Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[CH3:27][N:24]1[C:20]2[CH2:21][CH2:22][CH2:23][C:13]3[C:12]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:17][C:16]([NH2:18])=[N:15][C:14]=3[C:19]=2[CH:26]=[N:25]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2c-3cnn2C)cc1
Solvent: CC#N
Product: CN1CCN(c2nc(N)nc3c2CCCc2c-3cnn2C)CC1

Procedure:
A solution of the product from Example 8C (0.048 g, 0.12 mmol) and N-methylpiperazine (0.25 g, 0.25 mmol) in acetonitrile (1 mL) was heated in a microwave at 160° C. for 1 hour. The reaction mixture was partitioned in dichloromethane/water, the organic layer was separated, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with 5% methanol/dichloromethane/1% ammonium hydroxide to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.84 (m, 1 H), 5.96 (m, 2 H), 3.76 (s, 3 H), 3.07 (m, 4 H), 2.93 (t, J=6.27 Hz, 2 H), 2.59 (m, 2 H), 2.43 (m, 4 H), 2.22 (s, 3 H), 1.90 (m, 2 H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:12])([F:11])[CH2:9]I.[Cl:13][C:14]1[C:24]2[NH:23][C:22](=[O:25])[CH2:21][N:20]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.C(Cl)Cl>CN(C)C=O.[Cl-].[Na+].O>[Cl:13][C:14]1[C:24]2[N:23]([CH2:9][C:8]([F:12])([F:11])[F:7])[C:22](=[O:25])[CH2:21][N:20]=[C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)CI
Reactant: O=C1CN=C(c2ccccc2)c2cccc(Cl)c2N1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CN=C(c2ccccc2)c2cccc(Cl)c2N1CC(F)(F)F
Temperature: 50 °C
Yield: 39.5 %

Procedure:
Cesium carbonate (1.01 g, 3.08 mmol) was added to a solution of 2,2,2, -trifluoroethyl iodide (0.991 mL, 10.3 mmol) and 9-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (0.557 g, 2.06 mmol) in dimethylformamide. The reaction was heated at 50° C. for 96 h, adding more 2,2,2-trifluoroethyl iodide as needed. The reaction was worked up with methylene chloride and saturated brine. The residue was purified by chromatography (silica gel, 0–30% ethyl acetate in hexane gradient elution), giving the title compound (287 mg). 1H NMR (500 MHz, CDCl3) δ 7.66–7.23 (m, 8H), 5.20 (m, 1H), 4.85 (d, J=11 Hz, 1H), 4.24 (m, 1H), 3.79 (d, J=11 Hz, 1H).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1[C:16]([O:18]CC)=O.[C:21]1([CH2:27][C:28]([NH2:30])=[NH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O-].[Na+]>CO>[CH2:27]([C:28]1[NH:30][C:16](=[O:18])[C:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8][C:2]=2[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
1-Tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (See WO2006029154, example 1a, p 34) (1.32 g, 4.6 mmol) and 2-phenyl-acetamidine (750 mg, 4.4 mmol) were added to a solution of NaOMe (3.8M, 3.5 mL, 13.2 mmol) in MeOH (15.0 mL) at 0° C. and stirred at 0° C. to room temperature overnight. The reaction was quenched with water, partitioned with ethyl acetate and the phases separated. The combined organics layer were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the crude product as an orange gum. The residue was purified by flash column chromatography eluting with CH2Cl2:ethyl acetate (90:10 to 70:30) to afford the title compound as a white solid (1.30 g, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Br:11]
Reactant: BrBr
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: CC(=O)O
Product: Nc1ncc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 6-aminonicotinic acid (13.8 g, 0.1 mole) in glacial acetic acid (100 ml), bromine (16 g, 5 ml, 0.1 mole) in acetic acid (20 ml) is added slowly. The reaction mixture is stirred for 8 hours at room temperature and the acetic acid is removed under reduced pressure. The yellow solid residue is dissolved in water and carefully neutralized with 30% NH4OH. The separated solid is filtered and washed with water to give 18 g of solid; mass spectrum: 218 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 39.6 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 47, 0.190 g, 0.293 mmol) 2,2-Dimethylsuccinic anhydride (0.375 g, 2.932 mmol) and DMAP (0.071 g, 0.586 mmol) in pyridine (10 ml) were added at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with aqueous 1N HCl, then water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.090 g; Yield: 39.6%; 1H NMR (300 MHz, CDCl3): δ 5.96 (d, 111, J=8.1 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.52-4.44 (m, 1H), 4.16-4.07 (m, 1H), 3.79-3.58 (m, 1H), 3.50-3.31 (m, 3H), 3.18-3.07 (m, 1H), 2.91-2.87 (m, 1H), 2.71-2.56 (m, 2H), 2.56-2.37 (m, 2H), 2.30-2.19 (m, 1H), 2.01-1.81 (m, 3H), 1.80-1.10 (m, 35H), 0.95, 0.93, 0.88, 0.87 (s, 21H); Mass: [M+1]+ 777 (30%), [M+Na]+ 799 (100%); IR (KBr, cm−1): 3400, 2947, 2868, 1733, 1622, 1456, 1390, 1369, 1320, 1252, 1231, 1192, 1150, 1021, 978, 881; HPLC: 97.37%; M.R: 168.5° C.-176.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=1[CH:15]=O>C(O)C.[OH-].[Na+]>[C:9]([C:8](=[CH:15][C:14]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)#[N:10]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: N#CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1C=C(C#N)c1cccc(Cl)c1
Yield: 92.5 %

Procedure:
3-chlorophenylacetonitrile (purchased from Tokyo Kasei), 1.96 g (10.0 mmol), and 1.96 g (10.0 mmol) of 2,4,5-trimethoxybenzaldehyde (purchased from Lancaster) were dissolved in 10 ml of ethanol (purchased from Kokusan Kagaku) under heating, 2 drops of 20% aqueous sodium hydroxide solution was added to the solution and stirred over night, and the precipitate was crushed, and washed with ethanol twice and hexane twice, and dried to give 3.05 g (yield: 92.5%) of α-cyano-3-chloro-2',4',5'-trimethoxystilbene (as a yellow crystalline).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23](O)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:49][C:50]1[CH:51]=[C:52]([NH:53][C:23]([C:13]2[CH:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=2)=[O:24])[CH:54]=[CH:55][CH:56]=1
Reactant: Nc1cccc(Cl)c1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)Nc3cccc(Cl)c3)cc2-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL one-neck round-bottom flask, equipped with provisions for magnetic stirring, was charged with [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylic acid from Step 3 (0.500 g, 1.38 mmol), 1-hydroxybenzotriazole hydrate (0.206 g, 1.522 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.318 g, 1.66 mmol) and N,N-dimethylformamide (30 mL). The solution was stirred at room temperature for forty minutes, then 3-chloroaniline (0.154 mL, 1.453 mmol) was added. The reaction was held at room temperature for sixteen hours, then poured into an aqueous solution of citric acid (5%, 100 mL). The aqueous solution was extracted with ethyl acetate (2×60 mL), and the combined organic solutions were washed with aqueous citric acid (60 mL), saturated sodium bicarbonate solution (2×60 mL) and 50% saturated sodium chloride solution (2×60 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 20 mL of dichloromethane yielded, upon filtration and drying, 0.439 g (67%) of N-(3-chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide as a white solid: mp 207-212° C.; 1H NMR (CDCl3/CD3OD/300 MHz) 8.90 (s, 1H), 7.86 (d, J=8.66 Hz, 2H), 7.79 (t, J=2.01 Hz, 1H), 7.46 (dd, J=7.05 Hz, J=2.01 Hz, 1H), 7.33 (d, J=8.86 Hz, 2H), 7.21-7.11 (m, 3H), 7.02-6.94 (m, 4H). 19F NMR. (CDCl3/CD3OD/282.2 MHz): −111.38 (m). Mass spectrum, MH+=470. Anal. Calc'd for C22H16N4O3ClFS: C, 56.11; H, 3.42; N, 11.90; Cl, 6.81; S, 7.53. Found: C, 55.95; H, 3.50; N, 11.85; Cl, 6.82; S, 7.50.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-].C(O)(=O)C>CO.[OH-].[Na+]>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[S:9][C:8]=2[CH:16]=1)[CH3:2]
Reactant: CC(=O)c1ccc2cc(S(N)(=O)=O)sc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccc2cc(S(N)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
The acetyl compound from Example 38 (1.79 g, 7 mmole) was dissolved in 40 ml of CH3OH, cooled to 0° C. and NaBH4 (264 mg, 7 mmole) in 4 ml of 40% NaOH was added. The reaction mixture was stirred for 25 minutes then 2.5 g of NH4Cl was added followed by 1 ml glacial acetic acid. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (75 ml) and 20% saturated NaHCO3 (50 ml). The ethyl acetate layer was washed with H2O (50 ml) and the combined aqueous solution was back-extracted with ethyl acetate. The ethyl acetate extracts were combined and dried over Na2SO4. The solvent was removed in vacuo and the residue was crystallized from CHCl3 -dichloroethane yielding 1.56 g (86.7%) of product, m.p. 134°-35° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20](/[CH:25]=[CH:26]/[CH:27]=O)[CH:19]=[CH:18]2.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]=[CH:26][CH:27]=[C:33]1[S:29][C:30](=[O:35])[NH:31][C:32]1=[O:34])[CH:19]=[CH:18]2
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(/C=C/C=O)ccc2c1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=CC=C3SC(=O)NC3=O)ccc2c1
Yield: 73 %

Procedure:
According to the same manner as that described in Example 1, (E)-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl]acrolein was condensed with 2,4-thiazolidinedione to give 5-[3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthyl]propenylidene]-2,4-thiazolidinedione (yield: 73%). This product was recrystallized from chloroform-methanol. Yellow prisms, mp: 267-268° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:17][CH3:18])[C:13]=1[CH:14]([CH3:16])[CH3:15])[CH2:6]P(=O)([O-])[O-].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([CH:14]([CH3:16])[CH3:15])=[C:12]([O:17][CH3:18])[CH:11]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: COc1cc(CP(=O)([O-])[O-])cc(OC)c1C(C)C
Product: COc1cc(C=Cc2cc(F)cc(F)c2)cc(OC)c1C(C)C
Yield: 27 %

Procedure:
This material was prepared from (3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3,5-difluorobenzaldehyde in 27% yield in the same way as described in example 21. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.66 (qint., J=7.0 Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8-7.2 (m, 5H).
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([O-:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].O.O.O.[Na+].[O-:19][P:20]([O:23][P:24]([O:27][P:28]([O-:31])([O-:30])=[O:29])([O-:26])=[O:25])([O-:22])=[O:21].[Na+].[Na+].[Na+].[Na+].[Na+].O.O.[Cl-].[Ca+2].[Cl-].[Cl-].[Ca+2].[Cl-].[OH-].[Na+]>O>[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([OH:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[O-:31][P:28]([O:27][P:24]([O:23][P:20]([O-:22])([O-:21])=[O:19])([O-:26])=[O:25])([O-:30])=[O:29]
Reactant: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
2.03 g sodium alendronate trihydrate (6.25 mmol) and 6.9 g sodium tripolyphosphate, Na5P3O10 were added to 100 mL water, and the mixture was stirred until all dissolved. 10.34 g calcium chloride dihydrate were dissolved in 200 mL water. The calcium chloride solution was heated to 40° C. and the pH was adjusted to 7.0. The alendronate-tripolyphosphonate solution was added into the calcium chloride solution dropwise, keeping the pH of the resulting solution at 7.0 by adding 1N NaOH. The precipitate was collected by filtration and washed with water. The solid was dried in an oven at 120° C. overnight. 8.82 g of calcium complex salt of alendronate with tripolyphosphate was thus obtained.
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
3.5 g of ((S)-2-fluoro-1-methyl-ethyl)-benzene (25.32 mmol) were dissolved in 80 ml of dichloromethane. At 0-5° C., 11.81 g of chlorosulfonic acid (101.31 mmol), dissolved in 20 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature and 2 h at 30° C. The solvent was evaporated. 150 ml of diethyl ether were added to the residue, washed once with 150 ml of water, and the organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent to give 1.5 g of the title compound.
Reaction SMILES: C(ON=O)(C)(C)C.[CH2:8]([O:10][C:11]([C:13]1[C:24]2[CH:23]3[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[CH2:18][CH2:17][C:16]=2[S:15][C:14]=1N)=[O:12])[CH3:9]>C(O)C.O.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH2:8]([O:10][C:11]([C:13]1[C:24]2[CH:23]3[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:22]3)[CH2:18][CH2:17][C:16]=2[S:15][CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(N)sc2c1C1CN(C(=O)OC(C)(C)C)CC1CC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)ON=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1csc2c1C1CN(C(=O)OC(C)(C)C)CC1CC2
Temperature: 60 °C
Yield: 36 %

Procedure:
Tert-butylnitrite (7.09 g, 0.069 mol) was added to the product of step d) (16.8 g, 0.046 mol) dissolved in 200 mL of ethanol followed by the addition of copper diacetate (12.5 g, 0.069 mol). The reaction mixture was heated for one hour at 60° C., cooled to room temperature, diluted with 200 mL of water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 5-50% ethylacetate-hexane gradient to afford the subtitle compound (5.8 g, yield: 36%). MS calculated for C18H25NO4S +H: 352, observed: 352.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[C:12](=[CH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:3]1[C:13]2[C:12](=[CH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 78 h

Procedure:
Sodium hydroxide (1M, 2.5 ml, 2.5 mmol) was added to a solution of a 4:1 E/Z double-bond isomer mixture of ethyl 3-{4-[3-(6H-dibenzo[b,e]oxepin-11-ylidene)-propoxy]-phenyl}2-ethoxy-propionate (0.24 g, 0.51 mmol) in ethanol (5 ml) and the mixture stirred at room temperature for 78 h. The resulting mixture was partitioned between 1N hydrochloric acid (20 ml) and dichloromethane (20 ml), and the organic phase collected. The aqueous phase was further extracted with dichloromethane (3×20 ml) and the combined organics washed with brine, dried (Na2SO4) and evaporated to give a pale yellow gum. This was then purified by column chromatography on silica gel (3% methanol in dichloromethane eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow glass; 0.186 g (80%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN.[C:17]([BH3-])#[N:18].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Amine preparation: To a solution of 1-BOC-4-piperidone (1.0 g) in MeOH (10 mL) was added a solution of freshly prepared methylamine in MeOH (1.0 mL). The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (0.315 g) was added. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.85 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C(Cl)Cl.C([O:17][C:18](=[O:20])[CH3:19])(=O)C>[OH-].[Na+]>[CH3:6][C:7]([CH2:19][C:18]([OH:17])=[O:20])=[O:10].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2]
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)CC(=O)O
Temperature: 10 °C

Procedure:
240 g (0.9 mol) of dimeric p-isopropenyl phenol are dissolved under nitrogen in 800 g of 10% by weight aqueous sodium hydroxide. 400 ml of methylene chloride are then added and the reaction mixture is cooled to 10° C. 375 g (3.6 mols) of acetic acid anhydride are added dropwise with stirring at that temperature, and the mixture subsequently stirred for another hour at 5° to 10° C. The aqueous phase is then separated off, the organic phase is washed with water, bicarbonate solution and again with water and then dried over calcined sodium sulphate. Removal of the solvent by distillation is followed by distillation in a high vacuum, giving 285 g (90% of the theoretical) of diacetate of dimeric p-isopropenyl phenol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]([CH3:12])=[N:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([S:14]([Cl:13])(=[O:16])=[O:15])[C:4]([CH3:12])=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1cc(C)nn1C
Product: Cc1nn(C)c(C(=O)O)c1S(=O)(=O)Cl
Temperature: 5 °C
Reaction time: 10 h

Procedure:
Into 200 ml of chlorosulfonic acid, there was added dropwise 50.4 g (0.3 mol) of Ethyl 1,3-dimethyl-5-pyrazole carboxylate under cooling at 5° C. or lower. After heating at 120° C. under stirring for 10 hours, the reaction mixture was poured into ice-water and extracted with ether. After washing with water and drying, evaporation of the solvent gave 49 g of crude 1,3-dimethyl-4-chlorosulfonyl-5-pyrazole carboxylic acid as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(O)c1ccc(-c2ccccc2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, p-phenyl-acetophenone (0.8 mmol), i-propanol (2 mL) and a solution of potassium carbonate in i-propanol (0.8 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (10 atm) at −20° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-phenylphenyl)ethanol was obtained and the ee value (ee=99.2%) was measured by GC analysis.