Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:15]([O:17]C)=O)=[C:8]([C:12](Cl)=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][NH2:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7]3[C:15](=[O:17])[N:30]([C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:31]=[C:12]([OH:13])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN)cc1OC
Reactant: COC(=O)c1c(C(=O)Cl)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1OC
Temperature: 0 °C
Yield: 10.5 %

Procedure:
7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (7.00 g, 23.3 mM) was dissolved in tetrahydrofuran (210 mL) and added dropwise over 20 minutes to a cold (0 C) solution of 3,4-dimethoxyphenylhydrazine (9.80 g, 58.3 mM) in tetrahydrofuran (420 mL) with stirring. The resulting brown suspension was stirred at 0 C for 30 minutes and at room temperature for 2 hours. Ice/water slurry (450 mL) was added to the reaction mixture followed by 1N HCl (1.2 L) and the brown suspension was stirred for 1 hour. The solids were separated by filtration and washed with water and then ether to provide7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimethoxyphenyl)hydrazide (15 g, wet). The combined filtrate and washes were partially concentrated to remove the THF whereupon a precipitate formed. This precipitate was collected and washed with water and then ether to give the crude title compound (2.00 g). Recrystallization of this crude from refluxing methanol (500 mL) gave the title compound (0.98 g, 10%) as a tan powder, mp=334-336 C; MS(CI): 400 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C@:9]23[C:12]4[C:18]5[CH2:19][C@H:3]1[C@H:4]2[CH2:5][CH2:6][C@H:7]([OH:21])[C@H:8]3[O:14][C:13]=4[C:15]([OH:20])=[CH:16][CH:17]=5.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.COCCOC>[OH:20][C:15]1[C:13]2[O:14][C@@H:8]3[C:7](=[O:21])[CH2:6][CH2:5][C@H:4]4[C@:9]53[CH2:10][CH2:11][N:2]([CH3:1])[C@H:3]4[CH2:19][C:18]([C:12]=25)=[CH:17][CH:16]=1
Reactant: CN1CC[C@@]23c4c5ccc(O)c4O[C@@H]2[C@@H](O)CC[C@@H]3[C@@H]1C5
Agent: CC(C)(C)[O-]
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CN1CC[C@@]23c4c5ccc(O)c4O[C@@H]2C(=O)CC[C@@H]3[C@@H]1C5
Temperature: 85 °C
Yield: 42.9 %

Procedure:
To a suspension of 26 (8 mg, 0.028 mmol) and benzophenone (10.2 mg, 0.056 mmol) in a mixture of toluene (1 mL) and DME (1 mL) was added potassium tert-butoxide (18 mg, 0.16 mmol) at room temperature. The resulting reaction mixture was heated at 85° C. for 8 hours and then the solvent was evaporated under reduced pressure to obtain the crude reaction mixture, which was purified by column chromatography on silica gel using [CH2Cl2/MeOH (95:5)→CH2Cl2/MeOH (90:10)] as eluent to provide 4 (3.5 mg, 0.012 mmol, 44%) as a white solid along with unreacted starting material 26 (4 mg, 0.014 mmol, 53%). The physical and spectral properties of 4 were matched with those given in the literature.7
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[OH-].[Na+]>O>[CH:8](=[O:9])[C:12]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:18]
Reactant: CN(C)C=O
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccccc1O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3.3 g of 3-aminophenol, 7.0 g of 2-ethylhexyl bromide and 2.0 g of calcium carbonate powder were mixed together with 10 g of dimethylformamide and reacted in a nitrogen atmosphere at 120° C. for 2 hours. Then, 6.4 g of n-octyl bromide was added to the reaction system, and the reaction was further continued for 5 hours under the above conditions. After the reaction, the reaction mixture was returned to room temperature and extracted with toluene to obtain 3-(N-octyl-N-2-ethylhexyl)aminophenol. Then, 11 g of phosphorus oxychloride was added to 13 g of dimethylformamide and stirred for one hour at a temperature of not higher than 15° C., and then the above aminophenol derivative was dropwise added and mixed thereto, and the reaction was carried out at a reaction temperature of 70° C. for 1.5 hours. The reaction product was returned to room temperature, and then put into water containing 8.6 g of sodium hydroxide to obtain a corresponding salicylaldehyde derivative. Then, into 20 g of ethanol, 4.0 g of 2-benzothiazolylacetic acid ethyl ester, 7.7 g of the above salicylaldehyde derivative and 0.5 g of piperidine were mixed and dissolved and reacted at 80° C. for one hour to obtain the desired product as yellowish orange crystals.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][CH:50]([C:52]1[CH:62]=[C:61]([CH:63]([CH3:65])[CH3:64])[CH:60]=[C:59]([CH:66]([CH3:68])[CH3:67])[C:53]=1[O:54]CC(O)=O)[CH3:51]>>[CH3:68][CH:66]([C:59]1[CH:60]=[C:61]([CH:63]([CH3:65])[CH3:64])[CH:62]=[C:52]([CH:50]([CH3:51])[CH3:49])[C:53]=1[O:54][CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15])[CH3:67]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cc(C(C)C)c(OCC(=O)O)c(C(C)C)c1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1cc(C(C)C)c(OCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with [2,4,6-tris(1-methylethyl)phenoxy]acetic acid, mp 126°-128° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:27].F[P-](F)(F)(F)(F)F.CNC.C(N(CC)CC)C>CN(C=O)C.O>[C:18]([O:17][C:15]([NH:14][CH:13]([C:22]([N:26]([CH3:27])[CH3:25])=[O:24])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (10.0 g, 30.0 mmol) in DMF (100 mL) was added HATU (14.0 g, 36.0 mmol). After 2 hours, dimethylamine (4.9 g, 60 mmol) and triethylamine (15.0 g, 149 mmol) were added. After 16 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water gradient) to give benzyl {2-[(tert-butoxycarbonyl)amino]-3-(dimethylamino)-3-oxopropyl}carbamate. MS ESI calc'd. for C18H28N3O5 [M+H]+ 366. found 366. 1H NMR (400 MHz, CD3OD) δ 7.33-7.31 (m, 5H), 5.31-5.20 (m, 2H), 4.61-4.48 (m, 1H), 2.93 (s, 3H), 2.87 (s, 3H), 2.74-2.71 (m, 1H), 2.71-2.68 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.[C:36]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)(=[O:41])[CH2:37][C:38]([O-])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][O:42][C:36]([CH2:37][C:38]([NH:2][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][CH:19]=3)[CH:4]=2)=[O:39])=[O:41])=[CH:49][CH:48]=1
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)CC(=O)OCc2ccc(OC)cc2)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 mg of ethyl 4-amino-2-[p-(4 -phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 107 mg of mono-p-methoxybenzyl malonate and 5 ml of pyridine was added 90 mg of dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68. Thereafter the system was applied to silica gel column chromatography and eluted with a toluene-ethyl acetate (4:1) mixture to obtain 110 mg of caramel-like ethyl 4-(p-methoxybenzyloxycarbonyl)acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [H-].[Na+].CO[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1)=[O:6].[C:14](#[N:16])[CH3:15].C(Cl)Cl.CO>C1(C)C=CC=CC=1>[Cl:13][C:9]1[N:8]=[C:7]([C:5](=[O:6])[CH2:15][C:14]#[N:16])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of NaH (1.03 g, 26 mmol; 60% in mineral oil) in toluene (30 ml) was heated to 65° under an argon atmosphere. A solution of 6-chloro-pyridine-2-carboxylic acid methyl ester (4.4 g, 26 mmol) and acetonitrile (1.33 ml, 26 mmol) in toluene (20 ml; heating was required to dissolve the ester) was then added dropwise (exothermic), and the mixture was stirred at 65° for 24 h (compact slurry). After cooling to r.t., ice water was added while stirring. The aqueous phase was collected, washed with Et2O, neutralized with HCl, extracted with CH2Cl2, dried over MgSO4, filtered and evaporated. The product was obtained after silica gel chromatography using a CH2Cl2/MeOH gradient (2.04 g, 40%) as brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CNCCO
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCO)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 125 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5 g, 29 mmol), 2-Methylamino-ethanol (7 mL, 87 mmol) and anhydrous potassium carbonate (5.3 g, 38 mmol) in N,N-dimethylacetamide (10 ml) were stirred at 125° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water (30 mL), stirred vigorously and incubated at 4° C. overnight. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-[(3-Amino-4-nitro-phenyl)-methyl-amino]-ethanol (5.4 g, 88% yield) as a yellow solid and used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([P:12]([O:23][CH2:24][CH3:25])([CH2:14][P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:8][C:7]=1[C:26]([CH3:39])([CH3:38])[CH2:27][C:28]([O:30]CC1C=CC=CC=1)=[O:29])(=[O:4])[CH2:2][CH3:3]>CO.[Pd]>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([P:12]([O:23][CH2:24][CH3:25])([CH2:14][P:15]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])=[O:16])=[O:13])=[CH:8][C:7]=1[C:26]([CH3:39])([CH3:38])[CH2:27][C:28]([OH:30])=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)O)c1)OCC
Yield: 92.3 %

Procedure:
Compound 123 (300 mg, 0.515 mmol) was dissolved in methanol (5 mL) and hydrogenated over Pd/C (30%, 95 mg) under H2 (1 atm) for 3 hr. The catalyst was filtered off and the solvent removed under reduced pressure resulting in the pale-yellow liquid 124 (234 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.0, 3H), 1.25 (m, 9H), 1.49 (s, 3H), 1.52 (s, 3H), 2.55-2.68 (m, 4H), 2.72 (AB q, J=13.8, 2H), 3.90-4.13 (m, 6H), 7.15 (dd, J=3.5, 8.1, 1H), 7.67 (ddd, J=1.8, 8.3, 11.8, 1H), 7.84 (dd, J=1.8, 13.7, 1H): 31P (162 MHz, CDCl3) δ 17.53 (d, J=3.7, 1P), 31.82 (d, J=3.7, 1P).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:8]([C:24](O)=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C@@H:8]([C:24]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:25])[NH:7][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (1.41 ml) and Boc-L-Tyr(Bzl)-OH (6.00 g, manufactured by Peptide Institute, Inc.) were condensed to give N-(O-benzyl-Boc-L-tyrosyl)morpholine (8.10 g) as a white powder (yield quantitative). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (2.76 g) as obtained in Reference Example 8 to yield the title compound (compound 58; 6.14 g) as a white powder (yield 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:21]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[C:15]([OH:21])=[O:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCC[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]pentan-1-ol (37.1 g, 109 mmol in dry acetonitrile (500 mL) at −78° C. was added a solution of periodic acid (71.7 g) and chromium trioxide (144 mg) in dry acetonitrile (630 mL) over 1 hour. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was concentrated under reduced pressure to a total volume of approximately 500 mL. A solution of citric acid (22 g in 250 mL H2O) was added and the mixture was extracted with ethyl acetate (800 mL). The solution was washed with freshly prepared NaHSO3 (2×200 mL, 25 g solid dissolved to 200 mL with water) brine (300 mL), dried over MgSO4, filtered, and evaporated to give a pale orange solid, which was triturated with 5% ethyl acetate/hexanes to give (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid. Additional acid was obtained by concentrating the mother liquors, partitioning the residue between ether and aqueous NaHCO3, acidifying the aqueous layer with citric acid, extracting with ethyl acetate, drying over MgSO4, filtering, and evaporating the solvent.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([NH2:7])=[O:6])[CH:17]=[CH:16][CH:15]=2
Reactant: C#CCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(N)=O)c21

Procedure:
Using Method C above, 4-pentynamide (49 mg, 0.5 mmol) (prepared from 4-pentyonic acid according to Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (120 mg, 0.32 mmol) using (Ph3P)2PdCl2 (12 mg) and CuI (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynamide. (Yield 45 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH2:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:29]3[CH:30]=[CH:31][C:26]([CH2:25][O:24][CH2:22][CH3:23])=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CCOCc1ccc(I)cc1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: CCOCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-ethoxymethyl-4-iodo-benzene (for synthesis: M. Schamchal et al; J. Gen. Chem. USSR (Engl. Transl.); 34; 1964; 1830). White solid. MS (ESI): 463.2 MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2=[CH:11][S:12][CH:13]=[C:9]2[N:8]=[C:7]1[S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[O:5])[CH3:2].C(=O)(O)[O-:25].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2=[CH:11][S:12][CH:13]=[C:9]2[N:8]=[C:7]1[S:14]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[O:25])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)n1c(SCc2cc(OC)ccn2)nc2cscc21
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)n1c(S(=O)Cc2cc(OC)ccn2)nc2cscc21

Procedure:
To 750 mg (2.1 mmol) of 1-ethoxycarbonyl-2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole in 30 ml of methylene chloride and 25 ml of 0.5 N aqueous sodium bicarbonate solution were added dropwise, with stirring, initially 420 mg (2.1 mmol) and then a further 210 mg (1.05 mmol) of 3-chloroperbenzoic acid CH2Cl2. The organic phase was dried over MgSO4 and concentrated in vacuo, and the residue was crystallized from ethyl acetate. Melting point 143° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[C:5](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[CH:29][C:22]=3[O:21][CH3:20])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)CC(=O)C=Cc1cccc2[nH]ccc12
Reactant: COc1cc(OCc2cccnc2)ccc1C=O
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: O
Product: COc1cc(OCc2cccnc2)ccc1/C=C/C(=O)CC(=O)/C=C/c1cccc2[nH]ccc12
Temperature: 70 °C
Yield: 69.5 %

Procedure:
In a 20 mL reaction vessel were placed 31.0 mg (136 μmol) of 6-(1H-indol-4-yl)hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 33 mg (0.14 mmol) of 2-methoxy-4-(3-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 42.8 mg (70% yield) of the title compound as an orange powder.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:14]([OH:17])([OH:16])=[O:15])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.O.[OH-].[Na+:20]>C(O)(C)(C)C>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:10]([O-:12])([OH:13])=[O:11])([P:14]([OH:17])([OH:16])=[O:15])[OH:9])[CH:2]=1.[Na+:20]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O

Procedure:
20.0 g of risedronic acid, 70 ml of deionized water and 100 ml of ter-butanol are charged into a 1-liter reactor, equipped with mechanical stirrer and thermometer. The suspension, under stirring, is added with 70.7 ml of 1M NaOH. The admixture is kept under stirring for 10′, up to complete dissolution of the undissolved solids. The solution, whose pH is 4.60, is filtered on a paper filter and put into Lioguard chambers. The chambers are introduced into a lyophilizer and processed according to example 1. At the end 19.8 g of lyophilized amorphous sodium risedronate are thus obtained (yields 92.6%).
Reaction SMILES: [O:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>>[OH:17][CH2:12][CH2:13][CH2:14][C:15]([NH:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C1CCCO1
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Product: O=C(CCCO)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.8 g (0.03 mol) trans-4-nitroxycyclohexylamine are mixed with 5.7 ml 4-butyrolactone and stirred for 3 d at room temperature. For the removal of the excess lactone, it is filtered over a silicic gel acid with ethyl acetate. After collection of the pure fractions, it is distilled in a vacuum, triturated with ether and filtered off with suction. There remain 2.1 g of the title compound of the melting point 58°-60° C., i.e. 28% of theory.
Reaction SMILES: Cl[C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)CC)C>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(C(=O)Cl)=C(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=C(C)C
Yield: 30 %

Procedure:
In a manner similar to the procedure described in Example I, ethyl 2-chlorocarbonyl-3-methyl-2-butenoate (9.6 grams, 0.05 mole) prepared in Example XXV, 4-bromo-2-methylaniline (5.3 grams, 0.03 mole) and triethylamine (4.0 milliliters, 0.03 mole) were reacted to give 2.9 grams (0.009 mole) of ethyl 2-[(4-bromo- 2-methylphenyl)-aminocarbonyl]-3-methyl-2-butenoate as a white solid having a melting point of 116° C.-119° C. NMR analysis of the product indicated the following: