Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1.[CH3:32][C:33]([CH3:47])([O:35][C:36]([NH:38][C@H:39]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40](O)=[O:41])=[O:37])[CH3:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH2:18].[CH3:34][C:33]([CH3:47])([O:35][C:36]([NH:38][C@H:39]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:40]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1)=[O:41])=[O:37])[CH3:32]
Reactant: O=C1NC(CC2CNc3ccccc32)c2nc3ccccc3c(=O)n2-c2ccccc21
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(CC2NC(=O)c3ccccc3-n3c2nc2ccccc2c3=O)c2ccccc21
Product: O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
7-[(2,3-Dihydro-1H-indol-3-yl)methyl]quinazolino(3,2-A)-1,4-benzodiazepin-5,13-(6H,7H)-dione (250 mg, 0.612 mmole), 2(R)-((1,1-dimethylethoxy)carbonyl)amino-4-methylpentanoic acid (142 mg, 0.734 mmole), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (141 mg, 0.734 mmole), 1-hydroxybenzotriazole (99 mg, 0.734 mmole), and triethylamine (102 μl, 0.734 mmole) were mixed with 12 ml of dry dimethylformamide and the resulting mixture was protected from moisture and stirred at room temperature for 48 hours. The mixture was filtered, rotoevaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution, 10% citric acid and brine, then dried (MgSO4) and concentrated. The crude product thus obtained as a mixture of diastereomers was purified by preparative thick layer chromatography (silica gel, 97:3 hexane-ethyl acetate v/v) to afford isomer 2.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[F:15][C:16]1[CH:17]=C(Br)[CH:19]=[CH:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:6]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][NH:11]3)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(N2CC3CC2CN3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a mixture containing 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol), 3-fluoro-phenylbromide (103.8 mg, 0.6 mmol), Pd(AcO) (8 mg, 0.03 mmol), 2-(di-t-butylphosphino)biphenyl (20 mg, 0.07 mmol) and sodium t-butoxide (100 mg, 1 mmol) in toluene (3 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (60 mg, 41% yield for two steps) as TFA salt.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH2:16].[O:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:22][CH2:23]2)=[N:25]1.[O:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:22][CH2:23]2)=[N:25]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Product: O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2noc3ccccc23)CC1
Yield: 40 %

Procedure:
Reaction of 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione and 3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure of Example 3 and crystallization of the free base from isopropanol affords a 40% yield of 8-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione hemihydrate, m.p. 96°-98° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=O.[O-]CC.[Na+].[C:12](=[O:19])([O:16]CC)OCC.[S:20]1[CH:24]=[CH:23][C:22](C=O)=[CH:21]1>C(O)C.O.[OH-].[Na+]>[CH2:6]([O:5]/[C:3](=[CH:2]\[C:22]1[CH:23]=[CH:24][S:20][CH:21]=1)/[C:12]([OH:16])=[O:19])[CH3:7]
Reactant: CCOC(=O)OCC
Reactant: O=Cc1ccsc1
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCO/C(=C\c1ccsc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Following the procedure of (Vol. 8, No. 6, 2004, Organic Research & Development) with modification, this compound was synthesised as follows: Ethyl chloroacetate (44.8 ml, 421 mmol) and anhydrous ethanol (30 ml) were cooled to 10-12° C. A solution of sodium ethoxide in ethanol (21% w/w, 165 ml) was added over 25 min at 12-16° C. under N2. After addition was complete the reaction mixture was warmed to 25° C. and stirred for 1 h. The mixture was then cooled to 10° C. and solid NaOEt (33.3 g, 488 mmol) was then added portion-wise over 0.5 h at 10-14° C. Ethanol (20 ml) was then added followed by the addition of diethyl carbonate (31 ml, 256 mmol). The slurry was then cooled to 0-5° C. and then 3-thiophene carboxaldehyde (20.2 g, 179.5 mmol) was added over a period of 1 h. After addition was complete the mixture was stirred at 40° C. in an oil bath for 15 h. The slurry was then cooled to 10-15° C. and then water (40 ml) was added followed by the addition of aqueous NaOH (55 ml of a 10 M solution). The resulting slurry was then stirred at pH 14 for 3 h at 20° C. The mixture was then diluted with water (60 ml) and then placed under reduced pressure at 45° C. to remove most of the ethanol and some water. The resulting thick slurry was then cooled to 4° C. in an ice-bath and then treated with conc. HCl (115 ml) drop-wise. The resulting slurry was then stirred at room temperature for 1.5 h and then extracted with EtOAc (2×200 ml) and the organic layer washed with water, brine and then dried (sodium sulphate). Evaporation of the solvent under reduced pressure afforded a deep-brown residue. This was dissolved in 5 M NaOH (250 ml) and this solution was washed with EtOAc (100 ml). The basic aqueous was then cooled to 4° C. and acidified with conc. HCl (11 M) to pH 4-6. The product was extracted with diethyl ether (3×200 ml), washed with brine, dried (sodium sulphate) and the solvent removed under reduced pressure. The residue was then filtered through a pad of silica (eluent hexane:EtOAc 90:10). The solvent was removed under reduced pressure and then the residue recrystallised from Et2O/hexane to afford the title compound as yellow crystals (79%). M.p. 88-89° C. 1H NMR (CDCl3, 250 MHz) δ 11.16 (1H, br s, COOH), 7.73-7.75 (1H, dd, j=0.5 Hz, Ar), 7.44-7.47 (1H, dd, J=1 Hz, Ar), 7.25-7.28 (1H, m, Ar), 7.18 (1H, s, CH═C), 3.96-4.05 (2H, q, J=7 Hz, CH2CH3), 1.35 (3H, t, J=7 Hz, CH2CH3),). Found: C, 54.64; H, 5.08; Calculated for C9H10SO3 C, 54.54; H, 5.08. M/z [(Cl) 222 (M)+ 30%, 223 (M+H)+ 50%, 240 (M+NH4)+ 100%; Found: 223.09705; required for C12H15O4 223.09155]. M/z [(Cl) 198 (M)+ 22%, 199 (M+H)+ 50%, 216 (M+NH4)+ 100%].
Reaction SMILES: [C:1]([N:6]([C:22]1[C:27]([N+:28]([O-])=O)=[C:26]([CH3:31])[CH:25]=[CH:24][N:23]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]2[C:20]#[N:21])=[CH:10][CH:9]=1)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].C(O)C>[Cl:19][C:17]1[CH:16]=[C:15]([C:20]#[N:21])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:6]3[C:22]4=[N:23][CH:24]=[CH:25][C:26]([CH3:31])=[C:27]4[N:28]=[C:1]3[CH2:2][CH2:3][CH3:4])=[CH:9][CH:10]=2)[CH:18]=1
Reactant: CCCC(=O)N(Cc1ccc(-n2cc(Cl)cc2C#N)cc1)c1nccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-[N-butyryl-N-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]amino]-4-methyl-3-nitropyridine (700 mg), iron powder (894 mg), acetic acid (1.8 ml) and ethanol (15 ml) was stirred under reflux for 15 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned into ethyl acetate (100 ml) and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane-ethyl acetate =1:1) to give 3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (565 mg) as a pale yellow powder.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1)=[O:12].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O.Cl[Pd]Cl>[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:17][CH:18]=1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)nn1
Temperature: 80 °C
Yield: 12 %

Procedure:
Na2CO3 (183 mg, 1.73 mmol) was added to a stirred solution of 6-chloro-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (263 mg, 0.57 mmol) in DMF (6 mL). PdCl2 (dppf) (80.4 mg, 0.11 mmol) and phenyl boronic acid (89.9 mg, 0.69 mmol) were then added and the reaction mixture was heated at 80° C. for 2 hrs. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by preparative HPLC afford 34 mg (11% yield) of 6-Phenyl-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.2%. 1H NMR (DMSO-d6): δ 9.3 (t, 1H), 8.5 (d, 1H), 8.3 (t, 3H), 8.0-7.5 (m, 7H), 4.4 (d, 2H), 3.8 (d, 4H), 3.46 (bs, 2H), 3.2 (d, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30](C(Cl)=O)=[CH:29][CH:28]=1.[N:42]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[NH2:53])[CH:46]=[CH:45][CH:44]=[CH:43]1>>[C:36]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:38][C:39]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:10][C@H:9]2[C:24]([NH:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:42]2[CH:46]=[CH:45][CH:44]=[CH:43]2)=[O:26])=[O:7])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: Nc1ccccc1-n1cccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccccc1-n1cccc1)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54% purity by LC/MS. MS(ESI+): m/z=623.6.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:27])([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.CO.C(Cl)(Cl)[Cl:31]>C(O)C>[ClH:31].[OH:4][CH:2]([CH2:1][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:27][C:17]([CH3:26])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)COc1cccc2ccccc12
Product: Cl

Procedure:
A stirred solution of 1-naphthyl glycidyl ether (400 mg, 2 mmol) and 1,1-dimethyl-2-(4-fluorophenyl)ethylamine (334 mg, 2 mmol) in absolute ethanol (2 mL) was heated at 50-60° C. for 16 hours. Chromatography of the resulting reaction mixture through silica (5×30 cm) using a gradient of chloroform to 5% methanol in chloroform afforded the free base of the title compound: GC/EI-MS, m/z (rel. int.) 368 (M+1, 1), 352 (2), 258 (100), 183 (5), 157 (4), 127 (5), 115 (18), 109 (23), 71 (30).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:14][CH:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].[CH2:22]([N:24](CC1C=CC(OC)=CC=1)[C:25]1[C:30]2=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:29]2[N:28]=[C:27](S(C)(=O)=O)[N:26]=1)[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:9]1[C:8]([N:11]2[CH2:12][CH:13]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:14]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:27]1[N:26]=[C:25]([NH:24][CH2:22][CH3:23])[C:30]2=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:29]2[N:28]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(S(C)(=O)=O)nn2c(C#N)cnc12
Reactant: CN1CCN(C2CN(c3cc(C#N)cc(N)c3Cl)C2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC(N4CCN(C)CC4)C3)c2Cl)nn2c(C#N)cnc12

Procedure:
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile (Example 151C) (40 mg, 0.131 mmol), 4-(ethyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 7) (50.5 mg, 0.131 mmol), and Cs2CO3 (128 mg, 0.392 mmol) in DMF were heated at 45° C. for 14 h. LC/MS showed product formation. The mixture was filtered and rinsed with CH2Cl2, then concentrated and the crude was taken forward to the next reaction.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].[P:16](=O)([OH:19])([OH:18])[OH:17].P(Cl)(Cl)(Cl)=O>O.C1(C)C=CC=CC=1>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1
Reactant: OP(O)O
Reactant: O=P(O)(O)O
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 90 °C
Yield: 68 %

Procedure:
A 500 ml cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was charged with 3-pyridine acetic acid hydrochloride (6.94 g, 0.04 mole), phosphorous acid (9.84 g, 0.12 mole), ortho-phosphoric acid (11.80 g, 0.12 mole) and toluene (50 ml). The suspension was heated to 90° C. and phosphorous oxychloride (11.2 ml, 0.12 mole) was added dropwise during 20 minutes. The reaction mixture was then heated to 95° C. for 20.5 hours. Water (50 ml) was added after cooling the reaction mixture to 80° C. The mixture was stirred vigorously until the solidified product dissolved completely. The toluene and the aqueous phases were separated and the aqueous phase was heated at 95° C. for 5.5 hours. The aqueous phase was cooled to 25° C. and absolute ethanol (50 ml) was added to precipitate the final product. The suspension was cooled to 5° C. for 1 hour. The white product was filtered, washed with absolute ethanol (2×20 ml) and dried at 65° C. for 5 hours to obtain 7.70 g (68%) of risedronic acid monohydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)CC>[CH3:28][O:27][CH2:26]/[CH:25]=[CH:24]/[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCO
Product: COC/C=C/c1cc(C(=O)OC)c2ccccc2c1
Temperature: 90 °C

Procedure:
Methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.2 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 N aq. Na2CO3 (2 eq.) was added and the resulting biphasic suspension was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, 1 N aq. HCl, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21]C(OC(C)(C)C)=O)[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH2:21])[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCI (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:18])([CH3:17])[C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[N+:19]([O-])=O)=O.[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:6][C:7]2[CH:15]=[C:14]3[NH:13][C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[C:10]3=[CH:9][C:8]=2[N:19]=1
Reactant: COCC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 5, 1.6 g. (5.4 mmole) 6-methoxymethylcarbonylamino-5-nitro-3,3-dimethylindolin-2-one are dissolved in 160 ml. ethanol and hydrogenated in the presence of 0.8 g. 10% palladium on charcoal at normal pressure and ambient temperature. After 360 ml. of hydrogen have been taken up, the catalyst is filtered off with suction and the filtrate is evaporated to dryness in a vacuum. The residue is purified over a silica gel column (elution agent: dichloromethane/methanol 95:5 v/v). The appropriate fractions are evaporated to dryness and the residue is recrystallised from isopropanol. There are obtained 800 mg. (60% of theory) of the title compound; m.p. 203°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.CO[CH:20](OC)[CH2:21][C:22](=O)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]3[N:15]=[CH:20][CH:21]=[C:22]([CH3:23])[N:12]3[N:11]=2)=[CH:16][CH:17]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]3[N:15]=[C:22]([CH3:23])[CH:21]=[CH:20][N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Reactant: COC(CC(C)=O)OC
Product: Cc1ccn2nc(SCCOc3ccc(Cl)cc3)nc2n1
Product: Cc1ccnc2nc(SCCOc3ccc(Cl)cc3)nn12

Procedure:
The title compound was prepared according to the experimentals described for Example 23 above from 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine and acetylacetaldehyde dimethyl acetal. The two regioisomers were separated by silica gel chromatography. 2-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-5-methyl-[1,2,4]-triazolo[1,5-a]pyrimidine was obtained as off white crystals in 25% yield: EM (calc.): 320.0; MS (ESI) m/e: 321.0 (M+H)+. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.53 (d, 1H, J=6.8 Hz), 7.22 (d, 2H), 6.90 (d, 1H, J=6.8 Hz), 6.87 (d, 2H), 4.34 (t, 2H), 3.63 (t, 2H), 2.70 (s, 3H).
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[CH3:21]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: C1CCC(OC2CCCCO2)OC1
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A mixture of 5.7 g (0.026 moles) of (Z)-11-heptadecenol-tetrahydropyranyl ether (Formula III, R=CH3, Y=tetrahydropyranyl), 10 ml of acetic acid and 3 ml of acetyl chloride is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 30 g. of ice, and extracted with 100 ml. of hexane. The hexane solution is washed with water, dried over magnesium sulfate, the solvent is evaporated, and the residue is distilled in fine vacuo. 2.6 g. (51.6%) of (Z)-11-heptadecenyl acetate (Formula I, R=CH3) are obtained; b.p.: 122°-126° C./0.05 mmHg.