Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][CH:39]1[C:58](=[O:59])[N:41]2[C:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]12.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([NH:38][CH:39]2[C:58](=[O:59])[N:41]3[C:42]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]23)=[O:29])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC3CCCCO3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.362 g of the product of Step C, 0.244 g of tert.-butyl 7-amino-3-acetoxymethyl-ceph-3-eme-4-carboxylate, 0.280 g of dicyclohexylcarbodiimide and 4 ml of dry chloroform was stirred for 2 hour at room temperature and the mixture was vacuum filtered to remove dicyclohexylurea which was rinsed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 1 ml of ether. The solution was chromatographed over silica gel and was eluted with ether. The fractions with an Rf=0.38 were combined and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and effloresced. The mixture was vacuum filtered and the recovered product was rinsed with isopropyl ether to obtain 0.184 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4thiazolyl)-2-tetrahydropyranyloxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:49]>ClCCl>[CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[CH:42][N+:41]([O-:49])=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][CH2:3]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3ccncc3)C3CC3)cc2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cc[n+]([O-])cc3)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-[cyclopropyl(pyridin-4-ylmethyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 110, Step 1 (1 eq.) in dichloromethane (0.12 M) was added 3-chloroperoxybenzoic acid (1.3 eq.). The reaction mixture was stirred at RT for 1.5 h. The reaction was then quenched with 10% aq. Na2S2O3 and sat. aq. NaHCO3. The organic layer was separated and the aqueous layer were back extracted with ether. The combined organic extracts were washed with water, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, EtOAc→4:1 (v/v) EtOAc:MeOH) afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26](Cl)=[O:27])([CH3:22])[CH3:21].CO>O1CCCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:26]([C:25]2[CH:24]=[C:23]([C:20]([CH3:19])([CH3:21])[CH3:22])[C:31]([OH:32])=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:29]=2)=[O:27])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
2-Amino-4-thiazolecarboxylic acid ethyl ester (16.2 g, 100 mmol) and triethylamine (TEA, 10.5 g, 104 mmol) were combined in anhydrous tetrahydrofuran (THF, 200 mL) in a nitrogen atmosphere. To this was added slowly with stirring a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoylchloride (28 g, 104 mmol) in THF (100 mL). The reaction mixture was heated under reflux and monitored for disappearance of starting material by TLC (silica gel, 2% methanol in methylene chloride). After two days, the reaction mixture was cooled to room temperature and filtered to give 14.67 g of 2-[[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-carbonyl]-amino]-4-thiazolecarboxylic acid ethyl ester as a white solid, m.p. 233°-235° C. The filtrate was poured into ice water and extracted five times with diethyl ether. The ether phase was dried and evaporated and the residue was purified by flash chromatography on silica gel eluting with 20:80 hexane:methylene chloride to give 29.41 g of additional ethyl ester.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=3)=[N:27][CH:26]=1)[CH:20]([NH:39]C(OC(C)(C)C)=O)[C:19]2=[O:47])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:39][CH:20]1[C:19](=[O:47])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][C:28]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=3)=[N:27][CH:26]=1)=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccnc4)s3)CSC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccnc4)s3)CSC12
Yield: 84 %

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-nicotinoylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (9 g) in acetonitrile (134 cc) is treated with p-toluenesulphonic acid (7.6 g) according to the working method described in Example 24, to give 7-amino-2-benzhydryloxycarbonyl-3-(2-nicotinoylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.43 g) in the form of a cream powder.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[C:3]([OH:5])=[O:4].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[C:3]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: C#CC(C)(C)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63227.6 %

Procedure:
To a stirred solution of 2,2-dimethylbut-3-ynoic acid (87.7 g, 0.782 mmol) and benzyl alcohol (114.6 g, 0.938 mol) in dichloromethane (800 mL) was added DCC (193.5 g, 0.938 mmol) at −20° C. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (2% ethyl acetate in petroleum ether as eluant) to afford benzyl 2,2-dimethylbut-3-ynoate (100 g, 59% yield). 1H NMR (CDCl3, 400 MHz) δ 7.37-7.36 (m, 5H), 5.19 (s, 2H), 2.28 (s, 1H), 1.52 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[OH:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:16][C:13]1[N:12]=[N:11][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][O:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]4)=[CH:20][CH:19]=3)[CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: CCOc1ncnc2cc(O)ccc12
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ncnc2cc(OCCC3CCN(c4ccc(C)nn4)CC3)ccc12
Temperature: 90 °C
Yield: 17.6 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine (76 mg, 318 μmol), 7-hydroxy-4-ethoxyquinazoline (100 mg, 526 mmol), potassium carbonate (109 mg, 789 mmol) and potassium iodide (53 mg, 319 mmol) in DMF (5 mL) was heated at 90° C. overnight in an argon atmosphere. The mixture was concentrated, and the residue partitioned between ethyl acetate (100 mL), and water (20 mL). The organic phase was dried (MgSO4), filtered, concentrated and purified by column chromatography (silica), using gradient elution (ethyl acetate-methanol/EA). The combined fractions gave a white solid (22 mg, 18%). The 1H nmr data are recorded in Table 6 below.
Reaction SMILES: [CH3:1][N:2]([O:24][CH3:25])[C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH:12]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[H][H].[C].[Pd]>[CH3:1][N:2]([O:24][CH3:25])[C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH2:12]
Reactant: COc1ccc(NC(=O)OCc2ccccc2)c(C(=O)N(C)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C(=O)N(C)OC)c1
Yield: 104.2 %

Procedure:
In a mixture of ethyl acetate (8 ml) and methanol (10 ml) was dissolved N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-methyloxy-benzamide (0.55 g). To the solution was added 10% palladium-carbon (0.1 g). The mixture was stirred for 40 minutes at ordinary temperature under atmospheric pressure in hydrogen streams. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. From the concentrate, N-methyl-N-methyloxy 2-amino-5-methyloxy-benzamide (0.35 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[C:10]1=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:71][C:72]1[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][C:73]=1[NH:79][C:80]1[N:85]=[C:84]([C:86]2[CH:87]=[N:88][CH:89]=[N:90][CH:91]=2)[CH:83]=[CH:82][N:81]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:76][C:75]3[CH:77]=[CH:78][C:72]([CH3:71])=[C:73]([NH:79][C:80]4[N:85]=[C:84]([C:86]5[CH:91]=[N:90][CH:89]=[N:88][CH:87]=5)[CH:83]=[CH:82][N:81]=4)[CH:74]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:25])([F:27])[F:26])[C:10]1=[O:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)C1=O
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[C@H](NC(=O)OC(C)(C)C)C3=O)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Eight hundred mg of 4-[(S)-3-(t-butoxycarbonylamino)-2-oxopyrrolidin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 17) was dissolved in 7 ml of anhydrous N,N-dimethylformamide, and 0.67 ml of N,N-diisopropyl-N-ethylamine and 1.00 g of 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) were added in turn, followed by stirring at room temperature for 30 minutes. 4-Methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 453 mg of the objective compound as a pale yellow amorphous.
Reaction SMILES: C1COCC1.O.[NH2:7][C@@H:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10].[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[S:33]([NH:7][C@@H:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CCc1ccccc1)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Yield: 38.8 %

Procedure:
To a THF/water (5:3, 8 mL) solution of (S)α-amino4-phenyl-butyric acid (0.61 g, 0.0034 mol) and triethylamine (1 mL) at 10° C. was added dibenzofuran-2-sulfonyl chloride (1.0 g, 0.00375 mol) in one portion with stirring. The resulting solution was stirred at room temperature for 24 hours. The solution was then concentrated in vacuo and the residue redissolved in water (10 mL). This solution was cooled in an ice bath and then acidified with 1N HCl. An oil was deposited, which was then triturated with ethyl acetate and hexane to give the title product (0.54 g, 35%), Melting point=130-132° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCOCC1.CO.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-n2cccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.56 mL) was added to a solution mixture of the obtained methyl 2-(benzyloxy)-4-(1H-pyrazol-1-yl)benzoate (0.11 g) in dioxane (1.1 mL) and methanol (1.1 mL), followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.10 g of 2-(benzyloxy)-4-(1H-pyrazol-1-yl)benzoic acid as a white solid.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.[NH2:63][C@H:64]([C:90]([C:92]([CH3:95])([CH3:94])[CH3:93])=[O:91])[CH2:65][CH2:66][CH2:67][NH:68][C:69](=[NH:89])[NH:70][S:71]([C:74]1[C:87]([CH3:88])=[C:85]([CH3:86])[C:84]2[O:83][C:80]([CH3:82])([CH3:81])[CH2:79][CH2:78][C:77]=2[C:75]=1[CH3:76])(=[O:73])=[O:72].C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:63][C@H:64]([C:90]([C:92]([CH3:95])([CH3:94])[CH3:93])=[O:91])[CH2:65][CH2:66][CH2:67][NH:68][C:69](=[NH:89])[NH:70][S:71]([C:74]1[C:87]([CH3:88])=[C:85]([CH3:86])[C:84]2[O:83][C:80]([CH3:81])([CH3:82])[CH2:79][CH2:78][C:77]=2[C:75]=1[CH3:76])(=[O:72])=[O:73])=[O:5]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Reaction time: 0.17 h

Procedure:
A solution of commercially available Z-Pro-OH (3.9 g, 11.0 mmol) was dissolved in dry dichloromethane (25 ml) and cooled in an ice bath. HBTU (4.2 g, 11.0 mmol) was added followed by HOBt.H2O (1.68 g, 11.0 mmol) and DIEA (3.12 g, 24.2 mmol). The reaction mixture was stirred for 10 min and then to the above activated acid, H-Arg(Pmc)-t-Bu (5.0 g, 10.0 mmol) was added as a solid. The solution was allowed to come to RT and stirred for 20 h at RT. The mixture was poured into saturated sodium bicarbonate solution (100 mL) and stirred for 5 min. The organic layer was separated and washed with water (2×100 mL) and dried (sodium sulfate). Evaporation of the solvent yielded the product as colorless foam. Yield: 8.2 g (100%).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH:22]([CH3:24])[CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:25].CCOCC.O>CO.[OH-].[OH-].[Pd+2]>[ClH:25].[CH:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)([CH3:24])[CH3:23]
Reactant: CC(C)NC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)NC1(C(N)=O)CNC1

Procedure:
To a solution of 1-benzhydryl-3-isopropylaminoazetidine-3-carboxylic acid amide (I-3A-1b; 2.28 g, 7.05 mmol) in methanol (100 ml) was added 1M HCl in ether (14.8 ml, 14.8 mmol) and then water (10 ml). After the addition of 20% Pd(OH)2 on carbon (60% water; 1.43 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature overnight. The mixture was filtered through a pad of Celite®, and then concentrated, in vacuo. The residue was then concentrated, in vacuo, from toluene (2×), acetonitrile (2×) and then methanol to give I-3A-1c (1.59 g, 98%) as a tan solid: +APcI MS (M+1) 158.1; 1H NMR (400 MHz, CD3OD) δ 4.71 (d, J=13.3 Hz, 2H), 4.60 (d, J=13.3 Hz, 2H), 3.49 (septuplet, J=6.6 Hz, 1H), 1.34 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:5]([C:4]1[C:3]([F:10])=[C:2]([NH:1][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a light brown solution of 3-amino-2-fluorobenzonitrile (2.7141 g, 19.94 mmol) and potassium carbonate (4.13 g, 29.9 mmol) in THF (166 mL) was syringed benzyl carbonochloridate (4.49 mL, 29.9 mmol) under nitrogen, and the reaction was stirred overnight. The insoluble material was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with 1 N aqueous HCl (50 mL), water (50 mL) and brine (50 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give crude product which was stirred in hexanes (75 mL) for 1 hr. The insoluble material was filtered and washed with hexanes to give the desired product (4.4541 g, 16.48 mmol, 83% yield) as a light tan solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][N:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[N:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To lithium aluminium hydride (0.68 g, 18 mmol) suspended in dry THF (10 ml) was added dropwise a solution of methyl 6-methoxynicotinate (1 g, 6 mmol) in dry THF (5 ml). The reaction mixture was stirred for 2 h at r.t. then cooled (ice-bath) and quenched with water (2 ml) followed by the further addition of 1 N NaOH (6 ml) and water (2 ml). The cold-bath was removed and the mixture stirred for 30 min at r.t., filtered and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:1): colorless oil 0.45 g (51%);
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=1>>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: OCc1cccnc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccnc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and pyridin-3-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.27 (2H, s), 5.78 (1H, d, J=2.0 Hz), 7.41 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.36 (1H, dd, J=4.8 Hz, J=7.6 Hz), 7.58 (1H, d, J=2.0 Hz), 7.80 (1H, d, J=8.0 Hz), 8.03 (1H, s), 8.63 (1H, dd, J=1.2 Hz, J=4.8 Hz), 8.69-8.72 (2H, m). [M+H] Calc'd for C15H11N5O, 278. Found, 278.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17]>CN(C=O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][N:3]3[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]3[CH3:1])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-dimethylimidazole (0.633 g, 0.7 mmol) was taken up in dry DMF (15 ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added and the reaction mixture was stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration gave material that was purified on a silica gel column (CHCl3/MeOH): 1H NMR (300 MHz, CDCl3): δ 7.25 (d, 2H), 6.80 (d, 2H), 6.53 (s, 1H), 4.62 (s, 2H), 3.78 (br, 2H), 3.59 (br, 2H), 3.21 (br, 4H), 2.31 (s, 3H), 2.17 (s, 1H).
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[C:7]=1[C:29]([NH2:31])=[O:30]>CO.C1COCC1.[Pd]>[NH2:5][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:7]=1[C:29]([NH2:31])=[O:30]
Reactant: CC(C)(C)n1nc(-c2ccc(OCc3ccccc3)cc2)c(C(N)=O)c1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)n1nc(-c2ccc(O)cc2)c(C(N)=O)c1N
Temperature: 25 °C

Procedure:
Ammonium formate (160 mg, 2.5 mmol) and 10% Pd/C (50 mg) are added to a solution of 21 (2 mmol) from the preceding reaction in methanol (4 mL) and THF (2 mL). The mixture is stirred at room temperature. The reaction is monitored by tlc and after reaction occurs, the mixture is filtered through Celite and rinsed with ethyl acetate. The filtrate is diluted with ethyl acetate and is washed successively with aq. NaHCO3 and with half-saturated brine, then dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The desired 5-amino-1-(1,1-dimethylethyl)-3-(4-hydroxyphenyl)pyrazole-4-carboxamide 22 is obtained by purification of the crude product with HPLC.