Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B.[O:15]1CCCC1>>[C:1]([C@@H:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH2:8][CH2:7][C@H:6]1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=CCCc2occc21
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)[C@@H]1c2ccoc2CC[C@H]1O
Temperature: 4 °C
Reaction time: 2.5 h

Procedure:
A flame-dried 2000-mL 3-neck flask fitted with a 250-mL pressure equilibrated dropping funnel, and internal thermometer, and nitrogen inlet is charged with a solution of 4-tert-butyl-6,7 dihydrobenzofuran (24.26 g, 137.8 mmol) in dry tetrahydrofuran (300 mL). The solution is cooled to 4° C. then a solution of borane 1M in tetrahydrofuran, 142 mL) is added dropwise over 20 minutes such that the internal temperature does not exceed 5° C. during the addition. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature and stir for 2.5 hours. The reaction is then quenched by the dropwise addition of water (9.5 mL) followed (after hydrogen evolution was complete) by the addition of 2.5N NaOH (280 mL). Hydrogen peroxide (30% aqueous solution, 16 mL) is carefully added dropwise such that the reaction temperature is about 45° C. upon completion of the addition. An oil bath is added and the reaction mixture maintained at 45°-50° C. for one hour. The reaction mixture is allowed to cool, then diluted with 20% NaCl (500 mL). The layers are separated and the aqueous layer extracted with an additional portion of tetrahydrofuran (300 mL). The combined organic extracts are washed with 20% NaCl (500 mL), dried (MgSO4), and concentrated. Trituration with hexane afforded trans-4-tert butyl-4,5,6,7-tetrahydro-5-benzofuranol.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1C(=O)C[C@H](c2ccc(I)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)C[C@H](c2ccc(-c3ccc(F)cc3)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Yield: 50 %

Procedure:
(±)-(4R*,5R*)-5-[(1S*)Hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-iodophenyl)-1-methylpyrrolidin-2-one prepared as described in Example 21, step 1, (0.100 g, 0.204 mmol), Pd(PPh3)4 (0.025 g, 0.02 mmol) and 4-flourophenylboronic acid (0.037 g, 0.26 mmol) were stirred in anhyd. DME (1 mL). A 1M solution of Na2CO3 (0.55 mL, 0.55 mmol) in water was added and the resulting mixture was heated at the reflux temperature for 18 h. The reaction was cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (75% EtoAc/hex) to yield (±)-(4R*,5R*)-5-[(1S*)hydroxy(5-phenyl(2-thienyl))methyl]-4-[4-(4-fluorophenyl)phenyl]-1-methylpyrrolidin-2-one (0.046 g, 50%) as a yellow solid: mp 191-193° C.; 1H NMR (CDCl3) δ 2.29 (dd, J=14.5, 7.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.30 (s, 3H), 3.85-3.89 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.50 (d, J=6.5 Hz, 1H), 5.99 (d, J=6.1 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[F:14][C:15]1[C:20]2[NH:21]C(=O)[O:23][C:24](=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>C1(C)C=CC=CC=1>[NH2:21][C:20]1[C:15]([F:14])=[CH:16][CH:17]=[CH:18][C:19]=1[C:24]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[Cl:9])=[O:23]
Reactant: Nc1cccc(Br)c1Cl
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1c(F)cccc1C(=O)Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A mixture of 3-bromo-2-chloroaniline [prepared according to the procedure described in U.S. Pat. No. 8,242,260] (600 mg, 2.91 mmol) and toluene (10 mL) was cooled to 0° C. and slowly treated with 2 M trimethylaluminum in toluene (2.47 mL, 4.94 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. The mixture was treated with 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (684 mg, 3.78 mmol) and heated at 50° C. for 16 h. The mixture was cooled to 0° C. and treated dropwise with 1M aqueous HCl until gas evolution stopped, and stirred for 2 h while allowing to warm to room temperature. The mixture was extracted three times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide 2-amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide as a pale yellow solid (350 mg, 35% yield). Mass spectrum m/z 343, 345 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.46 (dd, J=8.4, 1.3 Hz, 1H), 8.42 (br. s., 1H), 7.43 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.15 (ddd, J=11.0, 8.0, 1.2 Hz, 1H), 6.69 (td, J=8.0, 5.1 Hz, 1H), 5.72 (br. s., 2H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38].N([O-])=O.[Na+].[BrH:43]>CC#N.O.[Cu]Br>[Br:43][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 6-(N-(4-amino-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (250 mg, 0.465 mmol) in MeCN (1 mL) maintained at 0° C. was added sodium nitrite (80 mg, 1.16 mmol) dissolved in water (0.50 mL). followed by 48% aqueous HBr (0.25 mL). The resulting mixture was treated with copper(I) bromide (133 mg, 0.930 mmol) in 48% aqueous HBr (0.30 mL). After stirring at 60° C. for 1 hour the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic solution was washed with water, dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/EtOAc) to afford the title compound in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36-8.51 (m, 1H) 8.05 (s, 1H) 7.92 (dd, J=8.89, 5.37 Hz, 2H) 7.49-7.62 (m, 1H) 7.31-7.49 (m, 3H) 7.09-7.26 (m, 2H) 4.69 (t, J=5.28 Hz, 1H) 3.46-3.60 (m, 2H) 3.30-3.40 (m, 3H) 2.72-2.87 (m, 5H) 2.04-2.22 (m, 1H) 0.70-1.06 (m, 3H) 0.41 (br. s., 1H).). LCMS (m/z, ES+)=601, 603 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:14]([Cl:25])[CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.O1CCOCC1>[Cl:25][C:14]1[CH:13]=[C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=3)=[CH:3][N:4]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2Cl)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2Cl)CC1

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60.0 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (46.0 mg, 0.28 mmol), Pd(PPh3)4 (40.0 mg, 0.035 mmol) and 1.5 M Na2CO3 (0.75 mL, 1.12 mmol) in 2:1 DMF-dioxane (3 mL). The crude residue is triturated with DCM and then the title compound is crystallised from EtOH (4 mg, 6%). LCMS: Rt 2.01 min (96%) m/z (APCI) 462 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.27 (3H, s), 2.49-2.54 (4H, t), 2.99 (4H, m), 7.19 (1H, d), 7.53 (1H, br s), 7.60 (1H, s), 7.76 (1H, s), 7.84 (2H, d), 7.98 (1H, dd), 8.04 (1H, s), 8.09 (2H, d), 8.13 (1H, br s), 8.35 (1H, s), 9.86 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: Cc1cncc(B(O)O)c1
Product: Cc1cncc(Cc2ccc(-c3ccccc3)nc2)c1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (70 mg, 0.28 mmol) and 5-methylpyridine-3-boronic acid (58 mg, 0.42 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel ethyl acetate as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light yellow solid. Yield: 56 mg, 77%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.30 (d, J=0.6 Hz, 3H), 3.98 (s, 2H), 7.28-7.32 (m, 1H), 7.38-7.44 (m, 1H), 7.44-7.55 (m, 3H), 7.67 (dd, J=8.0, 0.8 Hz, 1H), 7.96-8.01 (m, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.58 (dd, J=1.6, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.3, 35.7, 120.4, 126.7, 128.7, 128.9, 133.1, 133.8, 134.8, 136.8, 137.0, 139.0, 147.2, 148.6, 149.8, 155.8; (ESI): m/z=260.84 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[F:11])[CH3:2].C(Cl)Cl.CO>C(Cl)Cl>[CH2:1]([C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[F:11])[CH3:2]
Reactant: CCc1ncc(CO)cc1F
Solvent: CO
Solvent: ClCCl
Product: CCc1ncc(C=O)cc1F
Temperature: 40 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
CrO2 (Magtrieve) (796 mg, 9.48 mmol) was added to a solution of (6-ethyl-5-fluoro-3-pyridinyl)methanol (98 mg, 0.632 mmol) in DCM (5 ml) and the mixture was stirred at 40° C. for 6 h. TLC (10% DCM/MeOH) showed starting material remaining. An excess of CrO2 (Magtrieve) (530 mg, 6.32 mmol) was added. After stirring for 12 h, TLC showed the reaction had been completed. The resulting suspension was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give 57.4 mg of the title compound as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([OH:10])[N:7]=[C:6]([C:11]3[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.O>[C:20]([NH:24][S:16]([C:14]1[S:15][C:11]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:9]=[C:8]([OH:10])[N:7]=2)=[CH:12][CH:13]=1)(=[O:18])=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of crude 5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonyl chloride (1.9 g, 6.0 mmol, 1.0 equiv.), t-butylamine (25 mL) and TEA (10 mL) in CH2Cl2 (500 mL) was stirred at rt for 2 h. The reaction mixture was diluted with water, the organic layer was washed (brine), dried (Na2SO4), evaporated and purified by silica gel chromatography (EA/PE 1:1) to afford N-tert-butyl-5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (500 mg, 24%). LC-MS (m/z)=354.1 [M+H]+
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 69 %

Procedure:
To a suspension of 3.50 g (7.17 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.213 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.96 g (7.89 mmol) phenylboronic acid in 40 ml 1,2-dimethoxyethane a solution of 0.83 g (7.89 mmol) Na2CO3 in 15 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) and crystallised to give 2.4 g (69%) 2-methylsulfanyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p 109.7-110.7°.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:14]([OH:17])([OH:16])=[O:15])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.O.[OH-].[Na+:20]>C(O)(C)(C)C>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:10]([O-:12])([OH:13])=[O:11])([P:14]([OH:17])([OH:16])=[O:15])[OH:9])[CH:2]=1.[Na+:20]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O

Procedure:
20.0 g of risedronic acid, 70 ml of deionized water and 100 ml of ter-butanol are charged into a 1-liter reactor, equipped with mechanical stirrer and thermometer. The suspension, under stirring, is added with 70.7 ml of 1M NaOH. The admixture is kept under stirring for 10′, up to complete dissolution of the undissolved solids. The solution, whose pH is 4.60, is filtered on a paper filter and put into Lioguard chambers. The chambers are introduced into a lyophilizer and processed according to example 1. At the end 19.8 g of lyophilized amorphous sodium risedronate are thus obtained (yields 92.6%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)C(=O)OCC
Temperature: -30 °C
Reaction time: 18 h

Procedure:
A solution of diethyl bis(hydroxymethyl)malonate (46.95 g, 0.21 moles) (prepared by the method of P. Block, Jr., Organic Synthesis, Collective Volume V, 381 (1973)) in methylene chloride (500 mL) was treated with triethyl amine (63 mL) and cooled to −30° C. A mixture of methylsulfonyl chloride (35 mL) in methylene chloride (40 mL) was added to the reaction mixture dropwise over 20 minutes and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into ice water and the product was extracted with methylene chloride. The organic extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was recrystallized from t-butylmethyl ether and hexane to give 2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (55.04 g).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:12]=[O:13]>C1COCC1>[CH2:14]([NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1]1)=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN=C=O
Reactant: Oc1noc2ncccc12
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1oc2ncccc2c1=O

Procedure:
In analogy to example 1c, 100 mg (0.735 mmol) of isoxazolo[5,4-b]pyridin-3-ol were reacted with 112.2 mg (0.88 mmol) of 1-isocyanatohexane in THF at RT. Yield: 100 mg (52%), M+H+: 264.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>O=S(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc—hexanes) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1
Reactant: c1cocn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ncco2)cc1
Yield: 8.5 %

Procedure:
The title compound (0.16 g, 33%) was prepared from oxazole (0.74 g, 10.7 mmol) and 4-bromoanisole (2.0 g, 10.7 mmol) using the procedure of Example 146, step 1; 1HNMR (400 MHz, CDCl3) δ 8.0 (d, J=9.2 Hz, 2H), 7.66 (d, J=1.2 Hz, 1H), 7.19 (d, J=0.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[CH2:30][CH3:31]>>[CH2:30]([C:18]1[N:17]([CH2:16][CH2:15][S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[C:22](=[O:23])[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)[CH3:31]
Reactant: Oc1ccc(S)cc1
Reactant: CCc1nc(-c2ccccc2)cc(=O)n1CCCl
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccccc2)cc(=O)n1CCSc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
To 4-hydroxy thiophenol (2.016 g, 0.016 mol) in DMF (50 ml) K2CO3 (4.416 g, 0.032 mol) was added and stirred for 30 min. and then added 1-(2-chloroethyl)-2-ethyl-4-phenyl-1,6-dihydropyrimidin-6-one (4.3 g, 0.016 mol). The resulting mixture was stirred at room temperature for 15 h, filtered, washed with EtOAc and the combined filtrates were partitioned between water and EtOAc. The EtOAc layer was washed with water, brine, dried over Na2SO4 and evaporated the solvent to get the title compound as a gummy mass (1.25 g, 26%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:18])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:18][CH3:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.38 g. of 1-[2-(2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. of hexamethylphosphoramide under nitrogen is added 480 mg. of a 56% dispersion of sodium hydride in mineral oil. After stirring for 1 hour at room temperature, the temperature is adjusted to 50° C. and stirring is continued for 1 to 2 hours. The reaction mixture is then cooled to about 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter, the solution is stirred at 5° to 10° C. for 1 hour, then at room temperature for 4 hours and then heated at 50° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue may be chromatographed on silica gel to effect purification of the free base. Elution of the gel with 5 to 10% methanol in dichloromethane yields 1-[2-(2-naphthyl)-2-(methoxy)ethyl]imidazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]([O:11]CC)=O)[CH:4]=[CH:5][N:6]=1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:11])[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)CCn1ccnc1C
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1CCC(O)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 6 %

Procedure:
In a 200 ml two-neck flask, under an atmosphere of argon, a solution of ethyl 3-(2-methyl-1-imidazolyl)propionate (3.37 g, 18.5 mmol) in anhydrous tetrahydrofuran was added to 50 ml of 1.8M phenyllithium solution at 0° C. After stirred for 3.5 hours at 10° C., the mixture was allowed to stand overnight at room temperature. The solution was poured into water, which was extracted with ethyl acetate. The organic extract was washed with saturated saline solution and dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel chromatography (elution solvent; ethyl acetate-ethanol=10:1) and then recrystallized from n-hexane-ethyl acetate. This was further recrystallized from ethanol-benzene to give 320 mg of title compound as white needle-like crystals. Yield: 6%