Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[N:13]=2)[CH:8]=[CH:9][C:10]=1[CH3:11].Cl>O1CCCC1.C(O)(C)C.O1CCOCC1>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[N:13]=2)=[CH:6][C:5]=1[OH:4]
Reactant: COCOc1cc(-c2nc(C)no2)ccc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1noc(-c2ccc(C)c(O)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole (1.23 g, 5.25 mmol) in tetrahydrofuran/isopropanol (1:1, 30 mL) was added 13.1 mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethyl acetate/hexane to afford 2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol. (Yield 0.88 g, 88%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][CH:5]=1>O1CCOCC1.C(Cl)(Cl)Cl>[Br:1][C:21]1[C:20]2[C:15]([C:14]3[NH:13][S:12](=[O:25])(=[O:24])[N:11]([CH3:26])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[C:23]=3[CH:22]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CN1C(c2ccc(F)cc2)c2cc(Br)c3cccnc3c2NS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
Bromine (7.48 μl, 0.15 mmol) was added to a solution of 1-(4-fluoro-phenyl)-2-methyl-1,4-dihydro-2H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 382 (50 mg, 0.15 mmol) in dioxane:chloroform (1:1, 4 ml) at 0° C. and the mixture was stirred at 0° C. for 1 h. The resulting precipitate was collected by filtration and dried. The resulting solid was triturated from MeOH to give the title compound (17 mg, 28%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1[CH:26]=[C:25]2[C:27]([CH2:30][C:31](O)=[O:32])=[CH:28][NH:29][C:24]2=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.C(Cl)CCl>[NH:29]1[C:24]2[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=2)[C:27]([CH2:30][C:31]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:32])=[CH:28]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Reaction time: 8 h
Yield: 57.4 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 140 mg Indolyl-3-acetic acid, 98 mg HOBT and 0.6 ml Et3N are dissolved in 8 ml DMF. To this mixture are added 278 mg EDC and the mixture is stirred overnight. The reaction mixture is evaporated and the crude product is purified by silica gel flash chromatography. 180 mg of the title compound are obtained in 57% yield.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH2:15][S:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]4[CH2:15][S:14][CH2:13][C:9]=4[N:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[O:33])=[CH:37][CH:38]=1
Reactant: c1nc2c(c(N3CCNCC3)n1)CSC2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine (0.28 g, 1.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (5 mL) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.38 g, 1.3 mmol). After stirring for 30 minutes, HBTU (0.57 g, 1.5 mmol) was added. The mix was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.62 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 5.38-5.35 (m, 1H), 3.70-3.50 (m, 6H), 3.27-3.13 (m, 2H), 2.98-2.92 (m, 2H), 1.42 (s, 9H). MS (APCI+) [M+H]+ 505.
Reaction SMILES: [ClH:1].Cl.C1(NC2C=C(N3CCNCC3)C=CN=2)CCCC1.C1(N[C:27]2[CH:32]=[C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:30]=[CH:29][N:28]=2)CCCC1>C(O)=O.Cl>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:1])[CH:32]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(NC3CCCC3)c2)CC1
Reactant: Cl
Agent: c1cc(N2CCNCC2)cc(NC2CCCC2)n1
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.5 mmol) in toluene (100 mL) was added piperazine-1-carboxylic acid tert-butyl ester (3.2 g, 17.2 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N2(g) twice. A mixture of Xantphos (600 mg, 1.0 mmol) and Pd2(dba)3 (318 mg, 0.35 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to rt, diluted with H2O (75 mL), and extracted with EtOAc (3×). The combined organic layers were dried and concentrated to give a clear golden oil. The oil was purified on FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to give the title product as a beige solid (5.1 g, 100%). MS (ESI): mass calcd. for C14H20ClN3O2, 297.1; m/z found, 298.2 [M+H]+. 1H NMR (DMSO-d6): 7.95 (d, J=5.9, 1H), 6.88-6.78 (m, 2H), 3.46-3.32 (m, 8H), 1.42 (s, 9H). tert-Butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate. To a stirring solution of 4-(2-chloro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.55 mmol) in toluene (2 mL) in a vial was added cyclopentylamine (136 μL, 1.38 mmol) and sodium tert-butoxide (161 mg, 1.68 mmol). A mixture of racemic BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (18 mg, 0.027 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to rt and purified directly by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to provide the title compound as a white solid (34 mg, 17%). MS (ESI): mass calcd. for C16H30N4O2, 346.2; m/z found, 347.3 [M+H]+. 1H NMR (DMSO-d6): 7.65 (d, J=6.0, 1H), 6.10 (d, J=6.0, 1H), 5.92 (d, J=7.1, 1H), 5.78 (s, 1H) 4.08-4.02 (m, 1H), 3.41 (t, J=5.4, 4H), 3.16 (t, J=5.4, 4H), 1.89-1.82 (m, 2H), 1.67-1.61 (m, 2H), 1.59-1.48 (m, 2H), 1.42 (s, 9H), 1.43-1.35 (m, 2H). N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine dihydrochloride. To a stirring solution of tert-butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate (34 mg, 0.1 mmol) in 96% formic acid (4 mL) was added 6 N aq HCl (2 drops). The mixture was stirred for 2 h and concentrated to give the desired product as a white solid (26 mg, 93%). MS (ESI): mass calcd. for C14H22N4, 246.2; m/z found, 247.2 [M+H]+. 1H NMR (DMSO-d6): 9.32 (s, 2H), 7.89 (d, J=7.1, 1H), 7.69 (d, J=7.5, 1H), 6.58 (d, J=7.6, 1H), 6.04 (s, 1H), 4.03-3.96 (m, 1H), 3.73 (t, J=4.9, 4H), 3.20 (t, J=5.0, 4H), 2.03-1.95 (m, 2H), 1.73-1.68 (m, 2H), 1.64-1.52 (m, 2H), 1.50-1.42 (M, 2H). The compounds in Example 17 through Example 20 were prepared using methods analogous to those described for Example 16.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][N:9]=1)[CH3:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[CH3:26][NH2:27]>CO>[CH3:3][N:2]([CH2:4][C:5]1[S:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[C:21]([NH:27][CH3:26])=[N:20][S:19](=[O:25])(=[O:24])[N:18]=2)=[CH:8][N:9]=1)[CH3:1]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN
Reactant: CN(C)Cc1ncc(CSCCN)s1
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1cnc(CN(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (1.55 g; 6.7 mmoles) [prepared in Step D] in 60 ml of methanol was added dropwise over 40 minutes to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.19 g; 6.7 mmoles) in 130 ml of methanol that had been cooled to 8°. Upon completion of the addition, anhydrous methylamine was bubbled into the solution for 8 minutes, then stirred at ambient temperature overnight. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on 150 g of silica gel using a gradient elution of acetonitrile-methanol. The appropriate fractions were combined to give 1.05 g of product. Recrystallization from 2-propanol yielded the title compound, mp 170°-172°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB(C2[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=NC=2)O1.C(#[N:50])C>C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:35]4[CH:34]=[N:50][C:40]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:39][CH:36]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC#N
Reactant: CC1(C)OB(c2ccc(CCN3CCOCC3)nc2)OC1(C)C
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3ccc(N4CCOCC4)nc3)ccc1-2
Temperature: 140 °C

Procedure:
To a microwave vial was added 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide (0.100 grams, 0.243 mmol) in 2M sodium carbonate (0.500 mL) and ACN (0.636 mL), and then 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)morpholine (0.292 mmol) was added. This solution was degassed by bubbling nitrogen through the solution for several minutes. Finally, palladium tetrakis(triphenylphosphine)palladium(0) was added and the vial was tightly capped. The reaction mixture was then flash heated on a Biotage microwave at 140° C. for 20 minutes. The cooled reaction mixture was diluted with EtOAc and the organic was washed with water, then saline and dried (Na2SO4) before concentration to a solid. The crude material was purified by preparative RP-HPLC to give 267. MS: (ESI+)=495.1
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of (2S,3R)-N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (736 mg, 3.00 mmol) in DMF (10 mL) at rt was added imidazole (1.02 g, 15.0 mmol), DMAP (12.0 mg), and tert-butydiphenylsilyl chloride (988 mg, 3.60 mmol). After stirring overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (eluting with 30% EtOAc/hexane) to yield compound 1E (1.36 g).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>N1C=CC=CC=1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OC(F)F)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
0.18 mL of 4-difluoromethoxybenzene sulfonyl chloride (1.13 mmol) were added to a solution of 0.25 g of (1.13 mmol) 4-methoxy-3-(4-methyl-piperazin-1-yl)-phenylamine in 10 mL of pyridine. The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated at reduced pressure. After addition of toluene and dichloromethane the mixture was again evaporated twice. The thus obtained residue was partitioned between dichloromethane and 5% aqueous ammoniumchloride. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was further purified via HPLC to yield 0.395 g of the desired title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:33][C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCOCc1nc2c(c3cc(O)ccc3n3nnnc23)n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(c3cc(OCc4cccc(C(=O)OC)c4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 8 h

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-ol, 4.0 g, 11.75 mmol was dissolved in 100 mL of DMF and stirred with potassium carbonate (3.3 g, 23.5 mmol) for 30 minutes. To this mixture was added methyl 3-(bromomethyl)benzoate (2.8 g, 12.33 mmol) and the reaction was stirred overnight. The reaction was poured into 10 volumes of water and the precipitate was sequentially filtered, dissolved in dichloromethane, dried over magnesium sulfate, filtered, and concentrated to give 6.1 g of methyl 3-{[(5-ethoxymethyl-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-yl)oxy]methyl}benzoate as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[O:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[ClH:16].[F:29][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([CH2:19][CH2:18][CH2:17][N:13]3[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:15][CH2:14]3)=[N:21][O:22][C:23]=2[CH:28]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc2c(CCCN3CCC(CCCc4ccccc4)CC3)noc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To 40 ml of dimethylformamide was added 4.06 g of 4-(3-phenylpropyl)piperidine, 3.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of milled potassium carbonate, and 0.01 g of potassium iodide. After stirring at 90° C. for three hrs, the mixture was cooled, filtered and the filtrate was evaporated to an oil. The oil was stirred with 100 ml of water for ten mins and then extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solution was acidified to pH 1 with ethereal hydrogen chloride. The resultant precipitate was collected and dried to give 5.0 g (60%) of product, mp 95° C. Recrystallization from ethyl acetate/methanol (5:1) gave the analytical sample, mp 136°-137° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:12])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[CH:5]=1.Br[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=O)=[CH:16][C:15]=1[CH2:24]OC.[CH2:27](Cl)[CH2:28]Cl>CC#N.N1C=CC=CC=1>[CH3:21][O:20][CH2:18][C:17]1[CH:16]=[C:15]([C:24]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[CH:5]=3)[N:12]=2)[CH:14]=[CH:23][C:22]=1[C:8]1[CH:9]=[CH:4][CH:5]=[CH:6][C:27]=1[CH3:28]
Reactant: NC(=NO)c1ccnc(CO)c1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: ClCCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3ccnc(CO)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N′-hydroxy-2-(hydroxymethyl)isonicotinimidamide (Example 66, Step 1; 0.100 g; 0.30 mmol) and Intermediate A1 (0.108 g; 0.42 mmol) in MeCN (3 mL) was added EDC (0.060 g; 0.38 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. in the microwave for 30 minutes. This process was repeated 4 times and combined for work-up. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.76 (1 H, d, J=5.2 Hz), 8.44 (1 H, s), 8.18 (1 H, dd, J=7.9, 1.9 Hz), 8.06 (1 H, s), 7.99 (1 H, d, J=5.2 Hz), 7.39-7.22 (4 H, m), 7.13 (1 H, d, J=7.5 Hz), 4.90 (2 H, s), 4.28-4.18 (2 H, m), 3.65 (1 H, br s), 3.34 (3 H, s), 2.08 (3 H, s). LC/MS: 388 (M+H)+. HPLC (Method B) Rt 3.91 min (Purity: 98.1%).
Reaction SMILES: CS[C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.[Cl:13][C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([O:21][CH3:22])=[C:18]([CH:20]=1)[NH2:19]>C(O)CCC>[Cl:13][C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([O:21][CH3:22])=[C:18]([CH:20]=1)[NH:19][C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: CSC1=Nc2ccccc2CS1
Reactant: COc1cc(OC)c(Cl)cc1N
Solvent: CCCCO
Product: COc1cc(OC)c(NC2=Nc3ccccc3CS2)cc1Cl
Yield: 43 %

Procedure:
A mixture of 2-methylthio-4H-3,1-benzothiazine (48.8 g, 0.25 mole) and 5-chloro-2,4-dimethoxyaniline (46.8 g, 0.25 mole) in n-butanol (200 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol to give 36 g (43.4%) of product. Recrystallization from ethanol gave an analytical sample, m.p. 157°-158°.
Reaction SMILES: [NH2:1][C:2]1C=C[NH:4][N:3]=1.[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH3:12].N1CCCCC1.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23]C=1>C(O)C>[CH3:7][C:8]1[CH:9]=[C:10]([CH2:11][CH3:12])[N:3]2[N:4]=[C:24]([CH3:23])[C:25]([CH2:26][CH3:21])=[C:2]2[N:1]=1
Reactant: Nc1cc[nH]n1
Reactant: c1ccccc1
Reactant: CCC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1c(C)nn2c(CC)cc(C)nc12
Yield: 87 %

Procedure:
The compound was prepared, as described above, from 3-aminopyrazole (8.3 g) and hexane-2,4-dione (11.4 g) in ethanol with a catalytic amount of piperidine. The product was isolated as a colorless oil (14.0 g, 87% yield) via chromatography on basic alumina with benzene. Oil, b.p. 173°-177°/0.1mm. Mass spectrum M+ = 161.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:1]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Nc1ccccc1

Procedure:
Aniline, ethyl 2-bromoisobutyrate and potassium carbonate were reacted in DMF at 90° C. to obtain ethyl 2-anilino-2-methylpropanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[ClH:1].[ClH:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:10][CH2:9]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Yield: 118.3 %

Procedure:
The procedure described in Example 17(a) was followed, using 6.5 g of 1-(4-chlorophenethyl)piperazine, 6.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 4.6 g of 1-bromo-3-chloropropane. Work-up, as described above, gave 6.4 g (59% of theory) of 1-(4-chlorophenethyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[N:21]([CH2:28][C:29](O)=[O:30])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:29](=[O:30])[CH2:28][N:21]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[C:19]([C:18]([F:32])([F:17])[F:33])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), 2-[3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl]acetic acid (0.027 g, 0.11 mmol) and NEt3 (0.050 mL, 0.36 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.027 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.42 (dd, J=8.8, 4.4 Hz, 2H), 7.17 (dd, J=9.2, 8.0 Hz, 2H), 5.15 (s, 2H), 3.87 (m, 2H), 2.82 (t, J=6.2 Hz, 2H), 2.61 (m, 4H), 2.11 (m, 2H), 1.87 (m, 2H), 1.79 (m, 2H); MS: (ES) m/z calculated for C22H21F4N5O [M+H]+ 448.1, found 448.1.