Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), Cut (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:18][O:19][CH2:20][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1C(F)(F)F
Reaction time: 1 h

Procedure:
2-trifluoromethylphenol (50.00 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (85.14 g) and chloromethyl methyl ether (34.7 mL) were added to the solution, and then the mixture was stirred under water cooling for 1 hour. Water was added to the reaction solution, and then the mixture was extracted with n-hexane. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (64.13 g) as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.N.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
100 mg (0.76 mmol) of 1H-pyrrolo[2,3-b]pyridine 7-oxide (from example XV) in 3 ml of phosphorus oxychloride are heated at reflux until a clear solution is formed. After cooling to room temperature, the reaction mixture is carefully hydrolyzed with ice. The mixture is made alkaline using ammonia and extracted repeatedly with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure. This gives a yellow oil which is purified by preparative HPLC.
Reaction SMILES: CO.[C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)#[N:4].[BH4-].[Na+]>O1CCCC1>[C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)#[N:4]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To an ice and methanol cooled solution of 4 g. (0.0205 M) of 4-cyano-4-phenylcyclohexanone (a) (prepared as in J. Chem. Soc. 1959, 1446) in 150 ml. of tetrahydrofuran, a suspension of 1 g. of sodium borohydride in 50 ml. of tetrahydrofuran is added in 5 ml. portions in the course of about 10 minutes. The mixture is stirred for about 30 minutes and allowed to stand in the cold for about 18 hours. The bulk of the solvent is removed under vacuum and the residue treated with water. The precipitate is extracted with ether and the organic fraction washed successively with 2.5 N hydrochloric acid solution, saturated aqueous sodium bicarbonate, water and brine and then evaporated to dryness. The residue is recrystallized with benzene to give 1.81 g. (43.8% yield) of 4-cyano-4-phenylcyclohexanol (b) melting at 103° to 111° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[OH-].[Na+].[H][H]>[Ni]>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
2.6 Grams (0.01 mol) of 5-nitrotetrahydroanthraquinone, 52 grams (0.032 mol) of a 2.5% aqueous sodium hydroxide solution and 0.07 gram of a Raney nickel catalyst were placed in an electromagnetic agitation-type autocalve with an inner volume of 160 ml, followed by hydrogenation while agitating under a pressure of 3 to 6 kg/cm2G at room temperature. The hydrogenation reaction proceeded smoothly. 6 Hours after commencement of the reaction, 0.02 mol of hydrogen was absorbed and the absorption was stopped. Then, the hydrogen in the reaction system was replaced by nitrogen and the resultant reaction solution was filtered in a flow of nitrogen for separating the catalyst therefrom. Air was passed into the resultant filtrate for oxidation to obtain 2.1 grams of 1-aminoanthraquinone (at a yield of 93.1%). The purity was 97%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][C@H:3]1[CH2:9][OH:10].C(Cl)(=O)C(Cl)=O.[CH3:18][C@@H:19]([CH2:23][CH3:24])[C:20](O)=[O:21]>>[CH3:18][C@@H:19]([CH2:23][CH3:24])[C:20]([O:10][CH2:9][C@@H:3]1[CH2:4][C:5](=[C:6]([CH3:7])[CH3:8])[C:2]1([CH3:11])[CH3:1])=[O:21]
Reactant: CC(C)=C1C[C@@H](CO)C1(C)C
Reactant: CC[C@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C

Procedure:
A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[C:19]([Si:16]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[F:10])([CH3:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a mixture of 5-ethyl-2-fluorophenol (10 g, 71.4 mmol) and imidazole (5.4 g, 78.5 mmol) in DMF (100 mL) was added t-butyldimethylsilylchloride (10.8 g, 71.4 mmol) and stirred 18 h. Diluted with EtOAc and washed with H2O (3×50 mL) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 12.2 g of intermediate 368.1. 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (s, 6H) 0.97 (s, 9H) 1.16 (t, J=7.47 Hz, 3H) 2.52 (q, J=7.76 Hz, 2H) 6.63-6.72 (m, 2H) 6.90 (dd, J=10.77, 8.13 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][CH2:6][C:7]1([CH3:22])[CH2:12][O:11][CH:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[O:9][CH2:8]1)=[O:4].C([O-])=O.[NH4+].[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44].CCN(C(C)C)C(C)C.CCCP(=O)=O.C([O-])(O)=O.[Na+]>CO.[Pd].C(Cl)Cl>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:19][C:14]1[CH:15]=[N:16][N:17]([CH3:18])[C:13]=1[CH:10]1[O:11][CH2:12][C:7]([CH3:22])([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:24])([F:23])[F:1])[CH2:8][O:9]1)=[O:44]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1C1OCC(C)(CNC(=O)C(F)(F)F)CO1
Agent: [Pd]
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1OCC(C)(CNC(=O)C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide (410 mg, 1.16 mmol, intermediate 83) in MeOH (20 mL) was added ammonium formate (400 mg, 6.34 mmol) and 10% Pd/C (400 mg). The mixture was heated at reflux for 5 hr then cooled to room temperature. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in IPA (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (312 mg, 1.22 mmol) and DIPEA (0.62 mL, 3.47 mmol) were then added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.61 mL, 1.28 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. Saturated aqueous NaHCO3 solution (10 mL) and DCM (20 mL) were added. The organic layer was washed with 1 N HCl (10 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) gave 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide as an oil. To a solution of this oil in IPA (2 mL), THF (2 mL) and water (1 mL) was added K2CO3 (31 mg, 0.22 mmol) and the mixture heated at 50° C. for 18 hr. More K2CO3 (300 mg, 2.2 mmol) was added and the mixture heated in a microwave at 120° C. for 2.5 hr. The reaction mixture was cooled to room temperature, filtered washing with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The residue was passed through an SCX column eluting with 0-5% 7 N NH3 in MeOH/DCM) and purified by preparative HPLC to give 178 as a colourless solid (1 mg, 0.2% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.45 (s, 2H), 8.01 (s, 1H), 7.39-7.32 (m, 1H), 7.06 (t, J=8.8 Hz, 2H), 5.82 (s, 1H), 3.98 (d, J=11.6 Hz, 2H), 3.74-3.65 (m, 5H), 2.86 (s, 2H), 0.69 (s, 3H). LCMS (ES+) m/z 465 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:14])[CH:10]=[C:11]2[OH:13]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(O)c2cc(Br)ccc2[nH]1
Temperature: 140 °C
Reaction time: 18 h
Yield: 109.7 %

Procedure:
The product of Step 2 (14.7 g) was added to polyphosphoric acid (55.3 mL) and mixture was heated to 140° C. for 3 hrs. The reaction mixture was cooled slightly and poured into 3N HCl (168 mL). The pH was adjusted to 4 with 3N NaOH and resulting solid was filtered after cooling the reaction mixture to 10° C. The cake was washed with water and then slurried in 400 mL of 50% isopropanol/water for 18 hours. The solids were filtered, air dried to give a pasty solid which was dried in vacuo at 90° C. for 4 hours, ground in mortar/pestle and re-dried at 90° C. for another 18 hours to give 15 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:40]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[K+:40].[K+:40].[K+:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.030 g, 0.054 mmol) in ethanol (3 mL) was added KOH (9.0 mg, 0.16 mmol) in 0.5 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×8 mL), acetone (2×8 mL) and acetonitrile (2×8 mL) to afford tri-potassium(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (6) (0.028 g, 0.043 mmol, 78% yield) as a brown solid. 1H NMR (400 MHz, deuterium oxide) δ ppm 4.52 (s, 2H), 7.09 (d, J=7.78 Hz, 1H), 7.19-7.24 (m, 2H), 7.28-7.40 (m, 5H), 7.61-7.77 (m, 3H), 8.28 (d, J=4.27 Hz, 1H), 8.91 (t, J=1.88 Hz, 1H), 9.08 (d, J=2.26 Hz, 1H), 9.21 (d, J=1.76 Hz, 1H); LCMS Method A: retention time 1.60 min, [M+1]=549.2. HPLC Method B: Purity 96.0%, retention time 6.09 min, HPLC Method C: Purity 96.0%, retention time 5.86 min. Elemental analysis: MF C25H18N6SPO5.2.6 K.4.5 H2O, Calculated C 41.22; H, 3.72; N, 11.54; K, 14.12; H2O, 11.00; Found C, 40.79; H, 3.56; N, 11.17; K, 13.76; H2O, 10.49.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:16]([OH:17])[CH:15]([Cl:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1.Cl>FC(F)(F)C(O)=O.CO.C(OCC)C>[ClH:18].[NH2:2][CH:3]1[C:16](=[O:17])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: NC1Cc2ccc3ccccc3c2C(Cl)C1O
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1Cc2ccc3ccccc3c2CC1=O
Yield: 52.8 %

Procedure:
2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (265 mg) was refluxed in trifluoroacetic acid (25 ml) for 3 hours. The green mixture was evaporated in vacuo taken up into methanol and treated with activated charcoal for 2 hours at room temperature. Filtration and evaporation yielded a yellow oil which was diluted with methanol and acidified with a solution of hydrochloric acid in diethyl ether. The mixture was evaporated and the acidification process was repeated. Evaporation gave a residue which was recrystallized in a methanol/diethyl ether mixture to afford the title compound (122 mg) as a cream colored powder.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:4]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O.C(O)C>[CH:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH2:9][C:10]([P:12]([O-:14])([OH:15])=[O:13])([P:16]([OH:19])([OH:18])=[O:17])[OH:11])[CH:4]=1.[Na+:2]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 22 °C
Yield: 90 %

Procedure:
A solution of sodium hydroxide (7.4 g, 1 eq.) in a mixture of water/ethanol (50%, v/v) (150 ml) was added dropwise to a suspension of risedronic acid (50 g) and 5 g of EDTA (ca. 10% on a dry per-weight basis) in a mixture of water/ethanol (50%, v/v) (850 ml) at reflux temperature. The reaction mixture was stirred at reflux temperature until the pH was stable at about 4.2-4.7. The reaction mixture was cooled to a temperature of about 22° C. The precipitate was then filtered, washed twice with 50 ml mixture of water/ethanol (50%, v/v) and then with ethanol (1×50 ml) and dried over night at 50° C. to give 48.5 g (85%) of sodium risedronate white crystal substance of form B (water content by thermogravimetric analysis was 5.5%-7.5%). Less than 50 ppm of iron was found in the produce by AES.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: BrCCCCCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5 ml (32.75 mmol) 4-phenylbutanol with 10.1 ml (65.66 mmol) 1,6-dibromohexane is added 8 g (121.2 mmol) powdered KOH and 1.112 g (3.28 mmol) tetrabutylammonium hydrogen sulfate. After allowing the suspension to stir for 20 hr at room temperature, it is filtered and the filtrate dissolved in 50 ml Et2O. The resulting solution is washed with water, dried on anhydrous Na2SO4, the Et2O evaporated and the residue distilled in vacuum (0.1 mmHg), a first fraction up to 100° C. of a mixture of starting products and a second fraction at 150° C. of 4-(6-bromohexyloxy)butylbenzene weighing 7.60 g (74.4 %) being collected.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: BrCCCCCCOCCCCc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 10 ml (0.0655 mol) of 4-phenylbutanol and 20 ml of toluene is added within 15 minutes, with stirring, to a mixture of 20.2 ml (0.131 mol) of 1,6-dibromohexane, 16 g of powdered (0.242 mol KOH) caustic potash, 2.2 g (0.0066 mol) tetra-n-butylammonium hydrogen sulphate and 50 ml of toluene, at a temperature between 25 and 30° C. After it has all been added the mixture is rinsed with 5 ml of toluene and stirred for 2 hours at a temperature between 25 and 30° C. Then 75 ml of water are added, the organic phase is separated off and washed twice with 50 ml of water. The organic phase is concentrated under reduced pressure using the rotary evaporator and the residue is fractionally distilled under a high vacuum (p<0.1 mbar). 14.62 g (71% of theory) of the title compound are obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:36][C:37]1[C:38]([C:45]2[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:52])=[N:39][O:40][C:41]=1[CH:42]1[CH2:44][CH2:43]1>C1COCC1.O.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:36][C:37]2[C:38]([C:45]3[C:46]([Cl:52])=[CH:47][CH:48]=[CH:49][C:50]=3[Cl:51])=[N:39][O:40][C:41]=2[CH:42]2[CH2:44][CH2:43]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.8 %

Procedure:
To a solution of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester (1.88 g, 8.73 mmol) in anhydrous THF (15 mL) at 0° C. is added 18-crown-6 (2.3 g, 8.70 mmol) and tert-butyl alcohol, potassium derivative (8.8 mL, 1.0 M, 8.80 mmol). The mixture is stirred at room temperature for 20 minutes following which 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (1.8 g, 5.19 mmol) in THF is added over 2 minutes. The mixture is stirred for 2 h and water (10 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), concentrated, and purified via flash chromatography (120 g silica) eluting with a gradient of ethyl acetate in heptane (0 to 60%) to provide the title compound (420 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH2:24]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-amino-phenylacetic acid benzyl ester p-toluene sulphonic acid was prepared by adding 3-aminophenylacetic acid (10 g) and p-toluene sulphonic acid monohydrate (13.2 g) to benzyl alcohol (27.2 ml) in toluene (30 ml). The mixture was heated under reflux and the water formed collected in a Dean-Stark receiver. When all the water had been distilled off the mixture was allowed to cool to 25° C. before diluting with diethyl ester and placing in an ice-bath for 1 hr. The crystalline p-toluene sulphonate was filtered off and dried in a dissicator (23.5 g) NMR δ2.31(s)3H, 3.82(s)2H, 5.11(s)2H, 7.11(d)2H, 7.25-7.45(m)8H, 7.52(d)2H.