Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[ClH:13].N([O-])=O.[Na+].[OH-].[Na+]>O.[Cu](Cl)Cl.C1(C)C=CC=CC=1>[Cl:13][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Nc1ccn(-c2cccnc2)n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a 3-neck round bottomed flask (250 mL) was charged 3-(3-amino-1H-pyrazol-1-yl)pyridine (5.00 g, 31.2 mmol) and hydrogen chloride (37 wt %, 15 mL). The mixture was cooled to 0° C. A solution of sodium nitrite (4.31 g, 62.4 mmol) in water (15 mL) was added in portions at <1° C. over 20 minutes and the resulting brown solution was stirred at <0° C. for 2 hours. To a separate 3-neck round bottomed flask (250 mL) was charged copper(II) chloride (5.04 g, 37.5 mmol) and toluene (30 mL). It was cooled to 0° C. and the yellow solution was added in portions at <1° C. over 15 minutes. The resulting mixture was allowed to warm up, off-gassing was observed when the reaction temperature reached 18° C. The reaction was stirred at 20° C. for 18 hours. The reaction was basified with 50 wt % sodium hydroxide to pH ˜10. Celite® (10 g) was added and the resulting suspension was stirred for 10 minutes. The suspension was filtered through a Celite® pad (10 g) and the filter cake was rinsed with ethyl acetate (2×50 mL). The layers of the filtrates were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent. The fractions containing the desired product were concentrated to give the title compound as a white solid (3.80 g, 68%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=2.7 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (M, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)s1
Yield: 85.9 %

Procedure:
Beginning with 0.40 gm (1.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.34 gm (2.08 mMol) 5-methyl-2-thiophenecarbonyl chloride, 0.53 gm (86%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([C:8]1[N:12]([C:14]2[CH:24]=[CH:23][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc(Cc2ncc[nH]2)cc1
Product: OCc1ccc(-n2ccnc2Cc2ccccc2)cc1

Procedure:
Prepared from 2-benzylimidazol and ethyl 4-fluorobenzoate.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.CCN(CC)CC.[C:50](Cl)(=[O:54])[CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[C:50]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])(=[O:54])[CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (80 mg, 0.14 mmol) in DCM (1 mL) and Et3N (0.057 mL, 0.41 mmol) was added dropwise isobutyryl chloride (0.036 mL, 0.34 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give 2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-7-yloxy)ethyl isobutyrate (75 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16](=[O:32])(=[O:31])[NH:17]C(C2C=CC=CC=2)C2C=CC=CC=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH2:15][S:16](=[O:32])(=[O:31])[NH2:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CS(N)(=O)=O)CC1

Procedure:
5.19 g of 4-[(benzhydryl-sulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert.-butyl ester in 150 ml of MeOH are treated with 100 μl of triethylamine and the mixture obtained is hydrogenated overnight at RT with 10% Pd/C as a catalyst. From the mixture obtained the catalyst is filtrated off, solvent is evaporated and the evaporation residue is subjected to chromatography on silica gel. 4-Hydroxy-4-sulfamoylmethyl-piperidine-1-carboxylic acid tert.-butyl ester are obtained. m.p. 176-180°.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
DIPEA (3.86 mL, 22.2 mmol, 1.2 eq) was added to a mixture of ethyl 7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (6.27 g, 18.5 mmol) and glycine tert-butyl ester hydrochloride (3.72 g, 22.2 mmol) in dioxane (30 mL). The reaction mixture was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a light yellow solid. The crude solid was suspended in ether, filtered, and washed with water to give the desired ester as a white solid (6.53 g). MS (m/e)=368.1 (M+H-tBu)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[OH:6])[CH3:2].C(O[C:27]([CH3:30])([CH3:29])[CH3:28])(=O)C.S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[O:6][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:2]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Yield: 35.8 %

Procedure:
Ethyl-2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl]-2-hydroxyacetate (3 g, 7 mmol) was taken up in 20 mL dichloromethane and tert-butyl acetate (20 mL, 170 mmol) and the mixture coiled to 3° C. in an ice/water bath. Concentrated sulphuric acid (1.14 mL, 21 mmol) was then added dropwise and the mixture allowed to warm to room temperature over 3 hours. The reaction was quenched by the addition of 100 mL of 1M NaOH and 100 mL water and the organic layer separated. The organics were washed with brine (100 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chrmoatography using a gradient of EtOAc in heptane as eluant (0:100 to 30:70) to afford the title compound as a white solid (1.22 g, 36%). 1H NMR (400 MHz, CDCl3) δ 1.20 (t, 3H), 1.23 (s, 9H), 1.81-1.94 (m, 4H), 2.66 (s, 3H), 2.80-2.87 (m, 2H), 3.22-3.31 (m, 2H), 4.10-4.22 (m, 2H), 5.90 (s, 1H).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([O:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:19]
Reactant: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)C1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 2-chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.08 mmol) in 10 ml of DMF was added at room temperature 2,6-dichlorobenzoic acid (0.44 g; 2.3 mmol), potassium carbonate (0.43 g, 3.1 mmol), and tetrabutylammonium bromide (67 mg; 0.21 mmol) and the resulting solution was allowed to react at 60°-70° C. for 2 hours and then cooled. The mixture was diluted with ice/water, extracted with ether/ethyl acetate (5:1, 400 ml), and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography to afford 0.51 g (62%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =isopropyl; R3 =methyl) as a solid, m.p. 70°-71.5° C.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH2:36][OH:37])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.[ClH:46]>[Pd].CO>[ClH:46].[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@@H:15]([C:32]([NH:34][C@H:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:36][OH:37])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCN)NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl)-ethyl]ornithine amide (0.63 g; from step (c) above), 10% Pd/C (0.30 g), MeOH (100 mL) and concentrated HCl (1 mL) under hydrogen, 18 hours reaction time to give the crude sub-title compound as a solid (0.57 g) which was used without purification.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][CH:6]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:14][C:13]=3[OH:12])=[N:2][NH:3][C:11]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: NN
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1

Procedure:
Hydrazine hydrate (2 ml, ˜55%) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.57 g, 2 mmol) in ethanol (15 ml) and the mixture heated under reflux for ˜5 hrs., to give a pale brown solution. The solution was allowed to cool and concentrated to a pale yellow solid, the solids were washed with water, to give the pyrazole as an off-white solid, dried in vacuo, (0.45 g). Sample was recrystallised from boiling toluene, to give the 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale brown crystalline solid, washed with hexane, dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@@:10]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41]C)[N:36]=3)([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.OC1N=C(CC2(C)CCCNC2=O)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@@:10]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[N:36]=3)([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@](C)(Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC1(Cc2cccc(O)n2)CCCNC1=O
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@](C)(Cc2cccc(O)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 422 using the product of Example 424, (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(N)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1cccc(N)c1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10% Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided 3-(3-amino-phenyl)propionic acid methyl ester (6 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)N>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:28]1[CH:27]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (100 mg, 0.34 mmol) (Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in ethanol (2 mL), 3-chloroaniline (132 mg, 1.04 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 30 min and the final product was collected by filtration and washed with ethanol and diethylether to yield the title compound (65% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8]Cl.[Br-:11].[Li+].CCCCCCC>O>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][Br:11]
Reactant: [Br-]
Reactant: COC(=O)C=CCCCCl
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Product: COC(=O)C=CCCCBr
Reaction time: 6 h
Yield: 83 %

Procedure:
In an atmosphere of nitrogen, 6-chloro-2-hexenoic acid methyl ester (4Cl); 188.8 g {GC purity; 83.6%, pure amount; 157.9 g (0.971 mol)}, lithium bromide (126.5 g, 1.457 mol) and heptane (16 ml) were added to a 500 ml capacity flask, followed by stirring for 6 hours under heptane reflux. After completion of the reaction, heptane was added as an extraction solvent and water was added thereto to separate the organic layer. The solvent was evaporated under a reduced pressure using an evaporator, and then the residue was distilled under a reduced pressure (70 to 80° C./0.1 ton) to obtain 6-bromo-2-hexenoic acid methyl ester (4Br); 203.4 g {GC purity; 82.3%, pure amount (4Br); 167.5 g (0.809 mol, yield 83%/(4Cl)}.
Reaction SMILES: [OH:1][C@@:2]1([C:33]([F:36])([F:35])[F:34])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=O)[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O[N:38]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N.Cl>CN(C)C=O.O>[OH:1][C@@:2]1([C:33]([F:35])([F:34])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:38])=[O:30])[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: On1nnc2ccccc21
Reactant: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(N)=O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Under a nitrogen atmosphere, 2-{4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionic acid (66.7 g) was dissolved in N,N-dimethylformamide (480 ml), 1-hydroxybenzotriazole (HOBt) 1 hydrate (27.6 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (34.6 g) and 28% aqueous ammonia (24.5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled, water (630 ml) and 2N hydrochloric acid (330 ml) were added dropwise, and the mixture was extracted with ethyl acetate (800 ml). The obtained aqueous layer was extracted again with ethyl acetate (500 ml). The obtained organic layers were combined, and washed successively with water (500 ml, twice), saturated aqueous sodium hydrogen carbonate (500 ml), and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated to give the title compound (60.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[C:4]([F:25])[CH:3]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol) in dioxane (1.5 mL) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (0.269 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (9.9 mg), and 2M aq potassium carbonate (0.733 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The brown residue was purified by reverse phase HPLC (Gilson, Xbridge C-18:19×100 mm column; 25-55% acetonitrile/water+0.1% NH4OH). Product fractions were selected, combined and concentrated to dryness in vacuo to afford the title compound as a white amorphous solid (57 mg, 50% yield). MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6].[OH-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[CH3:33][C:34](C=O)=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:33][C:34]1[CH:8]([OH:10])[CH2:7][C:5](=[O:6])[C:4]=1[CH2:3][C:2]([F:1])([F:13])[F:14]
Reactant: CC(=O)C=O
Reactant: CCOC(=O)CC(=O)CCC(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1=C(CC(F)(F)F)C(=O)CC1O
Temperature: 37 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
98.8 g of the ethyl 4,4,4-trifluorobutyrylacetate thus obtained was added to 250 ml of a 10% sodium hydroxide solution and vigorously stirred for 12 hours. The pH value of the reaction solution was brought 7.5 with a 10% aqueous sulfuric acid solution. Then 250 ml of toluene, 2.86 g of sodium hydrogencarbonate and 6.43 g of hydrosulfite were added to the solution under an atmosphere of nitrogen and warmed to 37° C. 90 g of methyl glyoxal was added over 1 hour and allowed to react for 12 hours. After 50 g of sodium chloride was added to the solution, the mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was removed under reduced pressure. The obtained residue was mixed with 450 ml of 5% sodium hydroxide solution and vigorously stirred under ice-water cooling. The pH of the solution was adjusted to 7.3 with a 10% hydrochloric acid solution and then extracted three times with ethyl acetate. The ethyl acetate layer was combined and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was removed under reduced pressure. The obtained residue was distilled under reduced pressure to afford 45 g of the desired (RS)-2-methyl-3-(2,2,2-trifluoroethyl)-4-oxocyclopent-2-en-1-ol in a yield of 50%. (b.p. 100°-133° C., 0.52 mmHg)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]=2[F:16])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cc(F)ccc1F
Product: Fc1ccc(F)c(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 41, Step 1, using 3,5-dibromo-pyridine and 2,5-difluorophenylboronic acid.