Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.Cl.[N+:59]([C:62]1[CH:63]=[CH:64][C:65]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[N:66][CH:67]=1)([O-:61])=[O:60]>CN(C)C=O.ClCCl.O1CCCC1>[N+:59]([C:62]1[CH:63]=[CH:64][C:65]([NH:68][CH:69]2[CH2:74][CH2:73][N:72]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:22])[F:23])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:71][CH2:70]2)=[N:66][CH:67]=1)([O-:61])=[O:60]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (35 mg; 0.11 mmol, prepared in accordance with Example 3), diisopropylethyl amine (174 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (37 mg; 0.1 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (5-nitro-pyridin-2-yl)-piperidin-4-yl-amine dihydrochloride (29 mg; 0.1 mmol, prepared in accordance with Example 97) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 90 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (41 mg; 0.08 mmol). The structure was confirmed using Protocol II-A. Calculated mass=521; observed mass=521; HPLC retention time=3.20 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]2[S:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:8]1[S:9][C:5]2[C:4]([F:12])=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Fc1cc(F)c2sc(S)nc2c1
Solvent: CN(C)C=O
Product: Fc1cc(F)c2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.6 %

Procedure:
To a suspension of 2 g (9.841 mmol) 5,7-difluoro-benzothiazole-2-thiol in 10.7 mL (147.6 mmol) thionyl chloride was added drop wise 215 □L N,N-dimethylformamide at room temperature. The mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 659 mg (32.6%) of the title compound as an off-white solid. MS(m/e): 205 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (311 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow solid (550 mg, 85%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH3:12]I>CS(C)=O>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: CI
Reactant: COC(=O)C(C)(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCC(C)(C)C(=O)OC
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of 3.52 g (63 mmol) of powdered potassium hydroxide in DMSO (150 mL) are added 2 mL (16 mmol) of hydroxypivalic acid methyl ester, followed by 3.9 mL (63 mmol) of methyl iodide. The reaction mixture is stirred for 0.5 h, then quenched with water (300 mL). The reaction mixture is extracted with DCM (3×300 mL). The combined organic extracts are washed with water (2×150 mL), brine (50 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.76 g of 3-methoxy-2,2-dimethyl-propionic acid methyl ester as a pale yellow oil, which is used in the next step without further purification. Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (2H, s), 3.6 (3H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([CH3:33])[N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[C:31]([CH3:33])[N:32]=[C:24]([OH:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: Cc1cc(C(=O)O)cc(O)n1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: Cc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)cc(O)n1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-hydroxy-6-methylisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.42 (m, 1H), 1.54-1.72 (m, 5H), 1.80 (m, 1H), 2.16 (s, 3H), 3.21 (m, 1H), 3.44 (m, 1H), 4.19 (dd, 1H, J=10.3, 4.2 Hz), 4.37 (m, 1H), 4.61 (t, 1H, J=10.0 Hz), 5.14 (m, 1H), 5.88 (s, 1H), 6.02 (s, 1H), 6.61 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=8.4 Hz), 7.44 (t, 1H, J=8.4 Hz), 7.75 (br s, 1H), 8.34 (br s, 1H), 10.92 (s, 1H). MS 446 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:9][C:10]1[C:17]([C:18]#[C:19][Si](C)(C)C)=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([C:12]#[N:13])=[CH:14][CH:15]=[C:16]2[C:17]=1[CH:18]=[CH:19][N:1]2[C:2]([CH3:8])([C:3]([OH:5])([CH3:6])[CH3:4])[CH3:7]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(N)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)C(C)(C)n1ccc2c(Cl)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (0.063 g, 0.539 mmol), 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.113 g, 0.449 mmol), and K2CO3 (0.137 g, 0.988 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 1 h, the vial was sealed with a PTFE-faced crimp top and subjected to microwave heating; 1 h at 140° C. followed by 45 min at 160° C. (with air cooling). The mixture was poured into water/EtOAc and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 4-chloro-1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-5-carbonitrile (0.0066 g, 5% yield) as a tan solid (ca. 85% purity): 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=9.0 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 6.71 (d, J=3.4 Hz, 1H), 1.87 (s, 6H), 1.20 (s, 6H); MS (LCMS ES+) m/z 277 ([M+H]+, 65%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([NH2:18])=O)[NH:11]2.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]#[N:18])[NH:11]2
Reactant: NC(=O)c1cc2c(Br)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc2c(Br)cccc2[nH]1
Yield: 82.3 %

Procedure:
Phosphorous oxychloride (1.9 mL, 20 mmol) was added to a suspension of 4-bromo-1H-indole-2-carboxylic acid amide (1.32 g, 5.5 mmol.) in toluene (10 mL) and the mixture was stirred at reflux for 45 min. On cooling, the mixture was poured into an aqueous Na2CO3 solution (sat., 50 mL) and the mixture stirred until effervescence had subsided. The layers were separated, the aqueous phase extracted with EtOAc and the combined organic layers dried (MgSO4) and evaporated to dryness. The crude material was purified by column chromatography to afford the title compound as a solid (1.00 g, 82%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCCBr)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2ccc(Cl)cc2)CC1
Yield: 26.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.6 g) as starting compound, potassium carbonate (2.3 g) and 7-bromo-1-(4-chlorophenyl)-1-heptanone (2.2 g) were reacted and treated in the same manner as in Example 172 to give 0.60 g of 4-amino-5-chloro-N-((1-(7-(4-chlorophenyl)-7-oxoheptyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:29]([CH:28]1[CH2:27][CH2:26][C:25](=[O:45])[NH:24][C:23]1=[O:22])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccc(Cl)c4)c3C2=O)C(=O)N1
Yield: 89 %

Procedure:
3-(3-Chloro-benzylamino)-phthalic acid (4.8 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was slurried in diethyl ether (30 ml) for 18 h and filtered to give 1.42 g (89%) of product as a yellow solid: mp 207–209° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.55–7.28 (m, 6H), 7.03 (d, J=7.0 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 5.08 (dd, J=5.4 and 12.4 Hz, 1H), 4.58 (d, J=6.3 Hz, 2H), 2.98–2.83 (m, 1H), 2.64–2.46 (m, 2H), 2.08–2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.56, 169.84, 168.59, 167.11, 145.76, 141.68, 136.01, 133.10, 132.16, 130.25, 126.83, 126.68, 125.48, 117.40, 110.81, 109.74, 48.54, 41.54, 44.80, 30.87, 22.05; Anal. Calcd. For C20H16ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found: C, 60.22; H, 4.05; N, 10.38.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH2:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1)[CH3:14]
Reactant: CCc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
A solution of 2.02 g of (RS)-2-(2-oxoethyl)-6-ethyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.7 g (71%) of (R)-1-(7-ethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: C(N(CC)CC)C.F[C:9](F)(F)[C:10]([OH:12])=[O:11].[CH2:15]([N:22]([CH3:50])[CH2:23][CH2:24][CH:25]1[N:30]2[C:31](=[O:40])[N:32]([CH:37]([CH3:39])[CH3:38])[C:33](=[O:36])[C:34](O)=[C:29]2[C:28](=[O:41])[N:27]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:26]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([O:12][C:34]1[C:33](=[O:36])[N:32]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:40])[N:30]2[CH:25]([CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:50])[CH2:26][N:27]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:28](=[O:41])[C:29]=12)(=[O:11])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)Cc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c2n(c(=O)n(C(C)C)c1=O)C(CCN(C)Cc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (370 μL, 2.64 mmol) and DMAP (21 mg, 0.18 mmol) were added to a stirred solution of 4-{2-[benzyl(methyl)amino]ethyl}-2-(4-fluorobenzyl)-9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione trifluoroacetate (from Example 52, 535 mg, 0.88 mmol) in anhydrous CH2Cl2 (10 mL) at 0 C. Acetyl chloride (94 μL, 1.32 mmol) was added and the mixture was then stirred at room temperature for 20 min. The solvent was removed in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange solid which was carried directly into the hydrogenation step. ES MS (M+1)=537.6.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[CH:3]=1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>ClCCCl>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:2]2[N:7]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)=[C:6]3[N:5]=[C:4]([CH3:25])[CH:3]=2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-3A-4b; 109 mg, 0.280 mmol) and Argonaut™ PS-DIEA (97 mg, 0.38 mmol) in 1,2-dichloroethane (2.8 ml) was added piperazine-1-carboxylic acid tert-butyl ester (70.5 mg, 0.378 mmol). The mixture was stirred at room temperature for 19 hours, filtered, concentrated and then purified on a Biotage™ Flash 12M column using 0–35% ethyl acetate in hexanes as eluant to afford, after trituration from hexanes/methylene chloride, product 5A-1 (132 mg, 88%) as an off-white solid: +ESI MS (M+1) 538.4; 1H NMR (400 MHz, CD2Cl2) δ 7.48–7.32 (m, 6H), 7.22 (d, J=8.7 Hz, 2H), 6.13 (s, 1H), 3.73–3.61 (m, 8H), 2.56 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.71 (s, 1H), 8.38-8.41 (m, 1H), 7.89-8.02 (m, 2H), 7.72-7.75 (m, 1H), 7.46-7.49 (m, 2H), 7.38-7.44 (m, 4H), 7.36-7.40 (m, 2H), 3.70 (s, 2H), 2.41 (s, 3H); MS (APCI+) M/Z 404 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[BrH:18]>>[BrH:18].[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(N3CCNCC3)noc2c1
Agent: Br
Product: Oc1ccc2c(N3CCNCC3)noc2c1

Procedure:
Heat a stirred mixture of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (0.1 mol), and 62% w/w hydrobromic acid (116.5 mL) at 115° C. under nitrogen for 6 hours. Partially concentrate under reduced pressure (15-20 mm Hg) at 50 to 60° C., add water (100 mL) and concentrate again. Repeat this process two times. Treat the residual heterogenous slurry with water (150 mL), age at 5° C. for 0.5 hour, and collect the solid by vacuum filtration. Wash the filter cake twice with cold water and dry to afford 6-hydroxy-3-(1-piperazinyl)-1,2-benzisoxazole hydrobromide (33.7 g). Suspend the crude material in water (830 mL), heat to 95-97° C., treat with activated charcoal (6.64 g), age at 95-97° C. for 0.25 hour, vacuum filter through celite, cool the filtrate to 5° C. and after 0.5 hour collect the product by vacuum filtration. Wash the filter cake twice with cold water and dry at 80° C. in high vacuum for 4 hours to afford 6-hydroxy-3-(1-piperazinyl)-1,2-benzisoxazole hydrobromide (23.5 g, 79%). The material was 99.8% pure by HPLC (Nucleosil C-18 column, 5 micron, 4.6×25 cm; mobile phase: NH4H2PO4 (0.05N):acetonitrile, 55:45 v/v; flow rate 1 mL/min; UV detection at 220/240 nm. MS (EI) 219 (M+)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25]([Br:27])[CH:24]=[N:23]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:28]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]([F:28])=[C:25]([Br:27])[CH:24]=[N:23]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cnn(C2CCN(Cc3ccccc3)CC2)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(Br)cnn1C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of lithium diisopropylamide (1.0 M in THF/hexanes) (1.25 mL, 1.25 mmol) was slowly added to a −78° C. solution of 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (200 mg, 0.625 mmol) in THF (2.0 mL), and the reaction was allowed to stir at −78° C. for 1 hour. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (295 mg, 0.937 mmol) was added, and the reaction stirred for an additional 1 hour at −78° C. The reaction was quenched via the addition of saturated aqueous ammonium chloride (5 mL). The reaction was warmed to room temperature and concentrated in vacuo. Ethyl acetate (25 mL) was added, and the organic solution was washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine (53 mg, 25%) as a light yellow oil. MS (ESI, pos. ion) m/z 339 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CS(O[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])(=O)=O>>[C:17]([C:12]1[C:13](=[O:16])[N:14]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)([OH:19])=[O:18]
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)cc1F
Yield: 56 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 56.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([CH3:26])=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:34])[NH:12][C:11]([C:21]2[S:22][C:23]([CH3:26])=[N:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Yield: 70.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.88 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.73 g, 70%). The compound was characterized by the following spectroscopic data: