Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:24]([N:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(Cl)Cl>[C:24]([N:31]1[CH2:36][CH2:35][CH:34]([O:37][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1

Procedure:
With stirring, 8.16 ml (0.09 mol) of 3,4-dihydro-2H-pyran and 1.5 g (0.006 mol) of pyridinium-(toluene-4-sulfonate) are added to a solution of 12.08 g (0.06 mol) of N-BOC-4-hydroxypiperidine (cf. EP 0 278 621) in 300 ml of methylene chloride. The reaction mixture is stirred for 2.5 hours at room temperature, then washed with 2×50 ml of brine:water (1:1) mixture, dried over sodium sulfate and concentrated under vacuum, giving the title compound in the form of a colourless oil; Rf =0.58 (silica gel/ethyl acetate:hexane (2:1), which gradually solidifies in crystalline form at 0° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CO>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:9]1[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)cccc2F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2c(F)cccc2F)nc1
Yield: 63 %

Procedure:
Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd(OAc)2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80° C. for 18 hours. Cool reaction to room temperature. Add a solution of 1-bromo-2,6-difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd(OAc)2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80° C. for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10% ethyl acetate in hexane) to give 50 mg (20% yield) of 6-(2,6-difluorophenyl)pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with 1N sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the residue with 1N hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (ES): m/z 235.9 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]1
Reactant: COC(=O)Cl
Reactant: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(Oc2nc(-c3ccncn3)cc(=O)n2C)C1
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (0.10 g, 0.35 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (5 ml) was added methyl chloroformate (40 μl, 0.5 mmol) at 0° C. The resulting mixture was stirred for 2 hours and poured into 1N aqueous hydrochloric acid. The partitioned organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent; chloroform/methanol=100/0 to 90/10) to afford methyl 3-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidine-1-carboxylate as a white solid (52 mg, 0.15 mmol, 43%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O.CCCCCC>C1C=CC=CC=1>[Br:33][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: BrCCc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution of 25 g (145 mmole) of 2-(2-naphthyl)ethanol and 67.9 g (259 mmole) of triphenylphosphine in 200 ml of benzene was added in portions 46.1 g (259 mmole) of N-bromosuccinimide. A temperature of 45°-50° was maintained by cooling the reaction mixture as needed in an ice bath. After the mixture was poured into 750 ml of hexane and filtered, the filtrate was diluted with an additional 400 ml of hexane and allowed to stand overnight. The solution was concentrated to dryness and the resultant solid was purified by chromatography on silica gel. The title compound (30.5 g), m.p. 55°-57°, was homogeneous by thin-layer chromatography (5%, 10%, and 15% by volume ethyl acetate-hexane on silica gel plates), and was used in subsequent reactions without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22]#[N:23]>ClCCCl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([C:20]1[N:16]([CH3:15])[C:17]([CH2:21][C:22]#[N:23])=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1cccc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added dropwise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hyrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting residue is triturated with cold methanol to yield a precipitate of the desired product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo, and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. The desired product is isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 122-127° C. Analysis: Calcd. for C14H11ClN2O: N, 10.83%. Found: N, 10.52
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[C:19]([CH3:32])=[C:18]([CH3:33])[N:17]=1>CN(C)C=O>[ClH:15].[CH3:32][C:19]1[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[N:21][C:16]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][C:18]=1[CH3:33]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CCCCC2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 50.6 %

Procedure:
After cyclohexylamine(0.31 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 340 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[CH3:19]CN(CC)CC.C[N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1>C(Cl)Cl>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:32]([C:29]3[N:28]([CH3:19])[N:27]=[CH:31][CH:30]=3)(=[O:34])=[O:33])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(OS(=O)(=O)c3ccnn3C)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.8 mmol) and Et3N (0.4 ml, 4 mmol) in DCM (8 mL) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (433 mg, 2.4 mmol) slowly at −78° C. Then stirred at −78° C. to rt overnight. The resulting mixture was concentrated, chromatography on silica gel, (DCM/MeOH 9.5/0.5) to get white solid. Further purification by reverse-phase prep. HPLC to get the title compound colorless oil (64 mg). 1H NMR (400 MHz, DMSO-d6) δ 9.15 (br, 1H), 8.00 (s, 1H), 7.19 (s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 5.45 (q, 2H), 4.00 (t, 3H), 2.48 (d, 2H), 2.25 (d, 1H), 2.21 (s, 3H), 1.08 (t, 3H) ppm. MS (ESI) m/z=393.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][SH:15])[CH2:11][O:12][C:8]=2[CH:7]=1.CCN(C(C)C)C(C)C.CN(C=O)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][S:15][CH2:14][CH2:13][C@H:10]1[C:9]2[CH:16]=[CH:17][C:6]([O:5][CH2:4][C:3]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=3[Cl:1])=[CH:7][C:8]=2[O:12][CH2:11]1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: SCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CSCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a mixture of 2-((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)ethanethiol (30 mg), DIPEA (0.029 mL) and DMF (dry) (15 mL) was added ethyl 2-bromoacetate (21.15 mg). The mixture was stirred at room temperature under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (25.0 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:55][CH:54]=1>CC#N>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:52][C:53]3[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:55][CH:54]=3)=[O:17])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCCCNc1ccc2ncc(C(=O)O)n2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.64 mmol) in CH3CN (1 mL) were added BOP reagent (567 mg, 1.28 mmol), triethyl amine (0.26 mL, 1.92 mmol) and tert-butyl 4-aminobenzylcarbamate (143 mg, 0.64 mmol). The reaction was stirred for overnight. Then the reaction was purified ISCO column chromatography on silica gel (10% MeOH/DCM) to give tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate as white solid (280 mg, 100% yield). 20 mg was further purified by prep HPLC (neutral) to afford tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (5 mg) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.10 (s, 1H), 7.76 (d, J=9.70 Hz, 1H), 7.67 (d, J=8.38 Hz, 2H), 7.32 (d, J=8.38 Hz, 2H), 6.90 (d, J=9.70 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 2H), 3.47 (t, J=7.28 Hz, 2H), 1.79 (t, J=7.39 Hz, 2H), 1.46-1.57 (m, 10H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 439.9 [(M+H)+, calcd for C23H31N6O3 439.5].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[NH:24]2>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[N:24]2[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1
Reactant: CC(C)c1nc(CCl)cs1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(Cl)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 147-148° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H), 5.94 (s, 2H), 5.09 (d, J=16 Hz, 1H), 4.93 (d, J=9.7 Hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.76 (d, J=9.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.1, 156.1, 149.5, 148.5, 144.1, 141.4, 130.3, 129.6, 128.1, 123.2, 116.9, 115.2, 108.5, 102.7, 101.4, 92.8, 76.9, 57.9, 40.2, 32.4, 22.7, 22.6; MS (ES+) m/z 455.3 (M+1), 457.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:13]1[CH:18]=[C:17]2[C:19]([C:21](O)([OH:24])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20]>S(=O)(=O)(O)O>[OH:24][C:21]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:12])[CH3:11])[C:22](=[O:23])[C:16]2[C:17](=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:19]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C)c(C)cc1C1(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
N-(3,4-dimethylphenyl)acetamide (915 mg, 5.62 mmol) and ninhydrin (1.00 g, 5.62 mmol) were dissolved in conc. sulfuric acid (20 mL) and stirred at room temperature for 1.5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 800 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:3]=1
Reactant: COC(=O)c1cn(C(C)c2ccccc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C(C)c2ccccc2)cc1C(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
A mixture of methyl 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (90 mg, 0.37 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid as a white solid (60 mg, 70%). 1H NMR (300 MHz, d6-DMSO): δ 12.24 (s, 1H), 7.82 (s, 1H), 7.36-7.17 (m, 5H), 5.67 (q, J=7.2 Hz, 1H), 2.43 (s, 3H), 1.79 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:8]2[S:9][C:10](C(O)=O)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:38](C)[CH:39]=[O:40].C[Si](N=[N+]=[N-])(C)C>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:8]2[S:9][C:10]([N:38]=[C:39]=[O:40])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=Nc1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 2-((4-fluorobenzyl)(4-(pyridin-3-yl)benzyl)amino)thiazole-5-carboxylic acid (850 mg, 2.026 mmol) in dichloromethane (10.100 ml) and the solution was cooled to 0° C. Oxalyl chloride (0.266 ml, 3.04 mmol) and dimethylformamide (0.016 ml, 0.203 mmol) were added and some bubbling occurred. The solution was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0° C., and trimethylsilyl azide (0.538 ml, 4.05 mmol) was added. The mixture was warmed to room temperature, stirred for 30 minutes and concentrated under vacuum. Toluene (5 ml) was added and the mixture was heated to 95° C. for 2.5 hours. The toluene was removed and the resulting solid was triturated/sonicated with ether and filtered with ether washes to provide the title compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:16][CH:17]([CH2:38][CH2:39][C:40]([CH3:42])=[CH2:41])[CH:18]([CH3:37])[CH2:19][CH2:20][CH2:21][C:22]1([CH3:36])[CH:28]2[O:29][C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:26][CH2:27]2)[CH2:24][O:23]1)(=[O:15])[CH3:14].C([O-])(O)=O.[Na+].O>C1C=CC=CC=1.CCOCC>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:25]12[O:29][CH:28]([CH2:27][CH2:26]1)[C:22]([CH2:21][CH2:20][CH2:19][CH:18]([CH3:37])[CH:17]([O:16][C:13](=[O:15])[CH3:14])[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])([CH3:36])[O:23][CH2:24]2)[CH3:35]
Reactant: C=C(C)CCC(OC(C)=O)C(C)CCCC1(C)OCC2(CC(=O)OCC)CCC1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC12CCC(O1)C(C)(CCCC(C)C(CC=C(C)C)OC(C)=O)OC2
Temperature: 130 °C
Yield: 94.6 %

Procedure:
p-Toluenesulfonic acid monohydrate (8.2 mg) is added to benzene (12 ml). The mixture is stirred and refluxed in a Dean-Stark apparatus and some of the benzene (4 ml) is drained from the side-arm. The bicyclic acetoxy ester, ethyl(1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-8-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetate (85 mg, 0.2 mM), dissolved in benzene (6 ml), is added at room temperature to the above mixture and the resultant mixture is stirred and refluxed (bath at 130° C.) for two hours. The temperature of the heating bath is then lowered to 90° C. and the stirring is continued at 90° C. for sixteen hours and then at room temperature for seventy-two hours. The reaction mixture is added to saturated NaHCO3 --H2O (10 ml) and ether (20 ml). The organic layer is separated, washed with saturated NaCl--H2O, dried with Na2SO4, filtered, and evaporated in vacuo to give ethyl(1RS, 4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetate (80.4 mg, 95%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH2:28]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(C(C)C)c(CC=Cc2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from the intermediate obtained in Step A and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 8 H), 6.96 (m, 1 H), 6.32 (d, J=11 Hz, 0.4 H), 6.09 (dt, J=5.5, 16 Hz, 0.6 H), 5.96 (d, J=16 Hz, 0.6 H), 5.45 (dt, J=7, 11 Hz, 0.4 H), 4.37 (d, J=5 Hz, 1.25 H), 4.33 (d, J=5.5 Hz, 0.75 H), 3.41 (m, 1.6 H), 3.25 (m, 2 H), 3.08 (m, 0.4 H), 1.35 (m, 5 H), 1.30 (d, J=6.6 Hz, 5 H), 1.21 (m, 3 H). FAB-MS: calcd for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26. mp 72-73° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:35])[C@@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][N:10]=1)=[O:8])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[OH2:5].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[OH:5][NH:6][C:7]([C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:35])[C@@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[C:26]([Cl:34])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][N:10]=1)=[O:8]
Reactant: CC(C)(C)ONC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=O)NO)cn2)cc1Cl
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A solution of 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid tert-butoxy-amide (318.3 mg, 0.609 mol) in methylene chloride (2.3 mL) was treated with trifluoroacetic acid (4.6 mL) and stirred at 25° C. overnight, then at 40° C. for 10–11 h, followed by stirring again at 25° C. overnight. The reaction solution was then concentrated in vacuo. Reverse phase high-performance liquid chromatography (Rainin Dynamax system, 60 Å C-18 column, l=214 nm, 50 mL/min of 50–100% acetonitrile with 0.1% trifluoroacetic acid/water with 0.1% trifluoroacetic acid over 55 min) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid hydroxyamide (90.0 mg, 32%) as a pink foam: mp 134–139° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H23ClN4O5S (M+H)+ 467.1151, found 467.1155.