Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][S:4]([OH:7])(=O)=[O:5].[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1>>[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:4]([Cl:3])(=[O:7])=[O:5])=[CH:23][CH:22]=2)[N:10]=1
Reactant: CCn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cnc2c(Nc3ccc(S(=O)(=O)Cl)cc3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A three necked round bottomed flask of 250 ml equipped with a bubbler (NaOH) and a magnetic stirrer is charged with 32.2 ml of 98% chlorosulfonic acid (483 mmoles) and cooled to 0° C. 22 g of 2-chloro-9-ethyl-6-(phenyl-amino)-9H-purine (80 mmoles) are added slowly. The mixture is stirred at RT for 2 hours and at 60° C. for 1 hour. The crude mixture is then poured drop by drop into a water bath cooled to 0° C., filtered and dried at 50° C. under HV. 26.67 g (89% yield) of 2-chloro-6-(4-chlorosulfonyl-phenyl-amino)-9-ethyl-9H-purine are obtained as a white crystalline powder. Rf=0.52 (CH2Cl2/MeOH (95/5); m.p. decomp. 220° C.; ESI-MS: 372 (M+H)+; 1H-NMR (d6-DMSO, 200 MHz, TMS): 1.4 ppm (t, 3H, J1=7 Hz, H1), 4.2 ppm (q, 2H, J1=7 Hz, H2), 7.55 ppm (d, 2H, J2=9 Hz, H5), 7.75 ppm (d, 2H, J2=9 Hz, H6), 8.55 ppm (s, 1H, H3), 10.5 ppm (s, 1H, H4).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of Ethyl 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoate (14 g, 37 mmol) in Ethanol (80 mL) was added KOH (6.2 g, 111 mmol) and water (80 mL). The mixture was stirred at room temperature for 4 hours, and then concentrated under reduce pressure. The pH value of the solution was adjusted to 4 by concentrated HCl. The resulting mixture was extracted by EtOAc (200 mL×3). The organic layers were combined and dried over Na2SO4, then concentrated to give the desired compound (12 g, yield 92.5%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>[Ni].CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CNC(=O)c2cccc(Cl)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-chlorobenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, with the exception that Raney nickel and TEA in methanol was used for the hydrogenation step, to give Example 64. ESI-MS m/e 361.5 (M+1).
Reaction SMILES: [CH2:1]([NH:22][C:23](=[O:39])[CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([CH3:37])[C:27]=1[CH3:38])[CH:2]([NH:4][C:5](=[O:21])[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([CH3:19])[C:9]=1[CH3:20])C.C(N)CN>>[CH2:2]([NH:4][C:5](=[O:21])[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:11]([OH:18])=[C:10]([CH3:19])[C:9]=1[CH3:20])[CH2:1][NH:22][C:23](=[O:39])[CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:29]([OH:36])=[C:28]([CH3:37])[C:27]=1[CH3:38]
Reactant: Cc1c(CCC(=O)NCC(C)NC(=O)CCc2cc(C(C)(C)C)c(O)c(C)c2C)cc(C(C)(C)C)c(O)c1C
Solvent: NCCN
Product: Cc1c(CCC(=O)NCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C)c2C)cc(C(C)(C)C)c(O)c1C

Procedure:
N,N'-1,2-propylenebis-{3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionamide} is made in a similar manner by substituting 1,2-propylenediamine for ethylenediamine in the above procedure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH2:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([NH2:37])=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH:25][C:33](=[O:34])[C:32]1[CH:36]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=1[NH2:37])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared (0.6 g, 80%) from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.5 g, 1.5 mmol), 5-chloro-2-amino-benzoic acid (0.28 g, 1.65 mmol) as desribed in general procedure A.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:9][C:10]=1[C:11](OCC)=[O:12])=O)C.O.[NH2:29][NH2:30]>C(O)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:8]2[S:9][C:10]3[C:11](=[O:12])[NH:30][NH:29][C:4](=[O:3])[C:6]=3[N:7]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: CCOC(=O)c1nc(-c2ccc(OCC)c(OCC)c2)sc1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2nc3c(=O)[nH][nH]c(=O)c3s2)cc1OCC
Temperature: 130 °C

Procedure:
In 4 ml of ethanol was suspended 1 g of 4,5-diethoxycarbonyl-2-(3,4-diethoxyphenyl)thiazole. Thereto was added 2 ml of hydrazine hydrate. The mixture was sealed in a tube and heated at 130° C. for 48 hours. After cooling, the resulting crystals were collected by filtration, washed with ethanol, dried and recrystallized from dimethylformamide to obtain 220 mg of 2-(3,4-diethoxyphenyl)-5,6-dihydrothiazolo[4,5-d]pyridazine-4,7-dione.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:50])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].C(Cl)Cl>>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:50])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-dodecylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate in trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:12])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4]1[C:5]([OH:12])=[C:6]([CH:7]=[N+:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[O-:18])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOc1cccc(C=O)c1O
Reactant: CC(C)(C)NO
Product: CCOc1cccc(C=[N+]([O-])C(C)(C)C)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3-ethoxy-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 36.4% yield as a yellow crystalline solid, m.p. 91.9° C. (Rf=0.25 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:25]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:25])=[O:18]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCCCCCBr

Procedure:
A mixture of 22 g. of 16-bromohexadecanoic acid and 200 ml. of methanol is treated with 1.0 ml. of concentrated sulfuric acid and stirred under reflux for 24 hours. The mixture is treated with 10 g. of sodium acetate and the solvent is evaporated. The residue is partially soluble in 300 ml. of ether and the mixture is filtered. The ether solution is dried over magnesium sulfate and evaporated. The residue is crystallized from petroleum ether to yield methyl 16-bromohexadecanoate as a white solid.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[Cl:6][CH2:7][CH2:8][NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13].CC(C)=O>O>[Cl:6][CH2:7][CH2:8][N:9]1[CH:2]=[CH:1][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C=C(CC(=O)OC)NCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
The hydrolysis solution was added to a mechanically-stirred slurry of sodium acetate (17.8 g, 212 mmol) in water (15 mL) at 0° C. over 1 hour, then stirred for a further 10 minutes. Dimethyl 3-(2-chloroethylamino)-2-pentenedioate (20.0 g, 85 mmol) was added, followed by acetone (50 mL), and the solution allowed to warm to room temperature and stirred for 20 hours. The resulting slurry was cooled to 0° C. and kept at that temperature for 4 hours, then filtered through a coarse frit. The precipitate was washed with water (300 mL) and dried, to give 19.9 g (90% yield) of methyl N-(2-chloroethyl)-3-methoxycarbonyl-2-pyrroleacetate as white crystals, m.p. 110°-111° C.,
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([O:18]C)=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([OH:18])=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:8][CH:9]=1
Reactant: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Reaction time: 1 h
Yield: 88.6 %

Procedure:
LiOH (0.2 g, 8.4 mmol) was added into a suspension of methyl 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylate (1.2 g, 4.8 mmol) in THF (20 mL) and water (1 mL). The reaction was stirred for 1 hour. The reaction mixture was poured into water and the solution brought to pH 4 with 1M HCl. The mixture was extracted with EtOAc, washed with brine, dry with Na2SO4, filtered and concentrated to afford the title compound (1 g, 79% yield) as a light brown solid. LRMS (APCI pos) m/e 235.9 (M+1).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:15]=1>CO>[CH3:22][C:21]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:16]2[CH:15]=[C:14]([C:13](=[O:35])[NH:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)[CH:19]=[CH:18][C:17]=2[N:20]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Two milliliters of acetic acid and 5 ml of methanol were added to 0.490 g of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide, and the mixture was stirred at 70° C. for 8 hours. The reaction solution was concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1), and was then crystallized from ethyl acetate. The crystals were separated through filtration, and were dried to give 0.270 g of 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole (243).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.[NH2:33][NH2:34].O>CN(C=O)C>[CH2:24]([C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-phenylacetyl-1-(3-trifluoromethylphenyl)-1,8-naphthyridine-2(1H)-one (212 mg, 0.50 mmol) produced in Synthesis Example 2 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (172 mg, yield 82%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCOCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[C:1]([Br:5])[Br:2])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL methylene chloride was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL methylene chloride in a 1-L rb flask with ice bath cooling over 1.75 h. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formylpiperidine (from Step B2 above) in 100 mL methylene chloride was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL methylene chloride and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes until the total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% sodium bicarbonate, 300 mL water (2×), and 150 mL brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 53.5 g crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0˜15% ethyl acetate in hexanes) gave 21.595 g title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.I[CH3:13].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:13])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
A mixture of 6.87 g of ethyl 4-bromobenzoate (10) was allowed to react with 64 mL (1.4 M in toluene) of methyl magnesium bromide in THF at −40° C. for 1 hour, and the reaction mixture was gradually warmed to 0° C. The reaction was quenched with saturated aqueous ammonium chloride solution and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (50:1 to 10:1 hexanes-ethyl acetate) afforded 6.44 g (99% yield) of 2-(4-bromophenyl)propan-2-o1; MS (AP/CI) observed: 199.1 (M+H−H2O)+, 100%; 213.1, 215.1 (M−H)−, 60%, 80%. 2-(4-Bromophenyl)propan-2-o1 (1.77 g) and iodomethane (1.16 g) in THF (100 mL) were treated with sodium hydride, 60% in mineral oil (328 mg). After stirring for 24 h at room temperature, the reaction mixture was quenched with dilute aqueous hydrochloric acid, was extracted with ethyl acetate, and the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The resultant oil was purified by silica gel chromatography (200:1 hexanes-ethylacetate) to afford 0.5 g of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene; 13C NMR (400 MHz, CDCl3) δ 145.35, 131.53, 127.91, 121.00, 50.90, 28.60.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=1[CH3:33]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: Cc1cc(F)ccc1B(O)O
Product: Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 58.2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol (100 mg, 0.36 mmol) and 4-fluoro-2-methylphenylboronic acid (83 mg, 0.54 mmol) were coupled using the procedure in Example 30 to afford 2-[3-(2,4′-difluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol (83 mg, 58%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.04 (1H, s), 2.26 (3H, s), 6.95-7.05 (2H, m), 7.15-7.33 (3H, m), 7.40 (1H, dd, J 7 and 2), 7.51-7.56 (1H, m), 7.69 (1H, s), 8.06 (1H, d, J 7); m/z (ES+) 397 (100%, [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[O:23]=[CH:24][C@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])O)[OH:26]>>[Br:15][C:11]1[C:12](=[O:14])[NH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:1][CH:33]3[CH:31]([OH:32])[CH:29]([OH:30])[CH:27]([CH:25]([OH:26])[CH2:24][OH:23])[O:34]3)[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])=[N:9][C:10]=1[CH:16]([CH3:18])[CH3:17]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Product: CCCOc1ccc(NC2OC(C(O)CO)C(O)C2O)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 34 with mannose in the same manner as that of example 77. 1H NMR (DMSO-d6) δ: 7.47 (1H, d), 7.21 (1H, dd), 7.09 (1H, d), 4.75 (1H, d), 4.01 (2H, t), 3.78-3.37 (7H, m), 2.57 (2H, q), 2.46 (2H, q), 1.72 (2H, m), 1.18 (6H, d), 0.95 (3H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:17])([P:13]([OH:16])(=[O:15])[OH:14])[P:9]([OH:12])(=[O:11])[OH:10])[CH:2]=1.[OH-:18].[Na+:19]>O>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:9]([O-:11])([OH:12])=[O:10])([P:13]([OH:16])([OH:15])=[O:14])[OH:17])[CH:4]=1.[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:9]([O-:11])([OH:12])=[O:10])([P:13]([OH:16])([OH:15])=[O:14])[OH:17])[CH:4]=1.[OH2:18].[OH2:10].[OH2:10].[OH2:10].[OH2:10].[Na+:19].[Na+:19]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 25 °C
Yield: 194.1 %

Procedure:
To 60 ml of purified water, 10.0 g of 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid (risedronic acid) and 1.41 g of sodium hydroxide were added and dissolved at an elevated temperature of 65° C. After the dissolution, the resulting solution was cooled to 25° C. over 3 hours for crystallization. The obtained crystals were filtered and vacuum dried to obtain 8.0 g of risedronate sodium hemipentahydrate (64.7% of theoretical yield). (LOD by TGA=13.2%)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].O>CS(C)=O>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][N:4]([C:5]2[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=2)[C:1](=[O:3])[CH3:2])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(=O)Nc1ccc(C(=O)C(C)CC(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(C(=O)C(C)CC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
30.0 g (120 mmol) of 3-(4-acetamidobenzoyl)-butyric acid are added to a suspension of 7.6 g (253 mmol) of sodium hydride (80%) in 150 ml of dimethyl sulphoxide and the mixture is stirred for 30 minutes at 60° C. After the addition of 33.2 g (120 mmol) of N-(3-bromopropyl)-phthalimide, stirring is continued at 80° C. for 6 hours. After cooling, the reaction mixture is poured out on 200 ml of iced water and extracted with 3×100 ml of dichloromethane. The extracts are discarded. The aqueous phase is then adjusted to pH 6.5 with 2N hydrochloric acid and again extracted with 3×100 ml of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum. The oil obtained as residue crystallizes when triturated with 20 ml of ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:22][CH3:23].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:28]([Cl:44])=[CH:27][N:26]=1>>[Cl:44][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38](=[O:40])(=[O:39])[N:41]([CH3:42])[CH3:43])=[N:30][C:25]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:22][CH3:23])=[N:26][CH:27]=1
Reactant: CCN1C(=O)C(NC(=O)COC)CCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)COC)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2-methoxy-acetamide (100 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide were converted to the title compound (10 mgs) as a white powder. 1H-NMR (CDCl3): 9.45 (s, 1H), 8.54 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.54 (s, 2H), 7.32-7.28 (m, 1H), 6.91 (d, J=8.3 Hz, 1H), 4.59-4.52 (m, 1H), 4.38-4.32 (m, 1H), 3.93-3.80 (m, 4H), 3.46 (s, 3H), 3.12-3.10 (m, 1H), 2.79 (s, 3H), 2.78 (s, 1H), 2.68-2.53 (m, 2H), 2.05-1.98 (m, 1H), 1.27-1.16 (m, 5H). LC/MS. (M+H)+ found 632.22.