][C:2]2=[O:3]
Reactant: O[C@@H]1CC[C@H]2CO[C@@H]1O2
Solvent: ClCCl
Product: O=C1C=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thereafter, one part by weight of the 2-hydroxy dideoxy derivative (7) is dissolved in 10 to 50 parts by weight, preferably 20 parts by weight, of an organic solvent, preferably dichloromethane, thus forming a solution. 3 to 20 parts by weight of an oxidizing reagent, preferably 5 parts by weight thereof, is added to the solution thus prepared, thereby forming a mixture. This mixture is stirred at room temperature for 1 to 5 hours, thus causing a reaction in the mixture. Then, the oxidizing reagent is filtered off, and the solvent is distilled off under reduced pressure, whereby levoglucosenone (8) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([S:28][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
Under nitrogen atmosphere, to a mixture of methyl 2-chloro-3-nitrobenzoate (20.8 g, 96.5 mmol) and potassium carbonate (40.0 g, 289 mmol) in N,N-dimethylformamide (300 mL) was added benzyl mercaptan (11.5 mL, 98.0 mmol) at 0° C., and the mixture was stirred at 90° C. for 6 hr, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1→1/2) to give the title compound (28.5 g, yield 97%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:13][C:12]1[C:7]2[NH:6][C:3](=[O:4])[CH2:2][O:14][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1c(O)cccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(O)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
TEA (3.34 ml, 2 equiv.) and after chloroacetyl chloride (1.15 ml, 1.2 equiv.) were added dropwise to a solution of commercially available 2-aminobenzene-1,3-diol (1.5 g, 11.99 mmol) in 20 ml of DMF. After one hours of stirring at room temperature, K2CO3 (3.3 g, 2 equiv.) was added and the reaction was stirred at room temperature overnight. The solvent was evaporated and to the residue water was added. After filtration, the solid material was washed with MeOH and diethyl ether giving 410 mg of a grey solid. Yield=21% 1HNMR (DMSO, 200 MHz) δ 3.47 (1H, bs), 4.47 (2H, s), 6.44 (2H, m), 6.72 (1H, t, J=8 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1COc2cccc(O)c2N1
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A stirred solution of 2-aminobenzene-1,3-diol (2.0 g, 16.0 mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous DMF (30 mL) was treated with 2-chloroacetyl chloride (1.81 g, 16.0 mmol) and stirring continued for 16 h at room temperature, then K2CO3 (2.65 g, 19.2 mmol) was added and the mixture further stirred for 16 h at the same temperature. The reaction mixture was diluted with DCM (100 mL), washed twice with water and then with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatographic column of silicagel to give desired product (1.7 g, 64% yield) LCMS (m/z): 166.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C>O1CCOCC1.[Cu]I.CCOC(C)=O.CCCCCCC>[N:28]1[CH:27]=[C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=[N:30][CH:29]=1
Reactant: Brc1ccncn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cncnc4)c3n2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a flask was added 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (159 mg, 0.45 mmol), 4-Bromopyrimidine (87 mg, 0.55 mmol, commercially available [CAS 4595-59-9]), PdCl2(NCPh)2 (13 mg, 7 mol %), and CuI (10 mg, 12 mol %). The flask was charged with Ar, then 3 mL of dioxane (degassed with Ar), tri-(tert-butyl)phosphine (0.12 mL of a 0.25M soln in dioxane, 33 mol %), and diisopropylamine (0.15mL) were added. The r×n mixture was stirred at 23° C. under Ar overnight, then filtered through a pad of Si-gel, concentrated, purified by Si-gel chromatography (EtOAc/heptane 5-40:95-60) to give an orange solid. Recrytallization from EtOAc/heptane (1:2) yielded the product as an orange solid (131 mg, 68%). MS (ISP) 434.1[(M+H)+]; mp 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A stirred solution of 2-chloro-4-fluorobenzaldehyde (1.0 g, 6.3 mmol) in conc. sulphuric acid (8 ml) at 0° C. under argon was treated portionwise with potassium nitrate (0.70 g, 6.9 mmol) and maintained at 0° C. for 30 minutes, before warming to room temperature over 1.5 hrs. The reaction mixture was added to well stirred ice/water (100 ml) and then extracted with ethyl acetate. The extract was dried and concentrated to leave the title compound as a pale yellow oil (1.15 g, 90%).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:23][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH2:30]([NH:32][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[C:12]2[C:11]3=[C:16]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9][N:10]3[CH2:23][CH2:22][CH:21]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH3:31]
Reactant: O=C(O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCNC(=O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetic acid (16), (85 mg, 0.229 mmol) in dichloromethane (10 mL) were added Ethyl amine (0.015 mL, 0.229 mmol), EDCl (103 mg, 0.538 mmol), followed by HOBt (72 mg, 0.538 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 5% MeOH:CH2Cl2 to give N-ethyl-2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetamide (371), (27 mg, 29%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][NH:5][C:4]1=[O:7])[CH3:2].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].C(O)(=O)C.C(OO)(=O)C>C(Cl)Cl>[C:8]([O:11][CH:6]1[NH:5][C:4](=[O:7])[CH:3]1[CH2:1][CH3:2])(=[O:10])[CH3:9]
Reactant: CC(=O)[O-]
Reactant: CCC1CNC1=O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C(=O)NC1OC(C)=O
Temperature: -5 °C
Yield: 73.8 %

Procedure:
1.0 g of 3-ethylazetidine-2-one and 0.83 g of anhydrous sodium acetate were suspended in 20 ml of methylene chloride and cooled to -5° C., to which 0.35 g of ruthenium acetylacetonate complex was added. 3.8 ml of acetic acid solution containing 40% peracetic acid was dropped thereto carefully so as to maintain the temperature not higher than 0° C., followed by the procedures in Example 2 to obtain 1.17 g of the title compound (yield: 74.5%).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([F:13])[C:9](F)=[N:10][CH:11]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+]>O.C1COCC1.CN(C=O)C>[C:1]([NH:4][C:9]1[C:8]([F:13])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC(N)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, DMF (14 mL) and THF (44 mL) were added to acetamide (6.6 g, 112 mmol), and the mixture was warmed to 50° C. A 1.9 M sodium hexamethyldisilazide THF solution (51 mL, 96 mmol) was added dropwise thereto, and the mixture was stirred for 3 hours at the same temperature. 5-Chloro-2,3-difluoropyridine (7.0 g) was then added, THF (1.4 mL) was further added, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 0° C., an aqueous solution of citric acid monohydrate (20 g) and sodium chloride (4.9 g) in water (35 mL) was added, the mixture was warmed to room temperature, and the organic layer was separated. The organic layer was washed with a 20 wt % sodium chloride aqueous solution (35 mL), and the solvent was distilled off under reduced pressure. A mixed solvent (70 mL) of heptane and tert-butyl methyl ether (15:1) and water (35 mL) were added to the residue, and the mixture was stirred for 10 minutes at room temperature. The mixture was filtered, and the obtained solid was washed twice with water (35 mL). It was further washed with a mixed solvent (70 mL) of heptane and tert-butyl methyl ether (15:1), and dried under reduced pressure to obtain the title compound (6.5 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(Cl)Cl>O1CCCC1.CO>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=1)#[N:18]
Reactant: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5.85 g (25 mmole) of 4-azidomethyl-2'-cyanobiphenyl (from Example 15, Step A) in 50 ml of dry tetrahydrofuran was treated portionwise with 6.55 g (25 mmole) of triphenylphosphine over 3-4 minutes. The solution was stirred at ambient temperature under N2, and gas evolution proceeded at a moderate rate. A mild exotherm occurred, and the solution was cooled in a water bath as necessary. After 2 hours, by which time gas evolution had ceased, 675 μl (37.5 mmole ) of H2O was added, and stirring was continued at room temperature under N2. After 22 hours, the solution was concentrated in vacuo and the residual oil was chromatographed on a column of silica gel (gradient elution with 2-10% methanol in CH2Cl2). The residue from evaporation of the pooled product fractions was partitioned between ether-CH2Cl2 and saturated Na2CO3 (aqueous). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to yield 4.64 g (89%) of air-sensitive, nearly white crystals, mp 54°-55° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 209 (M+1)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:19][C:17]1[O:16][N:15]=[C:14]([CH3:13])[CH:18]=1
Reactant: BrCCCCCCBr
Reactant: Cc1cc(C)on1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(CCCCCCCBr)on1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 46.1 ml of diisopropylamine in 100 ml of tetrahydrofuran at 0°-5° C. was added 126 ml of 2.6M n-butyllithium in hexane over a period of about 20 minutes. The mixture was cooled to -50° C., 31.95 g of 3,5-dimethylisoxazole was added and the mixture stirred for 30 minutes. The latter mixture was cooled to -78° C. and 101.6 ml of 1,6-dibromohexane was added dropwise. After the addition was complete, the temperature of the reaction mixture was allowed to rise to room temperature and kept there for about 40 hours. Saturated aqueous ammonium chloride solution was then added and the mixture extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was distilled to remove excess dibromide (b.p. 50° C., 0.5 mm) and suspended in hexane. The suspension was decolorized with charcoal, filtered and cooled in a refrigerator overnight. The mixture was filtered and the filtrate concentrated in vacuo to give 57 g of 5-(7-bromoheptyl)-3-methylisoxazole as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:44](O)([CH3:47])([CH3:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:44]([O:21][C:20](=[O:22])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
2(R)-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid is reacted with t-butyl alcohol and dicyclohexyl carbodiimide (DCC) in 4-(dimethylamino) pyridine (DMAP) and tetrahydrofuran (THF) at room temperature to form 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C(O)C>[NH2:9][C:8]1[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: NNc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
Pivaloyl acetonitrile (30.0 g; 0.24 mole) and ethanol (200 ml) were placed into a 500 ml round bottom flask. Phenylhydrazine (23.6 ml; 0.24 mole) was added with stirring followed by acetic acid (13.8 ml). The reaction was refluxed for 5 hours. Part of the ethanol was stripped off and the residue was poured into ice water. The product was filtered off and washed with water. The solid was dissolved in hot ethanol (100 ml), diluted with water, stirred, filtered, and washed with water. The yield of solid, m.p. 65°-7° C. was 46.3 g (90%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21].CC(C)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
A solution of amorphous ibandronic acid (4.5 g) in water (11 ml) and sodium hydroxide (0.56 g, solid) was stirred at room temperature. The solution was added dropwise into acetone (100 ml). The resulting precipitate was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (2×10 ml), and dried in a vacuum oven at 50° C. for 24 hours to obtain 4.8 g of ibandronate sodium crystal form Q.