Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:11])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:2][CH3:3].[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1>>[C:1](=[O:11])([O:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Oc1ccccc1
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
A mixture of 75 g/h of methyl phenyl carbonate, 175 g/h of phenol and 3 g/h of octylstannonic acid was continuously fed into this reactor at the feeding point above the sieve-point column. At the same time, a gentle nitrogen stream of 2 [1.h-1 ] from the spiral tube evaporator was passed in the opposite direction to this starting material stream. After establishment of constant conditions, at the head of the apparatus, 195 g/h of a mixture of 2.2% by weight of methanol, 13.7% by weight of dimethyl carbonate and 84.1% by weight of phenol were continuously withdrawn, and at the foot of the column, 61 g/h of a mixture of 1.5% by weight of phenol, 0.9% by weight of methyl phenyl carbonate and 97.6% by weight of diphenyl carbonate were continuously withdrawn. This represented a space-time yield for the formation of diphenyl carbonate of 0.06 g/mlh, based on the reactor volume. 18.6% of the methyl phenyl carbonate used reacted with phenol, transesterifying to form diphenyl carbonate. The selectivity of the formation of diphenyl carbonate was >99.9%, that is no by-products could be detected.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])(=O)=O.[I-:15].[Na+].O>CC(C)=O>[CH3:10][C:9]([N+:11]([O-:13])=[O:12])([CH3:14])[CH2:8][CH2:7][CH2:6][I:15]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-Methyl-4-nitropentanol methanesulfonate (3.38 g, 15 mmol) was dissolved in acetone (50 ml) and sodium iodide (8.7 g, 58 mmol) was added. The mixture was stirred overnight. Water (20 ml) was added and acetone was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (50 ml). The extract was washed with 5% aqueous sodium thiosulfate solution (20 ml) and saturated brine (20 ml), and ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (3.84 g, yield 99.6%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O>C(O)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Yield: 48.2 %

Procedure:
A solution of 2-aminothiazole (50 g, 499.301 mmol), ethyl acetoacetate (96 ml, 748.885 mmol) and acetic acid (400 ml) was reacted together according to the procedure described in Intermediate 3, Step 1 to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 40 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:50])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[CH:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:22]2=[O:49])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(OC(=O)/C=C\C)C2C=CC=CC=2)C=CC=CC=1.N12CCCCC1C=NCCC2>O1CCCC1.C1C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([CH:16]2[N:21]3[C:22](=[O:49])[C@@H:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:50])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C/C=C\C(=O)OC(c1ccccc1)c1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 367 mg (0.5 mM) of a mixture consisting of 2-[4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1.0 mM) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 10 ml of dry tetrahydrofurane is stirred for 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulphate and freed from the solvent in vacuo. The residue is chromatographed on acid-washed silica gel, using toluene/ethyl acetate, 7:1, as the running agent, whereby pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester is obtained. Subsequent elution with toluene/ethyl acetate, 2:1, results in the isolation of a mixture which in addition to 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester also contains 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.B.CSC.Cl>O1CCCC1>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing, borane-methyl sulfide complex (15.1 ml of M solution, 151.0 mmol) was added drop-wise over 0.25 hours. The solution was warmed to room temperature and then heated at reflux for 4 h. A white precipitate formed during the reflux. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 mL) was added over 15 min and the solution stirred at room temperature for 2 h. The precipitate dissolved and the solvent was concentrated in vacuo to a volume of approximately 200 mL. The solution was poured into ethyl acetate (300 mL) and washed with water (2×200 mL), saturated sodium bicarbonate (2×200 mL), and saturated ammonium chloride (2×200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzyl alcohol was isolated as a white solid (21.3 g, 85.2 mmol)from hexanes.(90% yield): mp 105-110° C. 1H NMR (CDCl3 /300 MHz) 8.21 (s, 1H), 7.30-7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H). EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(C1C=CC(C)=NC=1)C.Cl[C:22](OCC)=[O:23].Cl>C(OCCCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:22](=[O:23])[NH:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)Cl
Agent: CCc1ccc(C)nc1
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
5-chlorosalicylamide (300 g, 1.75 mol) and water (900 ml) were placed in a 3 liter, 4-neck round-bottomed flask under a nitrogen atmosphere and stirred. 5-ethyl-2-methyl-pyridine (284 g, 2.27 mol) and n-butyl acetate (900 ml) were added to the mixture. The mixture was cooled to 0-5° C. (jacket-10° C.) and dropwise addition of ethyl chloroformate (233 g, 2.10 mol) was started. This addition continued over a period of approximately one hour. When the addition was completed, the reaction mixture was slowly heated (in about two hours) to reflux and kept under reflux for an additional period of about 5 hours (jacket 110° C., internal temperature (IT) 90° C.). The resulting slurry was allowed to cool to room temperature, and hydrochloric acid (28 ml, 37% m/m, 0.34 mol) was added and the mixture stirred for about 30 minutes. The resulting slurry was vacuum filtered, the filter cake was washed with n-butyl acetate followed by water (600 ml) and was allowed to dry overnight in vacuo at 60° C. 321 g (93%) of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (6-chloro carsalam) was isolated after drying.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[N+]([O-])(O)=[O:13]>CO.CC(C)=O.O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:13])[CH2:1]1
Reactant: O=[N+]([O-])O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 119 %

Procedure:
5.0 g. of Acetonine was dissolved in a mixed solvent comprising 10 g. of acetone and 10 g. of methanol. The solution was added dropwise with a solution of 2.1 g. of nitric acid containing 0.63 g. of water in 10 g. of acetone and 10 g. of methanol at 15°-20°C. After completion of the addition, the mixture was maintained at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 5 to obtain triacetonamine in a yield of 119%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8].[CH3:9][O-:10].[Na+].ClCCl.O>CO>[CH3:9][O:10][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8]
Reactant: C[O-]
Reactant: Cc1nc(N)sc1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1sc(N)nc1C

Procedure:
5-Bromo-4-methyl-thiazol-2-ylamine (0.5 g, 2.59 mmol) was dissolved in methanol abs. (10 mL). The solution was cooled with an ice-bath, then under stirring was added portionwise sodium methoxide (140 mg, 2.59 mmol) The black reaction mixture was stirred for 30 min. at rt then poured into a mixture of dichloromethane/water. The aqueous layer was extracted with two portions of dichloromethane. The combined, organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the crude product which was used without further purification. MS (EI): m/e 144.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 7-bromo-2,2-dimethylheptan-1-ol (36.0 g, 133.0 mmol) in dichloromethane (60 mL) was added p-toluenesulfonic acid (0.28 g, 1.3 mmol) and 3,4-dihydro-2H-pyran (18.54 g, 213 mmol) at 5-10° C. under cooling with an ice-water bath. The mixture was stirred and allowed to warm to room temperature overnight. The reaction solution was filtered through neutral alumina (200 g), which was rinsed with dichloromethane (500 mL). Concentration of the solvent gave the crude product as a brown oil, which was subjected to column chromatography on silica gel (240 g) using hexanes:ethyl acetate (50:1) as eluent to yield 2-(7-bromo-2,2-dimethylheptyloxy)-tetrahydropyran as a colorless oil (23.0 g, 48%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.54 (t, 1H, J=3.0 Hz), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3 Hz), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, nba): Calcd. for C14H27BrO2: 307.1272. found: 307.1245.
Reaction SMILES: CI.[C:3]([O-:6])([O-])=O.[K+].[K+].[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13](O)=[C:12]([Cl:18])[CH:11]=1.C(OCC)(=O)C>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:6][CH3:3])=[C:12]([Cl:18])[CH:11]=1
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
Methyl iodide (467 μL, 8.12 mmol) and K2CO3 (2.24 g, 16.24 mmol) were added to a solution of 4-bromo-2,6-dichlorophenol (982 mg, 4.06 mmol) in DMF (10 mL) and stirred at rt under Ar for 40 min. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane) to afford 4-bromo-2,6-dichloroanisole (768 mg, 74%) as a white solid. See, for example, Li, J.; et al. J. Med. Chem. 1996, 39, 1846–1856, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 2H), 3.81 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 131.5, 129.6, 116.5, 60.6. HREIMS calculated for C7H5BrCl2O (M+) 253.8905, found 253.8901.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:13][O:9][C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH3:11])=[O:10]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2CO3 and 7.6 ml (121.3 mmol) iodomethane at 0° C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 5.2 g (23.7 mmol, 98%) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)([Cl:12])=O.C(C1C=CC(OCCCCO)=CC=1)(C)(C)C>ClCCl>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Agent: CC(C)(C)c1ccc(OCCCCO)cc1
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1

Procedure:
Nicotinoyl chloride was prepared by treating 100 g (0.81 mole) of nicotinic acid with 280 ml of thionyl chloride at reflux for two hours. The excess thionyl chloride was removed in vacuo and the crystalline acid chloride hydrochloride was suspended in 500 ml of dichloromethane. To the stirred mixture was added 66 g (0.30 mole) of 4-p-t-butylphenoxy-1-butanol dissolved in 400 ml of dichloromethane. After forty-eight hours the mixture was washed with one liter of saturated sodium bicarbonate. The dichloromethane solution was dried over magnesium sulfate and evaporated to a syrupy residue. The material was chromatographed on 1 kg of silica gel with elution by dichloromethane-methanol, 96:4, to afford 43.8 g (45%) of the nicotinate ester as an oil. The hydrobromide salt was prepared by treatment of a solution of 43.8 g in 800 ml of ethyl acetate with 30 ml of 4.5 N hydrogen bromide in ether. The precipitate was collected, washed with pentane and dried, m.p. 132°-133° C.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(O)C.S(=O)(=O)(O)O>O>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 5 °C
Yield: 146.8 %

Procedure:
A mixture of 3β-benzoyloxy-14α,15α-epoxy-5α-cholest-7-ene (26, 12.0 g, 23.8 mmol), 95% ethanol (300 mL), and water (35 mL) was cooled to 5° C. in an ice water bath. To this solution was added, in portions of 5 mL, concentrated sulfuric acid (65.0 mL). After the addition (~5 min) the reaction mixture was heated under reflux for 22 h. Stirring must be effective to prevent clumping of the starting material. The clear reaction mixture was cooled to ambient temperature, then poured into ice (700 g). A sticky precipitate was formed (could not be filtered). The water phase was extracted three times with ethyl acetate (400, 200, and 200 mL). The combined ethyl acetate phase was washed with water, 5% sodium bicarbonate, and sodium chloride solution, and dried over sodium sulfate. Evaporation of the solvent gave a semisolid yellowish compound (14 g). The crude compound 27 was purified by flash chromatography (4.0×35 cm column) and eluted with ethyl acetate/hexane (1:3). Fractions containing product were combined and evaporated to give after crystallization from methanol/water pure product as fine needles 4.5 (47%). Mp, NMR, and IR data were in agreement with published data.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[S:35]([O-:39])([O-:38])(=[O:37])=[O:36]
Reactant: O=S(=O)(O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])[O-]

Procedure:
A suitable reactor is charged with acetone (38 mL). The acetone solution is sequentially charged with carvedilol (10.25 grams) and water (6 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution, 1N aqueous sulfuric acid (1 equiv., 25.2 mL) is added. The reaction mixture is stirred at between 17° C. and 35° C. and the solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water at 2 volumes or 20.5 mL. The cake is then added a mixture of acetone and water (10 to 1) for ripening between 20° C.-35° C. over 24 hours to 48 hours. The slurry is filtered and the cake is dried under vacuum to a constant weight. The final weight is 5.48 grams.
Reaction SMILES: [OH2:1].[C:2]1(C)C=CC=CC=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH2:19])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=[O:15]>O1CCCC1>[CH:18]1[C:10]([Cl:9])=[CH:11][C:12]2[NH:19][C:2]([O:15][C:14](=[O:16])[C:13]=2[CH:17]=1)=[O:1]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Yield: 93 %

Procedure:
According to the same manner as in Example 5, except that 171.6 g of water and 171.6 g of toluene were used in place of 78.9 g of water and 315.5 g of tetrahydrofuran, and that 4-chloroanthranilic acid was used in place of 4,5-dimethoxyanthranilic acid, 80.9 g of 7-chloroisatoic anhydride (purity: 91%) was obtained.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CC(C)=O>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
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
Yield: 76.8 %

Procedure:
A solution of sodium hydroxide (0.58 g) in water:acetone (20:80 v/v, 9 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetone (20:80 v/v, 49 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.0. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with acetone (1×50 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 3.8 g of ibandronate sodium crystal form T. Form T can exhibit a weight loss of about 5% and about 7% in TGA.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 106.7 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:ethanol (80:20 v/v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (80:20 v/v, 212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 3 hours to obtain a pH of 3.24. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dry to obtain 5.7 g of amorphous ibandronate sodium.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.C(Cl)Cl>[OH:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)C(C)C)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.0 g of 4'-hydroxy-3'-methoxy-2-methyl-propiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2N) in 40 ml of glacial acetic acid are added dropwise thereto while stiring within 15 minutes. After 15 minutes the reaction mixture is poured into ice-water and the separated crystals are filtered under suction, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up in methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 85°-87°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cccc2C=O)cc1
Yield: 65.5 %

Procedure:
To pyrrole-2-carboxaldehyde (1.0 g, 10.5 mmol) in THF (60 mL) was added KO'Bu (1.2 g, 10.5 mmol), Et4N+T (100 mg) and 4-methoxybenzyl chloride (1.4 mL, 10.5 mmol). After 1 day saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated. Column chromatography (EtOAc/hexanes, 1:9) provided 1.48 g (65%) of 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde as an oil.