Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:3]=1[CH3:21].C(O)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=3)[C:3]=2[CH3:21])=[CH:29][CH:28]=1
Reactant: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 97.5 °C
Yield: 83.8 %

Procedure:
To the solution of methyl 5-bromo-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7c, 3.0 g, 7.69 mmol) in a mixture of toluene:ethanol (25:75 ml) was added (4-methoxyphenyl)boronic acid (1.28 g, 8.46 mmol) and potassium carbonate (3.18 g, 23.07 mmol) at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.487 g, 0.422 mmol) under nitrogen and reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite, and then washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, that was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (2.69 g, 84%).
Reaction SMILES: [Na+].[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: Nc1c(C(=O)[O-])cccc1[N+](=O)[O-]
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of 2-amino-3-nitro-benzoic acid sodium salt (205 mg, 1.0 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (219 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 h and heated at 70° C. for 1 h, and then evaporated under reduced pressure. The residue was purified by chromatography (50:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (300 mg, 78%). 1H NMR (MeOH-d4) δ 2.44 (s, 3H), 2.50-2.85 (12H), 6.74 (dd, J=9 Hz and 9 Hz, 1H), 7.23 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 1H), 8.29 (d, J=9 Hz, 1H). ESI-MS m/z 384.5 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 89.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), and dimethylformamide (90 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and concentrated to afford 7.4 g of a yellow solid. The solid was chromatographed on a Waters Prep LC 500 utilizing dichloromethane/methanol (4%) as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recrystallized from ethyl alcohol to yield 3.1 g (38%) of 1-[4-[2-14-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxyl-3-methoxyphenyl]ethanone, as slightly yellow flakes, m.p.=132-134° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[I:23]I>C1COCC1>[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[I:23]
Reactant: II
Reactant: N#Cc1ncc(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ncc(F)c(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (5.60 mL, 39.27 mmol) in THF (40 mL) was cooled to 0° C. and n-BuLi (12.56 mL, 31.4 mmol) was added slowly. After 30 minutes, the reaction was cooled to −78° C. and 3,5-difluoropicolinonitrile (4.0 g, 28.6 mmol) in THF (25 mL) was added and the solution was stirred for 30 minutes. A solution of iodine (10.87 g, 42.8 mmol) in THF (35 mL) was cooled to (−78° C.) and added all at once. After about 30 seconds the reaction was quenched with sodium thiosulfate solution (10 mL) and water (20 mL). The mixture was extracted with EtOAc (2×150 mL) and the combined organics were extracted with brine, dried over Na2SO4 and concentrated to give a residue which was purified using silica column chromatography eluted with hexanes/EtOAc to give 3,5-difluoro-4-iodopicolinonitrile.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])[C@H:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[CH3:32][NH2:33]>C(Cl)Cl.C(O)C>[CH3:32][NH:33][C:11](=[O:31])[C@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine p-nitrophenylester (5.0 g, 11.9 mmol) in DCM at 0° C. was slowly added a solution of 8M methylamine (1.5 ml, 11.9 mmol) in ethanol. The reaction immediately turned bright yellow and was stirred for 0.5 h. The reaction was diluted with DCM (50 ml), washed with 10% sodium carbonate (1×50 ml), brine (2×50 ml) and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a white residue which was crystallised from ethyl acetate/hexane to give N-benzyloxycarbonyl-L-phenylalanine methylamide (3.0 g, 81%) as a white crystalline solid.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][O:37][CH2:38][C@H:39]([CH3:88])[O:40][C:41]1[CH:42]=[C:43]([C:58]2[NH:62][C:61]([C:63]([NH:65][CH2:66][CH2:67][S:68]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=O)=[CH:60][CH:59]=2)[CH:44]=[C:45]([O:47][C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:46]=1>ClCCl>[CH3:36][O:37][CH2:38][C@H:39]([CH3:88])[O:40][C:41]1[CH:42]=[C:43]([C:58]2[NH:62][C:61]([C:63]3[S:68][CH2:67][CH2:66][N:65]=3)=[CH:60][CH:59]=2)[CH:44]=[C:45]([O:47][C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:46]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]2)c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCS3)[nH]2)c1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Triphenylphosphine oxide (2.41 g, 8.7 mmol) was dissolved in dichloromethane (20 mL), and trifluoromethanesulfonic anhydride (0.73 mL, 4.3 mmol) was added dropwise slowly at 0° C. After stirring for 10 minutes, a dichloromethane (15 mL) solution of 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-N[2-(tritylthio)ethyl]-1H-pyrrole-2-carboxamide synthesized in Example (25b) was added. After reaction solution was stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired product (636 mg, yield 90%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)CCC(=O)O
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
Compound 2 (0.25 g, 1 eq.) was suspended in CH2Cl2 (12.5 ml, C=0.1M). Triethylamine (0.26 ml, 1.5 eq.) was added to the solution which was then stirred for 10 minutes. After stirring 4-dimethylamino pyridine (0.015 g, 0.1 eq.) and succinic anhydride (0.125 g, 1 eq.) were added and the reaction left to stir for 16 hours at room temperature. The reaction mixture was then shaken with 3×20 ml portions of hydrochloric acid (2M), the aqueous washings were subsequently extracted with 3×20 ml portions of diethyl ether. The DCM portion was discarded and the ether layers were combined and dried over anhydrous MgSO4, filtered and evaporated to yield a white solid 3 (0.199 g, 60% yield).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.[CH2:13]([O:15][C:16](=[O:28])/[C:17](=[CH:24]/OCC)/[C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH3:14]>CCO>[CH2:13]([O:15][C:16]([C:17]1[CH:24]=[N:2][NH:3][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:28])[CH3:14]
Reactant: NN
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at −20° C. and stirred for 10 mins. Then 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (Preparation 135, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 90:10) to afford the title compound as off white solid in 43% yield, 13 g.
Reaction SMILES: [CH2:1]1[CH2:16][O:15][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][CH2:6][C:7](=[O:13])[CH:8]=3)[O:2]1.C[O-].[Na+].[CH:20](OC)=[O:21]>C1COCC1>[CH2:16]1[CH2:1][O:2][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][C:6](=[CH:20][OH:21])[C:7](=[O:13])[CH:8]=3)[O:15]1
Reactant: CC12CCC(=O)C=C1CCCC21OCCO1
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC12CC(=CO)C(=O)C=C1CCCC21OCCO1
Reaction time: 0.5 h
Yield: 26103 %

Procedure:
A solution of 201 (20 g, 0.090 mmol) in THF (200 mL) was cooled to −5° C. in an ice/methanol bath. NaOMe (19.45 g, 0.360 mol) was added and the mixture stirred for 30 minutes. After slow addition of a cooled solution of methyl formate (55.5 mL, 0.900 mol) in 60 mL THF, the mixture was stirred at room temperature for 24 hours. The mixture was poured into ice-water-HCl (˜50 mL conc. HCl in 500 mL H2O), stirred for 5 minutes and then transferred to a separatory funnel. The aqueous layer was extracted with ether (3×100 mL) and the pooled organic extracts were washed with brine, dried (MgSO4), and concentrated. The yellow residue was flash chromatographed (0-50% EtOAc-hexanes) to yield 203 (5.88 g, 26%) as a yellow oil. 1H NMR (CDCl3) δ 1.22 (s, 3H), 1.6-1.9 (m, 4H), 2.02 (d, J=14 Hz, 1H), 2.2-2.5 (2H), 2.91 (d, J=14 Hz, 1H), 3.94.1 (m, 4H), 5.86 (d, J=2.0 Hz, 1H), 7.37 (s, 1H); 13C NMR (CDCl3) 188.72, 166.86, 165.35, 165.12, 124.59, 124.25, 111.92, 106.39, 65.33, 65.17, 65.04, 64.89, 46.00, 29.87, 21.33, 20.74, 20.59.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:19][CH:16]2[CH2:18][CH2:17]2)[N:3]=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=1
Reactant: NC1CC1
Reactant: CCN(CC)c1nc(Cl)c(C#N)c(Cl)n1
Solvent: CC(C)=O
Product: CCN(CC)c1nc(Cl)c(C#N)c(NC2CC2)n1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a stirred solution of 6.9 grams of 4,6-dichloro-2-diethylamino-5-pyrimidinecarbonitrile in 80 ml of acetone was added dropwise 3.2 grams of cyclopropylamine in 20 ml of acetone. The reaction mixture stood for 16 hours; then the acetone was removed by evaporation under reduced pressure. The residue was washed with water, and the resultant solid was collected. The solid was washed several times with water, then dried, to give 6.5 grams of crude product; mp, 100°-105°. The crude product was recrystallized from petroleum ether to give 2.5 grams of 4-chloro-6-cyclopropylamino-2-diethylamino-5-pyrimidinecarbonitrile; mp, 120°-122°.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2cccs2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (60.9 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-thiophenecarbonyl chloride (97%, 39.2 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 15 (82.1 mg, 98%). LRMS 300 (M-100)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>O>[OH:29][NH:28][C:20](=[NH:21])[C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[N:15][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1
Reactant: NO
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2ccc(-c3ccc(C(=N)NO)cc3)cn2)CC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 4-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)benzonitrile (330 mg, 1.1 mmol, prepared as described in Example 10), ethanol (15 mL), hydroxylamine hydrochloride (225 mg, 3.2 mmol), potassium carbonate (240 mg, 1.7 mmol) and water (1.5 mL) was stirred at reflux temperature overnight. The reaction mixture was allowed to cool to rt, and the solid was isolated by filtration and dried. The solid was then stirred with water (10 mL) to remove inorganic residues. The mixture was filtered and the solid was washed with water and a small portion of ethanol. Drying in vacuo afforded 260 mg (71%) of N-hydroxy-4-(6-(4-isopropylpiperazin-1-yl)pyridine-3-yl)benzamidine.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][O:59][CH3:60])[CH:54]=[CH:53][C:52]=2[CH3:61])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][O:59][CH3:60])[CH:54]=[CH:53][C:52]=2[CH3:61])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:31][CH:32]=2)[CH2:9][NH:8][CH2:15]3)=[O:25])[CH2:47][CH2:48]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCc1ccc(C)c(CNC2CC2)c1
Product: COCCc1ccc(C)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[5-(2-methoxy-ethyl)-2-methyl-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 664.1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:18].N.Cl>C(O)(C)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][SH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: NC(N)=S
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(C)O
Product: SCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 30.8 g of m-phenoxybenzyl bromide in 70 ml of isopropanol is reacted with 9.5 g of thiourea in 30 ml of water and the reaction mixture is refluxed briefly. After cooling, 25 ml of a 25% ammonia solution are added and the mixture is heated briefly to reflux and then allowed to cool, whereupon it is acidified with 18% hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated, affording the compound of the formula ##STR7## with a boiling point of 114°-116° C.'0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8].IC.[C:42]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[N:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:29])=[O:30])[CH3:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)NC(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the product obtained from Step B (59.3 mg, 0.1 mmol) and iodomethane (excess) in DMF was added solid K2CO3 (excess). The mixture was stirred at room temperature under N2 for 4 h. LC-MS indicated the completion of reaction. Most of the solvent was evaporated, and mixture was diluted with ethyl acetate, washed with water, brine and dried. After reverse phase HPLC (acetonitrile/water) purification, the desired tert-butyl 7-(3,4-dichlorophenyl)-6-((4-methoxyphenylsulfonyl)(methyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidine-4(7H)-carboxylate was obtained as white solid. LC-MS found: (M+1)+=607.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=1.[C:15]([S:18][CH2:19][CH2:20][C:21](Cl)=[O:22])(=[O:17])[CH3:16]>O.C(=O)(O)[O-].[Na+].CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[C:15]([S:18][CH2:19][CH2:20][C:21]([N:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8]1)=[O:22])(=[O:17])[CH3:16]
Reactant: O=C(O)C1CC(c2ccccn2)=NN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)SCCC(=O)N1N=C(c2ccccn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-3-(2-Pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (3.82 g) is dissolved in 100 ml of water containing 2.12 g of sodium bicarbonate at 10° C. 3-(Acetylthio)propionyl chloride (3.9 g) in 15 ml of ether and 20% sodium carbonate solution are added simultaneously; the pH is maintained between 7.5 and 8.5. The reaction mixture is then stirred at room temperature for 2 hours and extracted with ether (discarded). The aqueous layer is acidified with acetic acid and extracted with ethyl acetate three times. The solvent is dried over anhydrous magnesium sulfate and concentrated in vacuo, yielding the title compound.