Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:36])([F:35])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([O:22][CH2:21][C:13]2[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([C:10]([F:9])([F:35])[F:36])[CH:12]=2)[C@@H:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (0.134 ml) was added to a mixture of (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine (prepared from the hydrochloride salt, Example 5) (0.5 g) and potassium carbonate (0.468 g) in N,N-dimethylformamide (2 ml) and the mixture stirred at 23° C. for 2.5 h. Water (20 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (1×10 ml) and brine (1×10 ml) then dried (K2CO3) and concentrated to leave an oil. Purification on silica gel eluting with hexanes-ethyl acetate (19:1 then 9:1 then 4:1 then 1:1) provided the title compound as a solid, m.p.=89°-93° C. Found: C, 66.11; H, 5.25; N, 2.81. Calcd. for C27H25NOF6 ; C, 65.71; H, 5.11; N, 2.84%.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)[N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:29]1([C:23]2[CH:22]=[C:21]([C:18]3[N:17]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([CH2:34][CH3:35])[CH:11]=4)[O:20][N:19]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
Pd/C (150 mg, 10% Pd) is added to a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2-cyclopentyl-6-methoxy-pyridine (1040 mg, 2.22 mmol) in THF (20 mL) and methanol (20 mL). The mixture is stirred under 1 bar of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated and dried to give 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (672 mg) as an off-white solid; LC-MS**: tR=0.97 min, [M+H]+=380.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][C@H:11]1[C@H:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=2)[O:16][CH2:15][CH2:14][N:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12]1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:10][C@H:11]1[C@H:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=2)[O:16][CH2:15][CH2:14][N:13]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CC(=O)Nc2ccccc2N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cc2nc3ccccc3[nH]2)C1
Yield: 85.8 %

Procedure:
A solution of tert-butyl (6R,7R)-6-{2-[(2-aminophenyl)amino]-2-oxoethyl}-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (155 mg) in acetic acid (1.1 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (128 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[N:12]([C:20]([C:22]2[C:23]([CH:28]([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=2)=[O:21])C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH:9]2[CH2:11][CH:10]2[NH:12][C:20]([C:22]2[C:23]([CH:28]([F:30])[F:29])=[N:24][N:25]([CH3:27])[CH:26]=2)=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1cc(C(=O)N(C(=O)OC(C)(C)C)C2CC2c2ncc(Cl)cc2Cl)c(C(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C(=O)NC2CC2c2ncc(Cl)cc2Cl)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
0.200 g of tert-butyl [2-(3,5-dichloropyridin-2-yl)cyclopropyl]{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]carbonyl}carbamate (0.00039 mol) are dissolved in 5 ml of dichloromethane. 0.50 ml of trifluoroacetic acid are added to the reaction mixture which is left stirring at room temperature overnight. The reaction mixture is quenched with 15 ml of an aqueous solution of saturated sodium bicarbonate. After separation, the aqueous phase is extracted with dichloromethane (10 ml). The combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 120 mg of N-[2-(3,5-dichloropyridin-2-yl)cyclopropyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (76%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[O:38][C:39]2[C:45]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>>[C:49]([NH:48][CH2:47][CH2:46][C:45]1[C:39]2[O:38][C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:41][C:40]=2[CH:42]=[CH:43][CH:44]=1)(=[O:51])[CH3:50]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC(=O)NCCc1cccc2cc(CCl)oc12
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc3cccc(CCNC(C)=O)c3o2)cc1

Procedure:
Analogously to Method D, 1.18 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.64 g of N-[2-(2-chloromethylbenzofuran-7-yl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.12 (3:1 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:29][C:10]3=[N:11][CH:12]=[CH:13][C:14]([C:15]4[N:20]=[C:19]([NH:21][CH2:22][CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:18]=[CH:17][CH:16]=4)=[C:9]3[CH:8]=2)[CH2:3][CH2:2]1.C=O.O.[C:33]([BH3-])#N.[Na+]>CO.ClCCl>[CH3:33][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:29][C:10]3=[N:11][CH:12]=[CH:13][C:14]([C:15]4[N:20]=[C:19]([NH:21][CH2:22][CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:18]=[CH:17][CH:16]=4)=[C:9]3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cc(NCC2CCOCC2)nc(-c2ccnc3[nH]c(C4CCNCC4)cc23)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCC(c2cc3c(-c4cccc(NCC5CCOCC5)n4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 88C (15 mg, 0.04 mmol) in methanol (2 mL) was treated with 37% formaldehyde in water (12 mg, 0.4 mmol) and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (5 mg, 0.08 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with dichloromethane and washed with water. The organic phase was concentrated and purified by HPLC (Zorbax C-18, using a 0-100% gradient of water/acetonitrile, containing 0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.38 (m, 2H), 1.64-1.73 (m, 2H), 1.77-1.96 (m, 4H), 2.34 (d, J=13.56 Hz, 4H), 2.83 (d, J=4.75 Hz, 3H), 3.00-3.20 (m, 4H), 3.56 (d, J=11.53 Hz, 2H), 3.88 (dd, J=10.68, 3.22 Hz, 2H), 6.68 (d, J=8.48 Hz, 1H), 6.77-6.83 (m, 1H), 7.18 (d, J=7.80 Hz, 1H), 7.50 (d, J=5.09 Hz, 1H), 7.58-7.63 (m, 1H), 8.24-8.27 (m, 1H). LCMS: 406 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:20]>>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: N
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Temperature: 90 °C

Procedure:
2-(hydroxymethyl)-5-(4-methoxybenzyloxy)-4H-pyran-4-one (Intermediate 63, 6.44 g, 24.56 mmol) and ammonia (7N in MeOH) (59.6 ml, 417.45 mmol) were combined in a pressure reactor vessel and heated at 90° C. for 5 hours. The reaction mixture was cooled overnight then concentrated. The solid was suspended in water then collected by filtration. The title compound was obtained as a brown solid (3.48 g, 54%).
Reaction SMILES: N.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]=[C:11]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[NH2:24][C:25]([CH3:32])=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)(C)(C)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:24][C:25]([CH3:32])=[C:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C=C(C)N
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)c1ccccc1
Agent: N
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 9.3 %

Procedure:
Ammonia (0.5 ml, d=0.88) was added to a solution of methyl alpha-(2,3-dichlorophenylmethylene)-beta-oxobenzenepropanoate (2 g, 7.3 mmoles) and ethyl 3-amino-2-butenoate (0.77 g, 6.0 mmoles) in tert. butanol (8 ml) at 60°. The reaction was maintained at this temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60°-80°) mixtures. The title compound (0.25 g) was obtained after crystallisation from 2-propanol mp 185°-6°.
Reaction SMILES: Br[C:2]1[C:3]2[N:4](N=N[N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.CC(C)([O-])C.[K+].O1CCOCC1>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.O>[NH2:23][C:3]1[C:2]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3nnnn23)CC1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c(N)n2)CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 8.7 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(8-bromotetrazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (5.5 g, 14.3 mmol), thiophene-2-boronic acid (2.5 g, 21.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.43 mmol), potassium tert-butoxide (2.4 g, 21.5 mmol), 1,4-dioxane (200 mL) and water (50 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 80° C. under N2 for 10 h. Work-up: the reaction mixture was diluted with 0.1 M HCl (20 mL) and washed with EtOAc (150 mL×3). The aqueous layer was then basified with solid NaHCO3 and extracted with CH2Cl2 (150 mL×3). The combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2 to afford 0.70 g (12%) of the product, and 0.45 g (8.7%) of tert-butyl 4-(4-amino-5-(thiophen-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.[OH-].[Na+].Cl>O>[N:8]1([CH2:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a suspension of crude 4-piperidin-1-yl-butyric acid ethyl ester from the previous step (about 25 mmol) in 15 mL of water, NaOH (1.4 g, 25 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was then allowed to cool down to room temperature, the solution was acidified at 0° C. with HCl 6N and concentrated under reduced pressure. The residue was treated with EtOH and the sodium chloride which precipitated was filtered off. Evaporation of the solvent under reduced pressure afforded 2.8 g of the title compound as a white solid in 58% overall yield of steps a) and b)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19]C)=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17]C)=[O:9])[CH:7]=1.ClC1C=CC(OCC)=C(C(C2C=C(Cl)C=CC=2OCC)=O)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(Cl)ccc1OC
Agent: CCOc1ccc(Cl)cc1C(=O)c1cc(Cl)ccc1OCC
Product: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O

Procedure:
Bis(5-chloro-2-hydroxyphenyl)ketone (m.p. 154° C.; reference m.p. 152°-155° C.) was prepared by the demethylation of bis(5-chloro-2-methoxyphenyl)ketone following the method described by Moshfegh et al (Acta Chem Scand, 1957, 40, 1157-66) for the de-ethylation of bis(5-chloro-2-ethoxyphenyl)ketone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:22][C:23]2=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C1NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Yield: 48.7 %

Procedure:
In this reference example, to the mixture of 23.0 g of 1-benzyl-4-[N-(o-aminomethylphenyl)-amino]-piperidine and 200 ml of acetonitrile, 17.4 g of 1,1'-carbonyldiimidazole is added over a period of 3 hours with stirring at 40° to 60° C. Then, the resultant mixture is refluxed with heating for one hour, brought back to room temperature and stirred at room temperature for 2 hours. The crystals deposited are separated by filtration, successively washed with water and methanol and dried to obtain 16.8 g of a crude product. The crude product is recrystallized from methanol to obtain 12.18 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Cl.[OH-].[Na+]>CO.C1COCC1.O1CCOCC1>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][NH:19][OH:20])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=NO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde oxime (301 mg, 1.0 mmol) (obtained from preparation 17) in a mixture of methanol (7 ml) and THF (3 ml) was added 4 N HCl (2 ml) in dioxane at 30° C. and stirred for 10 min. at the same temperature. The reaction mixture was basified to pH 9 with 1 N NaOH and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4 and concentrated to yield the of title compound (272 mg, 90%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O)C.CO>C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](CNCc1ccc(F)cc1)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 4-fluorobenzylamine and ethanol essentially as described above in Example 94 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH2:15][CH:14]=[CH2:13])([OH:12])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: CCOCC
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
3-Oxo-azetidine-1-carboxylic acid tert-butyl ester (1.37 g, 8 mmol) was dissolved in Et2O (10 ml) and a 1M solution of allylmagnesiumbromid in Et2O (10.4 ml, 10.4 mmol) was added dropwise at 0° C. Stirring was continued at rt overnight. The reaction mixture was quenched with H2O, extracted twice with EtOAc, the organic layer were washed with brine, combined, dried over Na2 SO4, filtered off and concentrated under reduced pressure to give a orange oil. The crude product was purified by flash chromatography (silica gel, EtOAc/cyclohexane 15-25%) which furnished the product as an yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(OCC)(=O)C.C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:31][CH3:30])[CH:37]=3)=[CH:3][CH:4]=2)[N:9]=[C:10]([C:20]([C:22]([F:24])([F:23])[F:25])([C:26]([F:28])([F:29])[F:27])[OH:21])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
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+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 5 of Preparation 24, 3-methylthiophenylboronic acid (25.1 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, 0.01 mmol), and a 2N sodium carbonate solution (0.5 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 2 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 3.7 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[CH2:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[S:21](Cl)(=[O:23])=[O:22])[CH2:10][CH3:11]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:21]([C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:12]=1[CH2:9][CH2:10][CH3:11])(=[O:22])=[O:23]
Reactant: CCCc1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Solvent: C1CCOC1
Product: CCCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0.68 mmoles, 0.12 g) NaH (1.7 mmoles, 6.8 mg), 2-n-propylbenzo[b]thiophene-3-sulfonyl chloride (0.82 mmoles, 0.23 g) and THF (3 ml). Recrystallization from chloroform and hexanes provided 0.19 g (67%) of a yellow crystalline solid, m.p. 136-138° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:45]1[CH:50]=[CH:49][C:48]2[O:51][CH2:52][O:53][C:47]=2[CH:46]=1)[C@H:14]([N:16]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:17]([C@@H:19]([OH:33])[C@@H:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:45]1[CH:50]=[CH:49][C:48]2[O:51][CH2:52][O:53][C:47]=2[CH:46]=1)[C@H:14]([N:16]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:17]([C:19]([OH:33])=[C:20]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15]
Reactant: COC(=O)C[C@H](C(=O)OC(C)(C)C)[C@H](O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Yield: 40.9 %

Procedure:
36 mg of methyl (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxybutanoate in 2 ml of chloroform was stirred with 42 mg of the Dess-Martin reagent (periodenane) at room temperature for 1 hour. The reaction solution was poured into a mixture of saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by silica gel thin layer chromatography [Kieselgel™ 60F254, Art™ 5744; hexane/ethyl acetate=3/2] to give 14.7 mg (yield 41%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].C(O[C:13](=[O:15])[CH3:14])(=O)C>>[CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([O:6][C:13](=[O:15])[CH2:14][CH:2]([CH3:1])[CH2:3][CH3:4])=[O:5]
Reactant: CCC(C)CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CCC(C)CC(=O)OC(=O)CC(C)CC
Yield: 97 %

Procedure:
3-Methylpentanoic acid anhydride was prepared from 6 moles of 3-methylpentanoic acid and 4.5 moles of acetic acid anhydride, by distilling acetic acid and the excess acetic acid anhydride from the reaction mixture at atmospheric pressure to a pot temperature of 220° C. Thereafter the desired anhydride was purified by distillation under reduced pressure. Yield: 97% of theory.