Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]#[CH:3].[O-][C:15]#[N:16].[K+]>C(O)C.C(N(CC)CC)C.O>[C:15]([CH:3]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[S:4][CH2:1][CH2:2]1)#[N:16]
Reactant: N#C[O-]
Reactant: C#CCSc1cc2ccccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC1CCSc2[nH]c3ccccc3c21
Yield: 69 %

Procedure:
The product of the above (2) (13.2 g) is dissolved in a mixture of ethanol (300 ml) and triethylamine (20 ml). The solution is refluxed for 1 hour and further 2 hours after addition of a solution of potassium cyanate (25 g) in a mixture of ethanol (170 ml) and water (80 ml) and evaporated to remove the solvent. The residue is extracted with ether after addition of water. The extract is washed with water, dried and evaporated to remove the solvent. The oily residue (15 g) is chromatographed on an column of silica gel (450 g) and eluted with benzene. The eluate is condensed to give the title compound as crystals melting at 125°-126° C. Yield: 69%
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:18]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28].Cl>CCO.C1COCC1.CCOCC>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:18][CH2:31][C:29](=[O:30])[CH:27]=[CH:28]2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=CC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Reactant: C=CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=CC(c2ccc(OCc3ccccc3)cc2)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of KOH (110 mg, 2.0 mmol) in EtOH (3 mL) was added at 0° C. to a stirred solution of 4 (2.52 g, 7.9 mmol) and methyl vinyl ketone (0.61 g, 8.7 mmol) in THF (60 mL). The resulting mixture was stirred at room temperature overnight. Ether (200 mL) and HCl (50 mL, 10% aqueous solution) were added. The organic phase was washed with HCl (50 mL, 10% aqueous solution), H2O (50 mL), NaHCO3 (50 mL, saturated aqueous solution), dried over Na2SO4 and evaporated under reduced pressure. The crude material was dissolved in EtOH (40 mL) and HCl (2 mL, 37% aqueous solution) was added. The mixture was heated at 50° C. for 30 min under stirring. After cooling to room temperature, H2O (50 mL) was added. The mixture was extracted with diethyl ether (3×100 mL) and the combined organic phase was washed with NaHCO3 (2×50 mL, saturated aqueous solution) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to yield 2.89 g crude material. Purification by column chromatography (heptane:ethyl acetate 4:1 to 2:1) yielded 2.41 g, 82% as an off-white solid. 1H-NMR (CDCl3) δ; 7.44-7.35 (m, 6H), 7.35-7.28 (m, 2H), 7.17 (dt, 1H, J=7.5 Hz and 1.4 Hz), 7.11 (d, 2H, J=8.9 Hz), 7.02 (dd, 1H, J=7.0 Hz and 1.4 Hz), 6.92 (d, 2H, J=8.9 Hz), 6.19 (d, 1H, J=10.3 Hz), 5.04 (s, 2H), 2.90-2.81 (m, 1H), 2.62-2.52 (m, 1H), 2.44 (at, 2H, J=6.6 Hz); 13C-NMR (CDCl3) δ; 199.0, 161.3 (d, J=249.6 Hz), 157.9, 154.9 (d, J=3.8 Hz), 137.1 (d, J=12.1 Hz), 132.0 (d, J=10.8 Hz), 129.5 (d, J=8.8 Hz), 129.3, 128.8, 128.7 (d, J=4.2 Hz), 128.2, 128.1, 127.7, 124.3 (d, J=3.5 Hz), 117.2 (d, J=22.7), 115.0, 70.3, 47.3 (d, J=1.9 Hz), 35.1, 35.0;
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([O:30][CH2:31][CH3:32])[CH:22]=2)(=[O:28])=[O:27])[C:8]=1[CH3:16]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 414).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[N:24]([CH3:25])[C:23](=[O:26])[C:22]([F:28])([F:27])[CH2:21][N:20]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[C:19]=3[N:34]=2)=[CH:8][C:7]=1[F:35]>O1CCCC1CO>[CH:29]1([N:20]2[CH2:21][C:22]([F:28])([F:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]3[CH:17]=[N:16][C:15]([NH:14][C:9]4[C:10]([O:12][CH3:13])=[CH:11][C:6]([C:5]([OH:36])=[O:4])=[C:7]([F:35])[CH:8]=4)=[N:34][C:19]2=3)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)c1cc(OC)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
An aqueous solution of 5 mL of aqueous 2M (0.010 mole) of sodium hydroxide was added to a solution of 0.51 g (0.00106 mole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-2-fluoro-5-methoxy-benzoic acid methyl ester (I-168) in 20 mL of tetrahydrofuran-methanol (3:1). The mixture was heated at 50° C. for 18 hours and then concentrated under reduced pressure. The residue was dissolved in water and acidified to pH 2 with 2M hydrochloric acid. After stirring for 30 minutes, the solid was collected by filtration, washed with water and dried to give 0.50 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.O.[F-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][F:31])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCBr)c1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCF)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of N-cyclopropyl-1-{2-[2-(2-bromoethoxy)ethoxy]-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.23 g) obtained in Example 308a) in acetonitrile (10 ml) was added tetrabutylammonium fluoride monohydrate (0.39 g), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and the solvent, was evaporated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile-water) and recrystallized from acetonitrile-water to give the title compound as a white powder (0.04 g, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[CH3:31][CH2:32][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1.ClCCl>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]([OH:28])[CH2:31][CH3:32])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cn1CC
Temperature: -15 °C
Yield: 46 %

Procedure:
A mixture of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25 mmol) in THF (5 mL; anhydrous) was stirred and cooled to −15° C. To this was added an excess of EtMgBr (3.1 eq; 0.25 mL of 3.0 M solution in hexane), dropwise. The mixture was stirred at −15° C. for one hour. The reaction was worked up by carefully adding 1.0 mL of saturated aqueous ammonium chloride solution, diluting with dichloromethane (30 mL) and washing with water. The organic phase was dried over MgSO4, filtered and evaporated. Two products were separated from the crude mixture by chromatography on silica gel. The column was eluted with a chloroform/methanol mixture on a gradient (9:1 through 7:3). The more polar product was isolated and crystallized from ethyl acetate/hexane to give the title product as white crystals, 0.05 g (46% yield), mp 115-121° C.; MS (ES) m/z 434.2; [M−H]−
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(C2CCN(C(C)=O)CC2)nc2ccccc21

Procedure:
The title compound was prepared from 1-(4-(1-H-benzoimidazol-2-yl)-piperidin-1-yl)ethanone (from Step A), sodium hydride, allyl bromide and DMF.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][C:13]([NH:14][C:5]2[C:4]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH3:9])=[CH:11][CH:12]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1cccnc1O
Reactant: Cc1ccc(N)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours; and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(p-tolylamino)-2,3-pyridindione in a red powder. The yield was 32%-54%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[S:12])[NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C[CH2:24][OH:25]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:12][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:25][CH3:24])[CH:18]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Product: COc1cccc(-c2csc(-c3cccc([N+](=O)[O-])c3)n2)c1

Procedure:
A mixture of 3-nitrobenzenethioamide (2.73 g, 15 mmol) and 3-methoxy-α-[bromoacetophenone (3.43 g, 15 mmol) in EtOH (30 mL) is heated under reflux for 18 h. It is cooled and filtered to give 4 g of 2-(3′-nitrophenyl)-4[(3′-methoxy)phenyl]thiazole as a yellow solid, mp. 122-123° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH:34]([B-](F)(F)F)=[CH2:35].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.O>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([CH:34]=[CH2:35])=[CH:7][N:6]2[C:8]=1[C:12]1[S:13][C:14]([C:23]2[N:27]=[CH:26][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: C=Cc1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (1.04 g, 2.0 mmol) obtained by similar manner with Example 117-B(i) in DME (70 mL) and water (14 mL), were added potassiumvinyltrifluoroborate (410 mg, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (170 mg, 0.2 mmol) and cesium carbonate (1.90 g, 6.0 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 4 h. The reaction mixture was allowed to cool to rt, and then was added EtOAc (40 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (890 mg, 95%) as a gray solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](Cl)=[O:11])=[N:2]1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[C:27][CH2:28][NH2:29])[CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.O>[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[C:27][CH2:28][NH:29][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:11])[CH2:21][CH2:20]1
Reactant: O=C(Cl)c1nsc2ccccc12
Reactant: NCC#CCN1CCN(c2ncccn2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCC#CCN1CCN(c2ncccn2)CC1)c1nsc2ccccc12
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (2.55 g) and 1-(2-pyrimidyl)-4-(4-amino-2-butynyl)piperazine (3.0 g) in dichloromethane (100 ml) was stirred while triethylamine (3.62 ml) was added dropwise. Stirring was continued overnight. After 24 hr, the reaction mixture was diluted with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resiude was recrystallized from dichloromethane/ether/hexane to provide 3.67 g (72.3%) of product, mp 102°-104° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CN2CC[C@H](O)C2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
Triethylamine (0.509 ml, 3.65 mmol) was added to a cooled solution of (S)-3-hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (0.5 g, 2.436 mmol, intermediate I) in anhydrous DCM (12.18 ml) at 0° C. under a nitrogen atmosphere. Methanesulfonyl chloride (0.198 ml, 2.56 mmol) was then added dropwise and the reaction was allowed to stir at 0° C. for 15 min before quenching with a satd. sodium bicarbonate solution (10 mL). The mixture was allowed to warm to rt and the aqueous layer was separated and extracted with DCM (2×). The combined organic layers were dried over MgSO4 and evaporated in vacuo to give a white solid (0.73 g) which was then purified by silica gel chromatography (40 g of silica) eluting with a gradient of 0% to 50% ethyl acetate in hexanes to provide 0.63 g (91%) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([OH:23])[CH3:22]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([O:23][CH2:21][CH3:22])[N:7]2[N:8]=1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccnc2c(I)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a mixture of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 6.80 g, 17.4 mmol) in ethanol (175 ml) was added NaH (60% dispersion in oil, 439 mg, 18 mmol), portionwise. After stirring overnight, the suspended solids were isolated by vacuum filtration to afford, after drying, in vacuo, product I-11A-1a (6.87 g, 99%) as a solid: +APcI MS (M+1) 400.0; 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=5.0 Hz, 1H), 7.58–7.40 (m, 4H), 6.67 (d, J=5.0 Hz, 1H), 4.58 (q, J=7.1 Hz, 2H), 1.58 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.O>[C:14]([O:13][C:11]([NH:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[CH2:4][CH2:5]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CBr)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Temperature: 25 °C

Procedure:
A solution of 2.51 g (8.20 mM) of N-(trans-4-bromomethyl-1-cyclohexylmethyl)-N-(tert-butoxycarbonyl)amine, 1.32 g (8.19 mM) of 4-phenylpiperidine, and 2.3 ml (16.5 mM) of triethylamine in ethanol (10 ml) was refluxed under nitrogen for 64 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol-ethyl acetate: 10%) to provide the title compound as light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][C:28]=1[CH3:33])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:13]1[CH3:22]
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c(N3CCc4ccccc4[C@H]3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4[C@H]3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 42 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.64 g of the compound (7.77 mM) prepared in Example 6 and 15 ml of dimethyl-formamide, 1.33 ml of 4-fluoro-2-methylaniline(16.3 mM) was added, 1.50 g of the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:8]1[C:4]2[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:5]=2[CH2:6][S:7]1(=[O:10])=[O:9])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: O=S1(=O)Cc2ccc(F)cc2N1
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(F)ccc2CS1(=O)=O
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of 1,3-dihydro-6-fluoro-2,1-benzisothiazole-2,2-dioxide (2.57 g) in anhydrous pyridine (8 ml) was added ethyl chloroformate (1.79 g) at 0° C. under N2 atmosphere. The mixture was stirred for 30 minutes and concentrated in vacuo. Cold hydrochloric acid was added to the precipitate (pH=6). The resulting solution was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (methylene chloride-ethyl acetate 95:5) to give 1-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (3.1 g).
Reaction SMILES: [C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])(C)C)=[O:2].C(ON1C(=O)CCC1=O)(OCC1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=O.CCN(C(C)C)C(C)C.[ClH:47]>ClCCl.O1CCOCC1>[ClH:47].[C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])([O:3][CH2:4][CH:7]1[C:22]2[C:23](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)CCN
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCCC(N)C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
BOC-1,3-diaminopropane was reacted with Fmoc-OSu in dichloromethane in the presence of DIPEA, and the resulting product treated with 4M HCl in dioxane to afford Fmoc-1,3-diaminopropane hydrochloride in quantitative yield. To a solution of Fmoc-diaminopropane hydrochloride (1.1 g, 3.3 mmol), Compound 1 (1.27 g, 3.3 mmol) and Py-BOP (1.46 g, 3.3 mmol) in DMF (10 ml), was added DIPEA (1.15 ml, 6.6 mmol) and the mixture was stirred for 4 hours at room temperature.
Reaction SMILES: [Cl-].[F:2][C:3]([F:35])([F:34])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:32])[C:6]=1[CH3:33].C([Li])CCC.[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=O)[CH3:42].O>C1COCC1>[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=[CH:12]/[C:8]1[C:9]([CH3:11])=[CH:10][C:5]([O:4][C:3]([F:2])([F:34])[F:35])=[C:6]([CH3:33])[C:7]=1[CH3:32])[CH3:42]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)C=O
Reactant: Cc1cc(OC(F)(F)F)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 12.2 g (24 mmol) of (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyltriphenylphosphonium chloride in 490 ml of dry THF was cooled to 45° C. and treated rapidly (over ~5 minutes) with 11.1 ml (25.5 mmol) of n-butyl lithium (2.3M in hexane) at -35° to -45° C. The reaction mixture was maintained at that temperature for 15 minutes, allowed to warm slowly to -25° C. at which time it became a slightly turbid orange solution. The mixture was cooled to -45° to -50° C. and 7.0 g (33 mmol) of ethyl-(2E,4E,6E)-3,7-dimethyl-8-oxo-octatrienoate in 50 ml of dry THF was added rapidly. The orange color disappeared; the reaction mixture was stirred at -25° C. for 2 hours, then allowed to warm to 0° C. over 1 hour and maintained at that temperature for 2 hours. The mixture was then poured into 1 liter of cold water and extracted with 250-ml portions of hexane. The organic phase was combined, washed successively with 500 ml of cold water, 2×500 ml of a 60% by volume methanol-water solution, and 500 ml of saturated NaCl solution, dried (MgSO4), filtered and concentrated. The resulting yellow oil was purified by HPLC (2 silica gel columns, 2% ethyl acetate in hexane as elutant) to give 5.79 g of ethyl-(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate; mp 47°-49° C.