Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Br:12])[CH:11]=1)(=[O:5])=[O:4].[CH:14]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Br:12])[C:11]=1[CH3:14])(=[O:4])=[O:5]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)S(=O)(=O)c1cncc(Br)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Br)cncc1S(=O)(=O)N(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-pyridine-3-sulfonic acid dimethylamide (CAS #896160-99-9, 100 mg, 0.377 mmol) in THF (3.8 mL) at −78° C. was added lithium diisopropylamide (0.5 M solution in THF, 0.85 mL, 0.42 mmol). The reaction was stirred for 15 minutes, at which time iodomethane (0.030 mL, 0.48 mmol) was added. The reaction was stirred for an additional 15 minutes and was then quenched with saturated aqueous ammonium chloride. Next, the reaction was diluted with water, dichloromethane, and saturated aqueous sodium bicarbonate. The layers were separated and aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by semi-preparative reverse phase HPLC (20 to 90% acetonitrile/water w/0.1% NH4OH) to furnish 5-bromo-4-methyl-pyridine-3-sulfonic acid dimethylamide; MS: (ES+) m/z 279.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[O:18]=[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][C:29](=[O:33])[C:30](O)=[O:31])=[CH:27][C:21]=2[O:20]1>>[O:31]=[C:30]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)[C:29]([NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19](=[O:18])[O:20][C:21]=2[CH:27]=1)=[O:33]
Reactant: FC(F)(F)c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-trifluoromethyl-benzyl)-piperidine [J. Org. Chem., 64, 3763. (1999)] and N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) according to the method described in Example 43f. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 217° C. (isopropanol)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:15][C:16]([N:17]3[CH2:23][CH:22]4[O:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.C(N1C2=NC(C3C=C[C:73]([N:76]=[C:77]=[O:78])=CC=3)=NC(N3CC4OC(CC4)C3)=C2C=N1)C1C=CC=CC=1>ClCCl.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:26]=[CH:27][C:28]([NH:29][C:77]([NH:76][CH3:73])=[O:78])=[CH:30][CH:31]=3)=[N:15][C:16]([N:17]3[CH2:18][CH:19]4[O:24][CH:22]([CH2:21][CH2:20]4)[CH2:23]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1

Procedure:
A solution of 4-(1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (22 mg, 0.05 mmol) in a mixture of dichloromethane (3 mL) and tetrahydrofuran (2 mL) was treated with triphosgene (8 mg, 0.03 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1 mL)—was added to the 3-(1-benzyl-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-{4-[1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea. MS (ES+): 470.0 (M+H)+
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(C)nc2)c(=O)[nH]c1=O)OC
Yield: 48 %

Procedure:
5-(6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep57, 385 mg, 1.62 mmol), K2CO3 (224 mg, 1.62 mmol) and 3-bromo-1,1dimethoxy-propane (commercially available from Aldrich, 183 mg, 1.0 mmol) were suspended in dry DMF (8 mL). After stirring the reaction at room temperature for 24 hours, additional 3-bromo-1,1dimethoxy-propane (180 mg, 0.98 mmol) was added portionwise over a period of 96 h. Water was added and the mixture washed with diethyl ether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 320 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:16]1[CH:21]=[CH:20][C:19]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: Clc1ccc(Cl)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(CCCCCCCCCCCC)cc1
Temperature: 25 °C

Procedure:
n-Dodecylmagnesium bromide (235 mL, 235.0 mmol, 1.0 M in diethyl ether) was added dropwise over 15 minutes, to a solution of 1,4-dichlorobenzene (15.00 g, 102.0 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II)chloride ((dppp)Cl2Ni, 70 mg) in dry ether (70 mL) at 0° C. The reaction mixture was subsequently allowed to warm to room temperature for about 30 minutes, heated under reflux for 1 day, and cooled to 0° C. again. The reaction was carefully quenched with water (10 mL) and HCl (70 mL, 2 M) and the aqueous layer was extracted with ether (2×50 mL). The combined organic layers were washed with water (30 mL), dried over MgSO4, and filtered. The solvent was then removed in vacuo and the crude product was heated to 100° C. under high vacuum (˜20 mtorr) for 10 hours to remove n-octane and n-octylbromide. 1,4-Di-n-dodecylbenzene (1) was obtained as a white solid (35.00 g, 83%). 1H NMR (CDCl3): δ 0.88 (t, 6H), 1.30 (m, 36H), 1.61 (m, 4H), 2.59 (t, 4H), 7.10 (s, 4H) ppm.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OS([O-])=O.[Na+]>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S([O-])O
Agent: [Na+]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 50% solution of cornstarch hydrolyzate containing dextrose on a dry solids basis, 5 mM MgSo4 and 5 mM NaHSO3 was adjusted in pH to 7.8, and started downflow through the bed of immobilized isomerase at 61° C. Initial flow through the column was calculated from equation 1 and was set to provide a fructose conversion of about 44%. This flow of about 17 ml/hour was held constant except during assay of immobilized activity. Fructose content of the effluent was measured essentially by the method as for determining degree of isomerization.
Reaction SMILES: C(O)C.[OH-].[Na+].C([O:8][C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=[O:10])C>O>[C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)([OH:10])=[O:8]
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 48.5 %

Procedure:
10 ml of ethanol, 5 ml of water and 20 mg of sodium hydroxide were added to 100 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 10 minutes and concentrated under a reduced pressure, followed by the addition of 20 ml of water. The obtained mixture was neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration. Thus, 45 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[S:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17]N1C(=O)CCC1=O>C1COCC1.C(NC(C)C)(C)C>[Cl:17][C:3]1[C:4]2=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=[C:9]2[S:10][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2sc(F)cc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc2sc(F)c(Cl)c2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of 461 mg (2.74 mmol) of 2-fluoro-5-methylthieno [3.2-b]pyridine (Example 7, Step 1) and 14 μl (0.1 mmol) of diisopropylamine in 12 mL of THF was added 2.15 mL of n-butyl lithium (1.4M in hexane) at -78° C. After stirring at -78° C. for 10 min, a solution of 585 mg (4.4 mmol) of N-chlorosuccinimide in 10 mL of THF was added at -78° C. The mixture was stirred at -78° C. for 20 min, warmed up to 0° C., stirred at 0° C. for 30 min, and then partitioned between aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel with hexane/ethyl acetate=8:1 gave 350 mg (63%) of the title product.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:11][CH:10]=1)[CH3:8].C(O)C.[OH-].[Li+]>O1CCCC1>[C:35]([N:27]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C@H:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:10][CH:11]=2)=[O:16])[C@@H:18]([CH3:38])[CH2:19]1)(=[O:37])[CH3:36]
Reactant: COC(=O)CCCN(C)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)CCCC(=O)O)cc2)c2ccccc21
Temperature: 50 °C

Procedure:
(2S,4R)-4-[(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-methyl-amino]-butyric acid was prepared from (2S,4R)-4-[(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-methyl-amino]-butyric acid methyl ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and lithium hydroxide (1N) was added and heated 50° C. for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to afford the product after HPLC purification.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16]O)[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16][Cl:21])[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1OCC(=O)N(CO)C1c1ccccc1
Product: CC(=O)N1OCC(=O)N(CCl)C1c1ccccc1
Temperature: 0 °C
Yield: 53 %

Procedure:
0.5 g. (2 mmoles) of 2-acetyl-3-phenyl-4-hydroxymethyltetrahydro-1,2,4-oxadiazin-5-one are refluxed in 3 ml. of thionyl chloride for one hour. The solution is evaporated to dryness under reduced pressure. The residue is triturated with diethyl ether cooled to 0° C. and the product is filtered off and is subsequently recrystallized from a mixture of 2 ml. of chloroform and 6 ml. of n-hexane. 0.28 g. (53%) of 2-acetyl-3-phenyl-4-chloromethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 171° to 172° C.; RfA =0.7.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Reactant: NCc1ccc(F)cc1
Product: Cc1ccn2cc(-c3ccc(OCCCNCc4ccc(F)cc4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C, Example 8 (160 mg) and 4-fluorobenzylamine (1.0 mL) were heated at 100° C. for 40 minutes. The reaction was cooled to ambient temperature and purified via silica gel chromatography (methanol/dichloromethane) to yield the title compound (16 mg) in approximately 80% purity. 1HNMR (CDCl3): δ 7.97 (d, J=7.0 Hz, 1H), 7.85 (m, 2H), 7.69 (s, 1H), 7.36 (br s, 1H), 7.28 (m, 2H), 6.96 (m, 4H), 6.59 (dd, J=7.0 Hz, J=1.5 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H), 3.78 (s, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1C(Cl)=CC2N=C(S)NC=2C=1.[OH-].[K+].IC.[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[NH:24][C:20]=2[CH:19]=1>C(O)C>[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[N:24]([CH3:2])[C:20]=2[CH:19]=1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CSc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(Cl)c(Cl)cc2n1C

Procedure:
5,6-dichloro-2-mercaptobenzimidazole (8.76 g, 0.04 mol) in 50 ml 95% ethanol was treated with 10 ml of 45% aqueous potassium hydroxide to give a solution. Iodomethane (7 ml, 0.096 mol) was added. The reaction mixture was refluxed for two hours. Cooling overnight yielded precipitant, which was filtered, water-washed, and dried to yield 5.61 g, mp 115° C. The reaction filtrate was rotary evaporated and the residue reslurried in water. After filtration and drying, an additional 3.52 g was obtained, mp 110° C. NMR analysis indicated the presence of some 5,6-DiChloro-2-(methylthio)benzimidazole as an impurity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH:12](=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OC(=O)C)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1/[CH:12]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2
Reactant: COc1ccccc1C=O
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1/C=C1\CCCc2cc(C)cnc21

Procedure:
5,6,7,8-Tetrahydro-3-methylquinoline (6.6 g) was added to o-anisaldehyde (8.16 g) in acetic anhydride (10 ml) and was heated to reflux for 14 hours after which the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and was added to 2N HCl (150 ml), the aqueous layer was basified (Na2CO3) and extracted with ethyl acetate (4×100 ml) dried (MgSO4) and evaporated under reduced pressure. The residue was washed with several aliquots of hot hexane and was then dissolved in a small volume of boiling propan-2-ol and etherial hydrogen chloride was added in excess. On cooling a precipitate formed and was removed by filtration, washed with ether and dried under vacuum to give the title compound as the hydrochloride salt (2.6 g) m.p. 221°-222.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:32])[C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:32])[C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O

Procedure:
A 1.5 g quantity of the N-[2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 16 was dissolved in 50 ml of ethanol, and 0.1 g of 10% palladium carbon powder was added thereto. The mixture was stirred in a hydrogen atmosphere at 50° C. for two hours. The catalyst was removed by filtration, and the filtrate was then concentrated to give 1.3 g of white crystalline N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][C:28]#[N:29])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:30]1C=N[N:32]=[N:31]1.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.C(O)(C)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:19][CH:20]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1nnn[nH]1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2CC#N)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2Cc2nnn[nH]2)cc1

Procedure:
2-n-Butyl-4-chloro-1-[(2'-(cyanomethyl)biphenyl-4-yl)methyl]-5-(methoxymethyl)imidazole (5.20 g) was converted to the above tetrazole in 2 days using the procedure of Example 90, Part C. Work-up and flash chromatography over silica gel eluting with a gradient solvent system of 1:1 hexane/ethyl acetate to 1:1 ethyl acetate/isopropanol yielded 3.13 g of a light yellow solid; m.p. 149.0°-152.5°. NMR (200 MHz, CDCl3) δ 7.37-7.15 (m, 6H); 6.96 (d, 2H, J=9 Hz); 5.18 (s, 2H); 4.30 (s, 2H); 4.24 (s, 2H); 3.27 (s, 3H); 2.57 (t, 2H, J=7 Hz); 1.56 (t of t, 2H, J=7,7 Hz); 1.28 (t of q, 2H, J=7,7 Hz); 0.77 (t, 3H, J=7 Hz). Anal. Calcd. for C24H 27 ClN6O: C, 63.97, H, 6.03; Cl, 7.86. Found: C, 63.79; H, 6.04; Cl, 7.70.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[CH3:15])=O.[NH2:16][C:17]([NH2:19])=[S:18]>CCO>[CH3:13][N:12]([CH3:14])[C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:16]=[C:17]([NH2:19])[S:18][CH:2]=2)=[C:6]([CH3:15])[CH:7]=1
Reactant: NC(N)=S
Reactant: Cc1cc(N(C)C)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(N(C)C)cc(C)c1-c1csc(N)n1
Yield: 60.7 %

Procedure:
A mixture of 2-bromo-1-(4-(dimethylamino)-2,6-dimethylphenyl)ethanone (1-3, 0.900 g, 3.33 mmol) and thiourea (0.250 g, 3.33 mmol) in 95% EtOH (4.8 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (30 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and purified by flash column chromatography on silica gel to give 4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-amine (1-4, 0.50 g) as brown solids in 61% yield: 1H NMR (500 MHz, CDCl3) δ 6.45 (s, 2 H), 6.25 (s, 1 H), 4.90 (bs, 2 H), 2.93 (s, 6 H), 2.15 (s, 6 H).
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)([OH:3])=[O:2].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][O:18][C:19]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:4]([C:1]([OH:3])=[O:2])[CH2:5]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1CCCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)C1CCCCN(C(=O)OCc2ccccc2)C1

Procedure:
3-Carboxyhomopiperidine (Source: U.S. Pat. No. 4,409,146) is reacted with benzoxycarbonyl chloride to give 3-(carboxy)-1-homopiperidinecarboxylic acid phenylmethyl ester. This derivative is isolated and reacted with diborane in tetrahydrofuran to give 3-(hydroxymethyl)-1-homopiperidinecarboxylic acid phenylmethyl ester. This derivative is isolated and reacted with pyridinium chlorochromate to give 3-(formyl)-1-homopiperidine carboxylic acid phenylmethyl ester. The epoxide of this derivative is prepared by reacting with trimethyl sulfoxonium iodide and sodium hydride in an aprotic solvent. This epoxide is reacted with sodium phenoxide and the reaction mixture is acidified to give 2-(1-hydroxy-2-phenoxyethyl)-1-homopiperidinecarboxylic acid phenylmethyl ester which is hydrogenated over palladium on carbon to give the free base of the title compound. The free base is then converted to the hydrochloride salt as in Example 38.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:25])[S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C@H:10]([CH2:26][N:27]([CH:44]([CH3:46])[CH3:45])[C:28](=[O:43])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:44]([N:27]([CH2:26][C@H:10]1[C@H:11]([CH2:13][N:14]([CH3:25])[S:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH2:12][NH:8][CH2:9]1)[C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)([CH3:46])[CH3:45]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)S(=O)(=O)Cc2ccccc2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C)S(=O)(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R*,4S*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-[(methyl-phenylmethanesulfonyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (49 mg, 0.074 mmol) in 2 mL CH2Cl2, TFA (86 μL, 1.11 mmol) is added. The mixture is stirred 4 h at RT and then poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on an Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.2. MS (LC-MS): 563.0 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.55 min.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:24])[NH:11][C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][CH:14]=[N:13][C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:24])=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: C[C@@H](OC(=O)Nc1ncoc1-c1ccc(Br)cc1)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ocnc4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: [5-(4-bromo-phenyl)-oxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst.