Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.CON(C)[C:44]([C:46]1[O:47][CH:48]=[CH:49][CH:50]=1)=[O:45]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:44]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)=[O:45])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccco1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccco3)c(F)c2F)C[C@H](C)O1
Temperature: -70 °C
Yield: 75.5 %

Procedure:
To a stirred solution of (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3, 1 g, 2.02 mmol) in THF (8 mL) was added sBuLi (1.3 M in cyclohexane/hexanes, 3.1 ml, 4.03 mmol) at −70° C. under nitrogen atmosphere. After stirring for 1 h at this temperature, N-methoxy-N-methylfuran-2-carboxamide (0.939 g, 6.05 mmol) was added in 3 ml of THF. After stirring for 1½ h at −70° C., the reaction quenched with sat. ammonium chloride solution and the aqueous layer extracted by ethyl acetate (2×100 mL). The organic phases were combined, dried (Na2SO4), and concentrated. The residue purified over a silica gel flash column using a gradient of ethyl acetate in hexanes to give the title compound (0.90 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([F:10])[CH:3]=1.C(O)C.[C-:14]#[N:15].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:14]#[N:15])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Then, 18.5 g of 4-chloro-2-fluorobenzyl chloride was dissolved in a mixed solvent consisting of 130 ml of ethanol and 30 ml of water, to which 5.3 g of sodium cyanide was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was allowed to stand for cooling to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 15.1 g of 4-chloro-2-fluorophenylacetonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[C:6]([Cl:19])[N:5]=[CH:4][N:3]=1.[K+].[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[CH2:22].Cl>CO.CN(C)C=O>[Cl:19][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[CH2:22])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[C:7]=1[CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18]
Reactant: C=Cc1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1cccc(OC)c1Cc1c(Cl)ncnc1Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(Cl)c2Cc2c(OC)cccc2OC)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture of 80 mg of 4,6-dichloro-5-(2,6-dimethoxybenzyl)pyrimidine and 170 mg of p-vinylbenzenesulfonamide monopotassium salt (J. Am. Chem. Soc. 1956, 78, 2169) from the corresponding sulfonamide with potassium t-butylate in absolute MeOH and 10 ml of dimethylformamide was heated at 100° C. for 6 hours. Thereafter, the mixture was left to cool to 25° C. overnight. Now, 30 ml of 0.5N HCl were added to the reaction solution while stirring. The precipitated substance was removed by filtration under suction and recrystallized from toluene/n-hexane. There were obtained 25 mg of N-(6-chloro-5-(2,6-dimethoxy-benzyl)-4-pyrimidinyl)-p-vinylbenzenesulfonamide, melting point 197°-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([C@H:10]3[CH2:12][O:11]3)[C@@H:4]2[O:3]1.[NH3:14]>CO>[NH2:14][CH2:12][C@H:10]([C@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:13])([CH3:1])[O:3]2)[CH:7]=[CH:8]1)[OH:11]
Reactant: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C[C@H]2O1
Reactant: N
Solvent: CO
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C[C@H]2O1
Temperature: 100 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (2-4) (3 g, 16.5 mmol, 1.0 equiv) was dissolved in a solution of ammonia in methanol (200 mL, 7 N). The mixture was heated in the microwave at 100° C. for 30 minutes. The reaction was concentrated to afford desired (S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-5) as an amber oil that was carried to the next step without further purification. 1NMR (500 MHz, CDCl3): δ 5.98-5.86 (m, 1H); 5.91-5.65 (m, 1H); 5.13 (s, 1H); 4.80-4.45 (m, 1H); 3.03 (s, 1H); 2.95-2.83 (m, 2H); 2.74 (s, 2H); 2.61 (s, 2H); 1.41 (s, 3H); 1.35 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([Cl:20])[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(O)c2cccc(Br)n2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cccc(C(Cl)c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-[(6-bromopyridin-2-yl)(hydroxy)methyl]benzonitrile (4.88 g, 16.88 mmol) in CH2Cl2 (60 mL) @ 0° C. under N2 was added SOCl2 (2.01 mL, 16.88 mmol). The mixture was warmed to rt and stirred for 48 hr. The mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (25-50% CH2Cl2 in Hexanes) to give 3-[(6-bromopyridin-2-yl)(chloro)methyl]benzonitrile. LRMS m/z (M+H) Calcd.: 307.0, found: 307.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH:13](O)([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:15])[CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
Into an recovery flask, 16 mg (0.1 mmol) of 2-(4-methoxyphenyl)acetic acid, and 7 mg (0.1 mmol) of isopropanol were added, and dissolved in 5 ml of tetrahydrofuran. To this, 52 mg (0.2 mmol) of triphenylphosphine, and 177 mg (0.2 mmol) of the compound 14 of Example 8 were added, and stirred for 24 hours at room temperature. The solvent was distilled under a vacuum, acetonitrile was added, and filtration was carried out with an octadecylsilyl silica packed syringe, and from the filtrate, 16.7 mg of isopropyl-2-(4-methoxyphenyl)acetate was obtained. The yield was 70%.
Reaction SMILES: BrBr.Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:24]=[C:23]2[C:14]([O:15][C:16]3[C:17]([F:28])=[CH:18][C:19]([O:26][CH3:27])=[CH:20][C:21]=3[C:22]2=[O:25])=[CH:13][CH:12]=1.C1COCC1>C(OCC)C.[Zn]>[Br:10][C:11]1[CH:24]=[C:23]2[C:14]([O:15][C:16]3[C:17]([F:28])=[CH:18][C:19]([O:26][CH3:27])=[CH:20][C:21]=3[C:22]2([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:25])=[CH:13][CH:12]=1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Reactant: CCOC(=O)CBr
Agent: BrBr
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Bromine (0.797 ml, 15.47 mmol) was added to a suspension of zinc dust (8.09 g, 124 mmol in diethyl ether (150 ml) at RT. After 5 minutes, ethyl 2-bromoacetate (6.86 ml, 61.9 mmol) was added drop wise over a time period of 20 minutes and the reaction mixture was heated to reflux for 2 hours. 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (10 g, 30.9 mmol) was added in one portion, followed by THF (100 ml) and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was quenched with aqueous saturated NH4Cl solution (100 mL) and EtOAc (100 mL) and stirred 2 hours at RT. The solution was filtered and the organic phase was separated. The solvent was removed under educed pressure to afford ethyl 2-(7-bromo-4-fluoro-9-hydroxy-2-methoxy-9H-xanthen-9-yl)acetate (12.7 g, 30.9 mmol, 100% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][NH:13][C:12](=[S:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].O.[CH3:22]I>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][N:13]=[C:12]([S:17][CH3:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)CC(=S)NCCS1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
The compound (2.00 g, 6.54 mmol) obtained in Example 4-0) was dissolved in tetrahydrofuran (11 mL). Potassium hydroxide (2.16 g, 39.72 mmol), water (7 mL), and methyl iodide (2.44 mL, 39.27 mmol) were added to the solution at room temperature, and the mixture was stirred for 1 h under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.09 g, quant.) in a yellow oily form.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:48][CH:49]1[CH2:53][CH2:52][NH:51][CH2:50]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:48][CH:49]1[CH2:53][CH2:52][N:51]([C:21]([C:19]2[S:20][C:13]3[C:14](=[N:15][CH:16]=[CH:17][C:12]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:18]=2)=[O:23])[CH2:50]1
Reactant: OC1CCNC1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)ccc2[nH]1
Yield: 76.4 %

Procedure:
To a solution of 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid (0.10 g, 0.31 mmol), HATU (0.17 g, 0.46 mmol) and DMAP (0.040 g, 0.31 mmol) in DMF (3 mL) was added racemic 3-hydroxy-pyrrolidine (0.040 g, 0.46 mmol). After 3 h the reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and EtOAC (10 mL). The aquenched layer was further extracted with EtOAC (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 85:15) afforded the title compound as a yellow solid (0.093 g, 76%). MS: 393 (MH+); HPLC Rf: 3.41; HPLC purity: 87%.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[C:24]([O:28][CH2:29]Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]2[N:15]([CH2:29][O:28][C:24]([CH2:25][CH3:26])=[O:27])[N:16]=[N:17][N:18]=2)=[CH:12][C:11]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CCC(=O)OCCl
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)OCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
In similar manner to Example 12, azosemide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in DMF to yield 2-chloro-5-[1-(ethylcarbonyloxymethyl)-1H-tetrazol-5-yl]-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: CN(C)CN(C)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[O:21].[C:22](O)(=O)C.C(OC(=O)C)(=O)C>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:19])([CH3:20])[C:13](=[CH2:22])[C:12]2=[O:21]
Reactant: CC(=O)O
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Agent: CN(C)CN(C)C
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C=C1C(=O)c2cc(Br)ccc2OC1(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
N,N,N′,N′-tetramethylmethanediamine (4.8 g, 47 mmol) was added to a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (3.0 g, 12 mmol) and acetic acid (0.67 ml, 12 mmol) in tetrahydrofuran (43 ml), and the mixture was stirred at 70° C. for 24 hours. To the mixture was added acetic anhydride (4.4 ml, 47 mmol), and the mixture was stirred at 70° C. for 4 hours and concentrated in vacuo. The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to afford 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.8 g).
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([N+]#N)=[C:9]([CH2:17][CH3:18])[CH:8]=1.[CH3:19][OH:20]>[Cl-].[Zn+2].[Cl-]>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:20][CH3:19])=[C:9]([CH2:17][CH3:18])[CH:8]=1
Reactant: CCc1cc(Br)cc(CC)c1[N+]#N
Reactant: CO
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1cc(Br)cc(CC)c1OC
Temperature: 25 °C

Procedure:
A stirred solution containing 4-bromo-2,6-diethylbenzenediazonium tetrafluoroborate (17.25 g, 52.77 mmol) and freshly ground anhydrous zinc chloride (7.2 g, 52.9 mmol) in methanol (1.06 L) was refluxed for 6 h. The reaction was cooled to ambient temperature, quenched with H2O (1.2 L), saturated with solid sodium chloride and extracted with hexane. The combined organic extracts were sequentially washed with sat. aq. NaHCO3 (1×100 mL), with H2O (1×100 mL), with brine (1×100 mL), dried (Na2SO4) and concentrated to give 12.0 g (94%) of tide compound. 1H NMR: consistent. mass spectrum (EI), m/z 242 (M+).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([C:32]2[NH:31][C:30]3[CH:37]=[C:26]([O:25][C:21]4[N:22]=[CH:23][N:24]=[C:19]([N:14]5[CH2:13][CH2:12][C:5]6([O:4][C:3](=[O:17])[NH:2][C:7]7[N:8]=[CH:9][CH:10]=[CH:11][C:6]6=7)[CH2:16][CH2:15]5)[CH:20]=4)[CH:27]=[C:28]([CH3:38])[C:29]=3[N:33]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c(C3CC3)nc12

Procedure:
41 mg (0.16 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]-imidazole and 0.08 mL (0.48 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].N1CCOCC1.Cl>CS(C)=O>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][C:1]([CH:4]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]2=[O:10])=[O:3])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: CC(=O)C1C(=O)CCC1=O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: COc1cc(C=CC(=O)C2C(=O)CCC2=O)ccc1O

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.03 g.) was treated with 4-hydroxy-3-methoxybenzaldehyde (5.05 g.) in 50 ml. of dimethylsulfoxide at 80° C for 13 minutes in the presence of 4 ml. of morpholine. After cooling, 80 ml. of 1 N hydrochloric acid was added to the reaction mixture, depositing a crystalline product. The solid was collected by filtration, and washed with water and ethanol successively, and it was then dried. The Claiseu-Schmidt condensation product, 2-(4-hydroxy-3-methoxycinnamoyl)-1,3-cyclopentanedione, (1.3 g.) was obtained in an orange crystalline form, which showed mp. 274°- 275° C after recrystallization from dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (146 mg, 57%). MS (ISP) 513.3 [(M+H)+]; mp 292–293° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH2:14]S)[CH2:11][C@@H:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.O>[N:30]([CH2:14][CH2:13][N:12]1[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][C:7]=2[CH2:8][N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[C@H:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)=[N+:31]=[N-:32]
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCN=[N+]=[N-])C[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of Compound B of Example 27 (95.2 mg, 0.2 mmol) and sodium azide (15 mg, 0.23 mmol) in DMF (0.5 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and diluted with water. The solid was collected, washed with water and dried to afford the title compound, 83 mg (95%) LC/MS: m/e (M+H)+=439.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:43])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([F:42])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[Al](Br)(Br)Br.CSC>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[C:40]([F:41])=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:42])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:43])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1cc(F)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: Br[Al](Br)Br
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cc(F)c(C(=O)O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difluorobenzoate (75 mg, 0.118 mmol) in methylene chloride (10 ml), AlBr3 (Aldrich, 59 mg, 0.94 mmol) was added followed by dimethyl sulfide (Aldrich, 0.2 ml, 0.63 mmol). The mixture was stirred at rt for 2 hrs. The solvent was removed and the residue was treated with 3 ml of acetonitrile and 10 ml of water. The mixture was then extracted with ethyl acetate. Removal of solvent gave an off white solid. 72 mg. (ES+) m/z Calcd: [(M+H)+]: 622. found: 622.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of trans-2,4-dibenzyl glutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(R*,R*) -2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].B(F)(F)F>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2([NH2:7])[CH2:12][CH2:11]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Product: NC1(c2ccc(Br)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution of 4-bromo-2-fluorobenzonitrile (432 mg, 2.16 mmol) in THF (10 mL) at −78° C., was added titanium (IV) isopropoxide (0.7 mL, 2.4 mmol). After stirring for 10 minutes, ethylmagnesium bromide (1M, 4.75 mL, 4.75 mmol) was added and the reaction mixture warmed to 0° C. and then to rt. BF3.OEt (0.53 mL, 4.32 mmol) was then added and the reaction mixture stirred for an additional 1 h at rt. The reaction was quenched with saturated NH4Cl and NaOH (1N). Extraction with EtOAc, and drying over MgSO4 yielded crude product which was taken forward as crude in the next step. HPLC-MS tR=0.34 min (UV254 nm); mass calculated for formula C9H9BrFN 228.99, observed LCMS m/z 230.0 (M+H).
Reaction SMILES: [CH:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.P(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: BrP(Br)Br
Reactant: OC1Cc2cccc3cccc1c23
Solvent: CCOCC
Product: BrC1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acenaphthen-1-ol (88 mol) was dissolved in diethyl ether (150 mL) and cooled down to 0° C. Phosphorous tribromide (3.2 mL, 35 mmol) was then added slowly under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at room temperature and cooled to 0° C. The reaction mixture was partitioned with water and diethyl ether. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a yellow solid.