Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)=[CH:5][CH:4]=1.[CH2:16]=[O:17].O>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2oc(=O)[nH]c2=O)cc1
Reactant: C=O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reaction time: 2 h

Procedure:
2-(4-Methoxyphenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-methoxyphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:8]2)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:8]2)=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2nc(Cl)ncc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 2-chloro-8-(methylsulfonyl)-7H-purine (570 mg, 2.45 mmol) and N,N-diisopropylethylamine (3.42 mL, 19.60 mmol) in anhydrous DMF (16.7 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (2.17 mL, 12.25 mmol). The reaction was stirred under N2 at RT for 20 h, then added to EtOAc (1.0 L) and washed with saturated NH4Cl (0.2 L). The aqueous layer was separated and back-extracted with EtOAc (0.2 L). The organic layers combined and evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-40% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C12H19ClN4O3SSi 362.06 observed m/e: 385.30 (M+23)′ (Rt 1.33/2.0 min)
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].CO[C:21](OC)([N:23](C)C)[CH3:22]>>[C:9]1([SH:6]2(=[O:7])[CH:5]=[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=3)[N:23]=[C:21]([CH3:22])[NH:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N=S(=O)(C=Cc1ccccc1N)c1ccccc1
Reactant: COC(C)(OC)N(C)C
Product: CC1=NC(c2ccccc2)=C[SH](=O)(c2ccccc2)N1

Procedure:
Using the procedure of Step B of Example 1, the S-(2-aminostyryl)-S-phenyl-sulfoximine of Example 1 Step A was reacted with dimethyl acetamide dimethyl acetal to obtain 1,5-diphenyl-3-methyl-1H-1,2,4-thiadiazine-1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 25 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and (2S)-1-amino-2-propanol (0.05 mL), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(2S)-2-hydroxypropyl]-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (16 mg, 25% yield) as a white solid after purification by reverse phase HPLC. Analytical data was identical to that described in example 578.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Br.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1
Reactant: COc1ccccc1OCCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1OCCN1CCC(NC(=O)c2ccccc2)CC1
Yield: 83.3 %

Procedure:
2-(2-Methoxyphenoxy)ethyl bromide (2.31 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were well mixed and heated on a steam bath for 4 hr. The resultng mass was crushed and stirred in water (200 ml.) at 60° for 12 hr. Filtration afforded the crude base of the title compound (2.95 g.). Conversion to the hydrochloride by solution in ethanol/HCl and precipitation with ether provided 3.01 g. of the title compound, as the hydrochloride m.p. 193.4° .
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][Br:14])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)n1ncc(Cl)c(CBr)c1=O

Procedure:
2-tert-butyl-4-methyl-5-chloro 3(2H)-pyridazinone (3 g, 15 mmol) is dissolved in 25 ml of carbon tetrachloride and to it is added N-bromosuccinimide (2.6 g, 15 mmol) and benzoyl peroxide (14 mg). The mixture is then refluxed for 6 hours after which it is cooled and filtered. The filtrate is washed with water and dried. After removing the organic solvent the crude residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes: 9:1) to obtain the product.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][Br:34])[C:27]([OH:29])=O)[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:46][S:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:59]([NH2:60])[C:58](=[O:61])[N:53]2[C:54]=1[C:55]([OH:57])=[O:56]>C(O)=O>[CH3:46][S:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:59]([NH:60][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH2:20])[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][Br:34])[C:58](=[O:61])[N:53]2[C:54]=1[C:55]([OH:57])=[O:56]
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=CO
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCBr)c3csc(N)n3)[C@H]2SC1

Procedure:
Using the procedure of Example 17, 1.909 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetic acid (described in French Pat. No. 2,438,050), 0.68 g of tosyl chloride, 0.927 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid and 15 ml of 67% aqueous formic acid were reacted to obtain 0.615 g of pure syn isomer of 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-bromoethoxyimino}-acetamido]-ceph-3-eme-4-carboxylic acid with a melting point of 185° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: COc1ccccc1/C=C/C(=O)O
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: COc1ccccc1/C=C/C(=O)Nc1ccn(CCCCC(C)=O)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: C(OC([N:8]([CH2:19][CH2:20][CH2:21][P:22](=[O:33])([O:28]CCCC)[O:23]CCCC)[O:9]CC1C=CC(OC)=CC=1)=O)C(C)C.Cl>C(O)(=O)C>[OH:9][NH:8][CH2:19][CH2:20][CH2:21][P:22](=[O:23])([OH:33])[OH:28]
Reactant: CCCCOP(=O)(CCCN(OCc1ccc(OC)cc1)C(=O)OCC(C)C)OCCCC
Agent: Cl
Solvent: CC(=O)O
Product: O=P(O)(O)CCCNO
Reaction time: 21 h
Yield: 53.1 %

Procedure:
A mixture of dibutyl 3-[N-isobutoxycarbonyl-N-(p-methoxybenzyloxy)amino]propylphosphonate (6.04 g), conc. hydrochloric acid (60 ml) and acetic acid (60 ml) was refluxed with stirring for 21 hours. The resultant mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was concentrated under reduced pressure to give a residue, which was washed with acetonitrile and then dissolved in water (10 ml). To the solution were added pyridine (800 ml) and ethanol (4 ml), and then the mixture was allowed to stand overnight at 4° C. to give 3-(N-hydroxyamino)propylphosphonic acid (1.02 g) in the form of crystals. MP: 160°-166° C. (dec.).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37](O)=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[NH:41][NH2:42].Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:42][NH:41][C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(C(=O)O)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NNC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 150 mg of 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidine-4-carboxylic acid in 5 ml of chloroform were added 43.3 mg of tert-butyl carbazate and 63.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to ethyl acetate) to give the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:29])[N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:14]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:29])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[O:9][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)cc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc2c1C(=O)N(Cc1ccc(OC)cc1)C2=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 72.9 %

Procedure:
1-(2-Bromo-ethoxy)-2-methoxy-ethane (107 mg, 0.58 mmol) was added to a suspension of 4-hydroxy-2-(4-methoxy-benzyl)-isoindole-1,3-dione (150 mg, 0.53 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (2 mL). After 3.5 hours, a catalytic amount of potassium iodide was added. After a further 17 hours, the mixture was warmed to 60° C. After 3 hours, an additional amount of 1-(2-bromo-ethoxy)-2-methoxy-ethane (20 mg, 0.11 mmol) was added and the mixture maintained at 60° C. for a further 20 hours. The mixture was concentrated in vacuo then the residue was taken up in ethyl acetate and washed with potassium carbonate solution and brine. The organic phase was dried (MgSO4) and concentrated to give the title compound as a yellow oil (149 mg, 73%). 1H NMR (methanol-d4) 7.71 (1H, t), 7.43-7.40 (2H, m), 7.31-7.27 (2H, m), 6.87-6.83 (2H, m), 4.71 (2H, s), 4.37-4.34 (2H, m), 3.92-3.89 (2H, m), 3.77-3.74 (5H, m), 3.55-3.53 (2H, m), 3.33 (3H, s). MS:
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:19])[C:4](=[NH:8])[O:5]CC.[O:20]1CCC[CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[CH:3]1[O:2][C:21](=[O:20])[NH:5][C:4]1=[O:8]
Reactant: CCOC(=N)C(O)c1c(C)ccc2ccccc12
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
Following the procedure of Example 138, ethyl 1-hydroxy-1-(2-methyl-1-naphthyl)methanecarboximidate hydrochloride (0.47 g., 1.9 mmoles) in 30 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-methyl-1-naphthyl)oxazolidine-2,4-dione (185 mg., m.p. 145°-147° C., m/e 241). Recrystallization from hexane-ether gave an analytical sample (m.p. 147°-150° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1>>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(CBr)cc1
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1

Procedure:
Referring to FIG. 2, thus, a two-step procedure was explored whereby the amine of compound 1 was protected prior to conversion to compound 3. Specifically, the amino group of compound 1 was protected by reacting with α-bromo-p-xylene to give 4-methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2). This was followed by the simultaneous demethylation and deprotection of the N-benzyl group of compound 2 by ether cleavage with boron tribromide. This produced compound 3, with an overall yield of 27%.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:9][CH:10]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.OC1(C(C2C=CC(C#CC)=CC=2)CN2CCN(C(OC(C)(C)C)=O)CC2)CCCCC1.Cl>>[ClH:1].[ClH:1].[N:3]1([CH2:9][CH:10]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH3:19])=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CCCc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1
Agent: CC#Cc1ccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1
Agent: Cl
Product: CC#Cc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1

Procedure:
In an analogous manner to Example 135, step 4, 1-[2-piperazin-1-yl-1-(4-prop-1-ylphenyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(4-prop-1-ynylphenyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 327 ([M+H]+); HRMS: calcd for C21H30N2O.2.00 HCl, 398.1892; found (ESI), 327.2425.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.[C:18]([NH:25][C@H:26]([C:35]([OH:37])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.7 %

Procedure:
Potassium carbonate (1.23 g, 8.9 mmol) and methyl 6-chloronicotinate (1.8 g, 10.66 mmol) were added to a solution of Boc-tyrosine (1.0 g, 3.55 mmol) in anhydrous DMF (15 mL). The resulting suspension was refluxed at 70 deg C. under an atmosphere of argon. After 72 hrs, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.5 and extracted with EtOAc (2×100 mL). The resulting EtOAc layer was extracted with water (1×150 mL) and brine (1×150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated and flash chromatographed (30-40% ethyl acetate in hexane with 1% acetic acid) to yield desired ester, 17 as a solid (1.4 g). 1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 8.68 (br, 1H), 8.29 (dd, J=8.4 and 2.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.12 (m, 1H), 3.85 (s, 3H), 3.05 (dd, J=14.0 and 4.0 Hz, 1H), 2.84 (dd, J=14.0 and 10.8 Hz, 1H) 1.33 (s, 9H)
Reaction SMILES: [CH3:1][C@@:2]([S:14]([CH3:17])(=[O:16])=[O:15])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([O-:5])=[O:4].C1COCC1.CO.O.[Li+].[OH-].Cl>O>[CH3:1][C@@:2]([S:14]([CH3:17])(=[O:15])=[O:16])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([OH:5])=[O:4]
Reactant: Cc1cnn(CC[C@](C)(C(=O)[O-])S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cnn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate (182 mg 0.455 mmol, 1 eq) in 2:2:1 THF-MeOH-water (6 mL) was added 0.1 M aq. LiOH and the reaction mixture was allowed to stir overnight at RT. The reaction mixture was concentrated under reduced pressure (to remove organics) to provide an aqueous solution, which was diluted with water (5 mL) and acidified to pH=2 with 1 M HCl. Upon acidification, a white precipitate formed, which was filtered, washed with water, and dried under reduced pressure to give (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid. LC-MS M+H+261.1.
Reaction SMILES: N.[Na].[C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:35]1[CH:39]=[C:38]([CH2:40]Cl)[N:37]=[CH:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.C1COCC1>[C:16]([N:35]1[CH:39]=[C:38]([CH2:40][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[N:37]=[CH:36]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccncc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere a 100 ml flask was charged with 50 ml liquid ammonia, a small piece of sodium and a few crystals of Fe(NO3)3. Then about 0.25 g (11 mmol) sodium metal was added and the mixture was stirred at ca. -70° C. for 0.5 hours. Then, under stirring, and at about -70° C. 1.69 g (10 mmoles) of phenyl-(4-pyridinyl)methane dissolved in 5 ml anhydrous ether are added in 10 minutes. After stirring for 0.5 hours the mixture was allowed to warm up to the boiling temperature of ammonia and 3.21 g (9 mmoles) of (3) dissolved in 20 ml anhydrous THF was added dropwise. The mixture was allowed to warm up to room temperature while ammonia evaporated. To the residue 30 ml water was added and the mixture was extracted with methylene chloride. Then the methylene chloride was evaporated from the dried, combined solutions yielding crude derivative (4) used as such in the next stage.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH2:51]>CC(C)=O.C(Cl)(Cl)Cl>[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH:51][C:43](=[O:44])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][CH:34]=1)[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Triethylamine (5.7 ml.), then isobutylchloroformate (5.3 ml.), were added with stirring to a solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (16.68 g.) in acetone (175 ml.) maintained at -20° C. The solution was stirred for 10 minutes at -20° C., then D-alanine methyl ester hydrochloride (6.4 g.) and triethylamine (5.7 ml.) in chloroform (65 ml.) were added. Stirring was continued one hour at this temperature, then four hours at room temperature. The mixture was filtered and the filtrate was stripped of volatiles. The residue and the filtration solid were combined and distributed between water (200 ml.) and ethyl acetate (250 ml.). Part of the product was collected by filtration and washed with aqueous hydrochloric acid, water, saturated sodium bicarbonate and water. The ethyl acetate layer was washed with cold aqueous hydrochloric acid (0.5N), water, saturated aqueous sodium bicarbonate, water again and saturated aqueous sodium chloride and stripped of volatiles, yielding another part of the product. The two parts were combined and recrystallized from absolute ethanol, affording (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-D-alanine methyl ester (15.28 g.; m.r. 161°-163° C.; [α]D25 -11.7°, c=2, dimethylformamide)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[NH4+:14]>[Ni].CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:14])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)OCO2
Reaction time: 24 h
Yield: 45 %

Procedure:
A suspension of Raney nickel (1 mL) in methanol (5 mL) and ammonium hydroxide (1 mL) was added to a solution of 1-(1,3-benzodioxol-5-yl)acetaldehyde, oxime (Preparation 1, 8.98 g, 50 mmole) in methanol (50 mL). The reaction mixture was hydrogenated (shaken on a Parr hydrogenator under H2 atmosphere at 60 psi) for 24 hours. The reaction mixture was filtered, and the resultant filtrate was concentrated in vacuo to provide the title compound as an oil (3.68 g, 45%).