Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][CH2:36][C:37]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:38]
Reactant: COCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 3-methoxypropionic acid (0.15 ml, 1.6 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.255 g), melting point: 149° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:13][NH2:14]>>[NH2:1][C:2]1[C:3]([C:9]([NH:14][CH3:13])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CN
Product: CNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (7.5 g, 32.32 mmol) was suspended in 40% aqueous methylamine and the resulting mixture stirred vigorously at RT for 4 hours. The resultant precipitate was collected, washed with water and dried to give the desired product (6.73 g, 90% Yield). 1H NMR (400.0 MHz, DMSO) d 2.76 (s, 3H), 7.75 (br s, 2H), 8.34 (s, 1H), 8.58 (b rs, 1H) ppm; MS (ES+) 232.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=O)[CH3:21]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:20]1[CH3:21]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COc1ccccc1NC(C)=O
Product: COc1ccccc1-n1c(C)nc2ccccc21
Yield: 50.4 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-(2-methoxyphenyl)-acetamide (99 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (60 mg, 50%). 1H NMR (DMSO) δ 2.29 (s, 3 H), 3.73 (s, 3 H), 6.88 (d, J=8.1 Hz, 1 H), 7.08-7.18 (m, 3 H), 7.31 (d, J=7.6 Hz, 1 H), 7.41 (d, J=7.9 Hz, 1 H), 7.54-7.58 (m, 2 H); 13C NMR δ 13.5, 55.6, 109.6, 112.9, 118.2, 121.0, 121.5, 121.9, 123.5, 129.0, 130.7, 136.2, 142.4, 151.9, 154.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@@H]1CO1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.12 g, 0.28 mmol), 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (52.4 mg, 0.248 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.212 g, 0.56 mmol) and iPr2NEt (0.25 mL, 1.4 mmol) in CH2Cl2 (3 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (4 g column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((5)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (58 mg, 35.4%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3+H [(M+H)+]: 660.2315. found: 660.2316.
Reaction SMILES: Cl[C:2](Cl)([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:15]([NH:23][NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.CCOCC>[CH2:15]([NH:23][N:24]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Cl)(Cl)C(=O)O
Reactant: NNCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(=NNCCc1ccccc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of 5.7 g. 2,2-dichloropropionic acid and 2.8 g. potassium carbonate in 40 ml water is added a solution of 6.9 g. phenethylhydrazine hydrochloride and 5.6 g. potassium carbonate in 20 ml water. The mixture is heated with stirring to 90° C., a further solution of 5.6 g. potassium carbonate in 20 ml water is dropped in over 30 minutes and further stirred for 60 minutes at 90° C. Afterwards the still alkaline solution is cooled to ambient temperature, shaken out with ether and acidified with concentrated hydrochloric acid. 2-(phenethylhydrazono)-propionic acid crystallizes out and is recrystallized from toluene. The yield is 3.3 g. (40% of theory); m.p. 74°-76° C.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24](C(=O)C)[C:23]([O:29][N:30]=[C:31]([CH3:33])C)=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CCO.CCOC(C)=O>[Cl:34][C:22]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:20]([CH2:19][OH:18])[N:25]=[C:24]2[C:31]([CH3:33])=[N:30][O:29][C:23]=12
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1ON=C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)nc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(6-((tert-Butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-(propan-2-ylideneaminooxy)pyridin-2-yl)ethanone (Intermediate 336, 821 mg, 1.35 mmol) was dissolved in 13 ml of EtOH. Aqueous 1M HCl, (4.33 ml, 4.33 mmol) was added to give an immediate precipitate, which dissolved to give a hazy yellow solution. The mixture was heated at 75° C. After 1 hour, 15 minutes, the reaction was cooled and diluted with EtOAc. Added saturated NaHCO3 to quench was followed by extraction 2× with EtOAc. The combined organic phase was dried over MgSO4 and concentrated. The crude was purified on Si02 using 15-40% EtOAc/hexanes. Recovered 389 mg (88%) of the title compound as white solid.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([Cl:18])[CH:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(NC23CC4CC(CC(C4)C2)C3)n1
Product: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1
Yield: 86 %

Procedure:
By reacting 2-(1-adamantylamino)-4,6-dichloropyrimidine with pyrrolidine as described in Example 12, the title compound is obtained in a yield of 86%, m.p.: 178°-180° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>CN(C)C=O.COC(C)(C)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH:14]([CH3:16])[CH2:15][CH:10]([CH3:9])[CH2:11]2)[S:6][N:5]=1
Reactant: CC1CNCC(C)C1
Reactant: CSc1nsc(Cl)n1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CSc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
In 9 ml of N,N-dimethylformamide was dissolved 740 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, and 1.25 g of 3,5-dimethylpiperidine (a mixture of 8:2 geometrical isomers) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of 10% hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 860 mg of 3-methylthio-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:33](=[O:34])[N:18]2[CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]([N:23]=[C:24]=[O:25])=[CH:21][S:22][C@H:17]12)=[O:14]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:33](=[O:34])[N:18]2[C:19]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:20]([NH:23][C:24]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:25])[CH2:21][S:22][C@H:17]12)=[O:14]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)C1C(N=C=O)=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Product: CC(C)(C)OC(=O)C1=C(NC(=O)N2CCOCC2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
Benzhydryl 7-phenylacetamido-3-isocyanato-2-cephem-4-carboxylate reacts with 2 equivalents of isopropylamine in tetrahydrofuran at 0° for approximately 1 hour to provide benzhydryl 7-phenylacetamido-3-isopropylureido-3-cephem-4-carboxylate. Likewise morpholine reacts under similar conditions with tert-butyl 7-(2-thienylacetamido)-3-isocyanato-2-cephem-4-carboxylate to provide tert-butyl 7 -(2-thienylacetamido)-3-morpholinocarbonylamino-3-cephem-4-carboxylate. When 4'-methoxybenzyl 7-(tert-butoxycarbonylamino)-3-isocyanato-2-cephem-4carboxylate is reacted with 2.5 equivalents of N-methylaniline in methylene chloride at 0° for about 1 hour, the product isolated, after chromatography, is 4'-methoxybenzyl 7-(tert-butoxycarbonylamino)-3-(N-methyl-N-phenylureido)-3-cephem-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:12])([F:13])[F:11])[CH2:3][C:4]([CH2:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])([C:7]#[N:8])[C:5]#[N:6]
Reactant: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)C(F)(F)F)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.5 %

Procedure:
In 50 ml of acetone, 2.0 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile and 5.3 g of 2,2,3,4,4,4-hexafluorobutyl trifluoromethanesulfonate were dissolved, 1.9 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2,2-bis(2,2,3,4,4,4-hexafluorobutyl)malononitrile (hereinafter, referred to as the present compound (95)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH:16]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1)([CH3:18])[CH3:17]
Reactant: OCCc1cn[nH]c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(CCO)cn1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
To a solution of 1.0 gm (9.0 mMol) 2-(4-pyrazolyl)-1-ethanol in 36 mL dimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonate followed by the dropwise addition of a solution of 0.89 mL (9.0 mMol) 2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was then cooled to ambient and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was then washed with water followed by saturated aqueous sodium chloride and was then dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 0.36 gm (26.0%) of the title compound as a brown oil.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])[NH2:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:3]2[N:4]([N:13]=[N:2][N:1]=2)[N:5]=1
Reactant: O=N[O-]
Reactant: NNc1nnc(Cl)cc1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)nn2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To an ice-cold suspension of 3-hydrazino-4-carboxy-6-chloro-pyridazine (1.88 g; 0.01 mole) in 15% acetic acid, a solution of sodium nitrite (0.70 g) in water (5 ml) was added dropwise. After stirring for one hour at 5°-10° C. the separated precipitate was filtered, washed with anhydrous ethanol. The solid was suspended in 2 N HCl, the mixture was stirred for 30 minutes, the solid was stirred off, washed with cold water and dried under vacuum at 70° C. to give 1.73 g (87%) of the title compound, m.p. 225° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1cccnc1
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 87.5 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Pyridine acetic acid (25 g) in 500 ml of chlorobenzene added to phosphorous acid (35.5 g). The reaction mixture was heated up to 85-90° C. To the reaction mixture phosphorous trichloride (58.97 g) was added slowly to obtain a yellowish rigid, thick mass. The reaction mass was cooled to ambient temperature. The solvent was decanted. Demineralized water (200 ml) was added to the reaction mass and refluxed azeotropically, to remove residual chlorobenzene. Filtered through hyflo bed while hot, washed with hot demineralized water. The reaction mass was cooled to 0-5° C., stirred for 1.0 hour, filtered the solid and washed to get risedronic acid (30.0 g, yield 58%) having purity of 83.98% by HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[C:30]1([C:36]2([CH2:39]O)[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:39][C:36]3([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: OCC1(c2ccccc2)CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(c3ccccc3)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-phenylcyclopropyl)methanol (0.87 g) and tributylphosphine (2 mL) in THF (100 mL) was added 1,1′(azodicarbonyl)dipiperidine (2 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 21%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].C([O:24][C:25](=[O:55])[C@@H:26]([NH:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:47]2[CH2:52][CH2:51][CH:50]([CH:53]=O)[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH2:53][CH:50]1[CH2:51][CH2:52][N:47]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([NH:34][C@@H:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([OH:55])=[O:24])=[O:36])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:48][CH2:49]1
Reactant: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.320 g, 1.3 mmol), (2S)-2-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureido}-3-phenyl-propionic acid benzyl ester (1.3 mmol) and glacial acetic acid (0.074 g, 1.3 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.086 g, 1.3 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give 0.12 g of the product.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].Cl.[F:8][C:9]1([F:34])[CH2:11][CH:10]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1)[CH2:18][CH2:17]2.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([CH2:3][C:4]([NH:33][C@H:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:12][CH:10]4[CH2:11][C:9]4([F:34])[F:8])[CH:15]=3)[CH2:20]2)=[CH:26][CH:27]=1)[CH3:32])=[O:6])#[N:2]
Reactant: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)CC#N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C

Procedure:
1.70 mg (20.0 μmol) Cyanoacetic acid, 4.09 mg (10.0 μmol) (S)-1-{4-[6-(2,2-difluoro-cyclopropylmethoxy)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-phenyl}-ethylamine hydrochloride (example XXXIII.1) and 6.88 μL (40.0 μmol) DIPEA in 0.5 mL ACN are stirred at r.t. Then 4.18 mg (15.0 μmol) CIP are added and the resulting mixture is stirred at r.t. over night. The reaction is quenched by the addition of 25 μL aq. K2CO3 solution (c=3 mol/L), filtered over basic aluminum oxide and concentrated by evaporation.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.Cl.[CH3:15]O>>[NH2:1][C@H:2]([C:11]([O:13][CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccc(Br)cc1

Procedure:
1.0 g (4.01 mmol) H-Phe(4-Br)—OH were refluxed in 20 ml methanol with 2.1 ml HCl (4 M in 1,4-dioxane) over night. Evaporation of the solvent gave H-Phe(4-Br)—OMe*HCl as white solid. 1.0 g (3.4 mmol) of this hydrochloride and 1.7 ml (10.2 mmol) DIPEA were suspended in 8 ml THF and 0.41 ml (3.4 mmol) 2,4,6-trimethylbenzoyl chloride were added dropwise at 0° C. After 18 h at room temperature the reaction was quenched with water and the solvent was removed. The residue was suspended in ethyl acetate, washed with saturated Na2SO4 and brine to give compound (13) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:17])[CH2:15]Cl)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]([C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[CH:11][CH:12]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CCl)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)COc2ccc(F)cc2)cc1

Procedure:
Following the procedure outlined in Example 11(a), 4-fluorophenol was interacted with an equimolar quantity of p-methylphenacyl chloride in the presence of potassium carbonate to give ω-(4-fluorophenoxy)-p-methylacetophenone which melted at 95°-96°C after recrystallization from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)OC1(C)CCCCC1)c1ccc(N)cc1
Yield: 67.1 %

Procedure:
A stirred solution of 34.9 g of 1-methylcyclohexyl 2-(p-nitrophenyl)-propionate in 250 ml of absolute ethanol was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon catalyst. After the uptake of hydrogen gas was complete, the catalyst was filtered off through celite and the filtrate was evaporated to dryness. Trituration of the residue with petroleum ether gave 21.02 g (67% yield) of 1-methylcyclohexyl 2-(p-aminophenyl)-propionate as creamy white crystals melting at 85°-87° C.