Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[OH-].[K+]>C(O)CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:5]([C@H:4]([CH3:22])[C:3]([OH:2])=[O:23])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 4.7 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (42.5 g, 0.127 mole) in ethylene glycol 8250 ml) was refluxed under nitrogen atmosphere for one hour and then cooled. Water (40 ml) and solid potassium hydroxide pellets (10.13 g, 0.181 mole) were added and the solution was refluxed for an additional two hours, filtered into ice water (1 liter) and acidifed with 3N hydrochloric acid solution to give a solid which was collected by filtration and rinsed with water to give 29 g of crude title compound (76% yield). A 3.5-g portion of the solid was recrystallized twice from isopropyl alcohol/water and dried under high vaccum at 50° C. overnight to give 1.81 g of title compound, mp 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[NH:11][C:10]([CH2:12][C:13]#[N:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].CC(CC)=[O:28]>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:7]2[N:11]([CH2:23][CH3:24])[C:10]([CH2:12][C:13]#[N:14])=[CH:9][CH:8]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cc2ccc(Cl)cc2)[nH]1
Reactant: CCC(C)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 24.4 g. (0.1 mole) 5-(p-chlorobenzyl)-pyrrole-2-acetonitrile, 41.7 g. (0.3 mole) of potassium carbonate and 16.1 g. (0.105 mole) of ethyl iodide in 300 ml. of methylethylketone is refluxed overnight. The reaction mixture is then poured into water and extracted with chloroform. The organic solutions are combined, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. The residue is crystallized from 2 -propanol to give about 13 g. of crude solid. The solid is sublimed overnight at 140° C. and 0.025 mm. Hg. The sublimate is successively recrystallized from 2-propanol, benzene and hexane to give 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile as a white solid, m.p. 145-147° C. Analysis: Calcd. for C15H13ClN2O: N, 10.2%. Found: N, 10.54%.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>COCCOC>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][C:7]34[C:15](=[O:16])[N:14]([C:17]5[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=5)[C:13](=[O:25])[N:12]3[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=2)[CH:29]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCCN12
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4cccnc4)cc3)CCCCN12
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.360 g) and 3-pyridineboronic acid (0.225 g) in DME (20 mL) was added CsF (0.615 g) and the mixture was degassed with nitrogen. After 10 minutes, Pd(PPh3)4 was added and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated. The residue was redissolved in EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: hexane/acetone: 3/2, Chromatotron) afforded the titled compound (0.172 g). MS (m/z) 466 (MH+). mp 276.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:37])=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([O:20]CC1C=CC=CC=1)[CH:17]=[CH:16][C:15]=4[O:28]CC1C=CC=CC=1.B(Cl)(Cl)[Cl:39]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:37])=[C:12]3[C:13](=[O:36])[C:14]4[C:19]([C:6]([C:7]=23)=[N:5]1)=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=4[OH:28].[ClH:39]
Reactant: ClB(Cl)Cl
Reactant: NCCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1-2
Product: Cl
Product: NCCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(O)ccc(O)c1-2

Procedure:
2-(2-Aminoethyl)-5-chloro-7,10-dihydroxyanthra-[1,9-cd]pyrazol-6(2H)-one is prepared from 2-(2-aminoethyl)-5-chloro-7,10-bis(phenylmethoxy)anthra[1,9-cd]-pyrazol-6(2H)-one and boron trichloride as described in Example 54 to give the product as a salt with 1.0 equivalent of hydrogen chloride solvated with 0.7 equivalent of water; mp 265°-268° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[C:26]1([C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:32]([NH:34][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:36])(=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolveed in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 94%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][C:15]([C:22]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=O)=[CH:16][CH:17]=4)[C:12](=[O:30])[C:11]=3[CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC=C)C(C1C=CC2C3C(=CC(C(N(CC=C)CC=C)=O)=CC=3)C(=O)C=2C=1)=O)C=C.C(N(CC)C(C1C=CC2C3C(=CC(C(N(CC)CC)=O)=CC=3)C(=O)C=2C=1)=O)C>>[N:1]1([CH2:7][C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][C:15]([CH2:22][N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:16][CH:17]=4)[CH:12]([OH:30])[C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2cc(C(=O)N3CCCCC3)ccc2-c2ccc(C(=O)N3CCCCC3)cc21
Agent: C=CCN(CC=C)C(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)N(CC=C)CC=C)ccc1-2
Agent: CCN(CC)C(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)N(CC)CC)ccc1-2
Product: OC1c2cc(CN3CCCCC3)ccc2-c2ccc(CN3CCCCC3)cc21

Procedure:
Following essentially the same procedure but substituting an equivalent molar amount of 2,7-bis(piperidinocarbonyl)fluoren-9-one and N,N,N',N'-tetraallyl-9-oxo-fluorene-2,7-dicarboxamide for the N,N,N',N'-tetraethyl-9-oxofluorene-2,7-dicarboxamide above, results in the formation of 2,7-bis(piperidinomethyl)fluoren-9-ol, having a m.p. of 152.5°-3.5°C,λmax0.1N HCl 231, and E 1cm1% 688, and 2,7-bis(diallylaminomethyl)fluoren-9-ol hydrochloride, respectively, having a m.p. 220.5°-1.5°C, λmax0.1N HCl 282, and E cm1% 531.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:20][CH3:21])(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:21][O:20][C:10](=[O:19])[CH2:11][CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 70.7 %

Procedure:
Using tert-butyl ({5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (1 g), 3-thienylboronic acid (553 mg), sodium carbonate (687 mg) and tetrakis(triphenylphosphine)palladium (374 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 712 mg, 71%).
Reaction SMILES: [I:1]CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(C)C)C1.S([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C@H:55]1[CH2:72][CH2:71][C@@:70]2([CH3:73])[C:57](=[CH:58][CH2:59][C@@H:60]3[C@@H:69]2[CH2:68][CH2:67][C@@:65]2([CH3:66])[C@H:61]3[CH2:62][CH2:63][C@@H:64]2[C:74]([O:76][CH3:77])=[O:75])[CH2:56]1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O>>[I:1][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C@H:55]1[CH2:72][CH2:71][C@@:70]2([CH3:73])[C:57](=[CH:58][CH2:59][C@@H:60]3[C@@H:69]2[CH2:68][CH2:67][C@@:65]2([CH3:66])[C@H:61]3[CH2:62][CH2:63][C@@H:64]2[C:74]([O:76][CH3:77])=[O:75])[CH2:56]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of 17β-carbomethoxy-androst-5-en-3β-yl 6-iodohexyl ether, there was prepared 6-(17β-carbomethoxy-androst-5-en-3β-yloxy)-hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([O:13][C:14]1[C:19]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([O:33]C)=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([O:13][C:14]1[C:19]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)CCNC(=O)OC(C)(C)C)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)CCNC(=O)OC(C)(C)C)c12
Temperature: 25 °C

Procedure:
Methyl 4-(2-(4-(tert-butoxycarbonylamino)butan-2yloxy)pyridin-3ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (600 mg) was dissolved in methanol (10 ml) and NaOH (1M; 2.5 ml) was added. The reaction mixture was heated at reflux for 15 minutes. Then it was cooled to room temperature and HCl (1M; 2.5 ml) was added. Methanol was evaporated and the residue was dissolved in dichloromethane. The mixture was washed with water, the organic layer was dried and concentrated in vacuo. The residue was triturated with Et2O.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CN(C)C=O.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH:19]=[CH2:18])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 42 mg, 1.05 mmol) was added at room temperature to a solution of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1.00 mmol) in N,N-dimethylformamide (4 ml), then after 10 min a solution of 4-bromo-1-butene (148 mg, 1.10 mmol) in tetrahydrofuran (1 ml) was added dropwise. The reaction mixture was stirred for 3 h at room temperature, then another portion of 4-bromo-1-butene (40 mg, 0.30 mmol) was added dropwise, and the reaction mixture was heated at 50° C. for 18 h. After cooling, the reaction mixture was partitioned between water and heptane/ethyl acetate 1:1. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane/ethyl acetate 1:1) afforded the title compound (217 mg, 81%). Colorless oil, MS (ISP)=255.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:16][O:14][C:13]([C:11]1[S:12][C:8]([C:3]([CH2:4][CH3:5])([CH2:6][OH:7])[CH2:1][CH3:2])=[CH:9][CH:10]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)(CO)c1ccc(C(=O)O)s1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(CC)(CO)c1ccc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of 5-(1-ethyl-1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid (0.750 g, 3.28 mmol) in DMF (16.0 mL) is treated with K2CO3 (0.684 g, 6.00 mmol), iodomethane (0.27 mL, 4.34 mmol), and stirred at rt overnight. The mixture is poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 5-(1-ethyl-1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid methyl ester (0.571 g, 72%) as a clear syrup. MS (ES): 243.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Br.[C:17](O)(=O)C>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: Br
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of the compound from Step A (77.3 g), 48% HBr (310 ml), and acetic acid (620 ml) was heated under reflux for 18 hours. The resulting mixture was cooled to room temperature and poured into 3 liters of water. The resulting solution was extracted with ethyl acetate (3×500 ml). The 200 ml), dried over Na2SO4, the solvents were removed by evaporation and the residue was dissolved in 10% HCl/methanol (500 ml). After 1 hour at room temperature the volatile components were removed by evaporation in vacuo. The resulting residue was triturated with hexane to yield the title compound, mp 115°-116°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17].[H][H].[C:24](Cl)(Cl)=[O:25].[Na]>O1CCOCC1>[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[O:17][C:24]1=[O:25]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: O=C(Cl)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Product: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1F

Procedure:
To a slurry of 0.50 g of sodium hydride in 25 ml of dioxane under argon is added 2.80 g of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid in small portions. When hydrogen evolution is ceased, the mixture is cooled in an ice bath and phosgene is passed over the surface of the stirring mixture. An obvious reaction ensues, with dissolution of the sodium salt and evolution of more hydrogen. When the hydrogen evolution appears to have ceased, the ice bath is removed and the addition of phosgene is continued until the solution appears nearly saturated. The reaction mixture is then filtered through a glass frit to remove insoluble salts and the filtrate is distilled at 15-20 mm pressure to remove phosgene and about 15 ml of the dioxane solvent. The residue is then diluted with hexane and allowed to stand at RT until crystallization is complete. The anhydride is collected by filtration, washed with hexane and dried under vacuum, with care being taken to minimize exposure to moisture, to yield 3-(2-fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:28]1[N:29]([CH2:36][C@:37]2([CH3:40])[CH2:39][O:38]2)[CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[N:32]=1>CN(C=O)C>[CH3:39][C@@:37]1([CH2:40][O:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)[O:38][C:28]2=[N:32][C:31]([N+:33]([O-:35])=[O:34])=[CH:30][N:29]2[CH2:36]1
Reactant: Oc1ccc(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
4-[4-(4-Trifluoromethoxyphenyl)piperazin-1-yl]phenol (1.7 g, 5.02 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (221 mg, 5.53 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (1.2 g, 5.53 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then recrystallized from ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (1.02 g, yield 39%) as a light yellow powder.
Reaction SMILES: C[O:2]C(OC)C1C=CC=CC=1O.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:26]1([P:19](=[O:2])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(OC)c1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of 4.2 g. of [1(S),4R]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-hydroxy-L-proline, methyl ester, 3 g. of 2-(dimethoxymethyl)-phenol, 4.6 g. of triphenylphosphine dissolved in 15 ml. of tetrahydrofuran there is added 3.1 g. of diethylazodicarboxylate dissolved in 5 ml. of tetrahydrofuran (nitrogen atmosphere). The mixture becomes warm. The solution is stirred overnight. Addition of ether/petroleum ether yields 1.1 g. of dicarbethoxyhydrazine which is filtered off. Addition of more petroleum ether to the filtrate furnishes oily triphenylphosphine oxide which on trituration with ether turns solid; 2.5 g. The filtrate is absorbed on Baker silica and flash chromatographed. Elution with 85% ether - 10% petroleum ether elutes the pure product in six fractions, 250 ml. each, yielding 2.99 g. of [1(S),4S]-1-[3-(benzoylthio)-2methyl-1-oxopropyl]-4-[2-(dimethoxymethyl)phenoxy]-L-proline, methyl ester. A small sample is characterized and analyzed as its 2,4-dinitrophenyl hydrazine derivative.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)=[CH:10][C:9]([F:31])=[CH:8][N:7]=1.[OH-].[Li+]>C1COCC1.CO>[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)=[CH:10][C:9]([F:31])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3CCCN)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCCCc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 70 °C
Yield: 11.7 %

Procedure:
To (R)-ethyl 5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate hydrochloride (160 mg, 0.356 mmol) in THF/MeOH (2 mL/1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol). The reaction mixture was heated to 70° C. for 5 hours, then concentrated under reduced pressure. Water (10 mL) was added and the mixture washed with Et2O (2×5 mL), then neutralized with HCl (1M) to pH=4. The aqueous solution was extracted with DCM (2×10 mL). The organic extract was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude desired product (16.0 mg, 11.7% yield). MS (apci) m/z=385.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(C)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H NMR (CDCl3) δ 10.13 (s, 1H) 8.62 (d, J=4.8 Hz, 1H) 7.73 (d, J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49 (dd, J=8.8 Hz, 2.4 Hz, 1H) 7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz, 2H) 7.13 (s, 1H) 6.95 (d, J=4.8 Hz, 1H) 3.62 (s, 3H) 2.90 (t, J=8 Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz, 2H). MS: m/z=473.0 (M++1).