Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH2:23])[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[Si:24]([O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH2:44][CH2:45][CH2:46][C:47]2=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:47]1[C:48]2[C:43](=[C:42]([O:41][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:51]=[CH:50][CH:49]=2)[CH2:44][CH2:45][CH2:46]1)[C:6]1[O:7][C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 78.3 %

Procedure:
The mixture of (1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (5.8 g), 5-tert-butyldiphenylsilyloxy-1-tetralone (11 g) and p-toluenesulphonic acid (32 mg) in toluene (150 ml) was heated under reflux in Dean-Stark apparatus for 48 hours. After the solvent was removed in vacuo, the residue was dissolved in a mixture of methanol (50 ml) and THF (200 ml) and NaBH4(0.4 g) was added to the solution at −78° C. After being stirred for 4 hours at the same temperature, the solution was allowed to stand at the room temperature for 30 minutes, then poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (10.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][N:21]([CH3:24])[C:20](=[O:25])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:23]=[CH:22][N:21]([CH3:24])[C:20](=[O:25])[CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cn1ccc(Br)cc1=O
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cn1ccc(-c2ccc(F)nc2)cc1=O
Temperature: 120 °C

Procedure:
To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 2.242 mmol) was added PdCl2(dppf) (68.3 mg, 0.093 mmol), 4-bromo-1-methylpyridin-2(1H)-one (351 mg, 1.868 mmol), 2M Na2CO3 (4.1 mL) and DME (8.3 mL) at room temperature. The reaction mixture was heated at microwave synthesizer for 10 min at 120° C. The reaction mixture was extracted with EtOAc. The organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered off, and concentrated in vacuo. The crude 6-fluoro-1′-methyl-[3,4′-bipyridin]-2′(1′H)-one was purified by flash chromatography (gradient EtOAc in DCM). LCMS (m/z): 205.2 (MH+), 0.47 min.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl>[CH2:22]([C:19]1[N:18]=[C:17]([CH:16]=[CH:15][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:21][N:20]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Reaction time: 0.62 h

Procedure:
To a cooled solution of 0.997 mL of 1M boron tribromide (0.9 mmol) in 2 mL dichloromethane, 0.150 g (0.433 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-octyl-[1,2,4]oxadiazole (compound of Example 48) dissolved in 1 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain 25° C. to 30° C. slowly, over a period of 1 h. The reaction mass was further stirred at 25° C. to 30° C. for 4-5 h. After completion of the reaction, the reaction mixture was quenched in 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH2:25][CH3:26])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Agent: Cl
Product: CCC1(C)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B9) and (benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclo hexane/EA=6:4) to yield the title compound.
Reaction SMILES: C(N[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O)C(C)C.[ClH:14]>>[ClH:14].[CH2:8]([Cl:14])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:6]=1
Reactant: CC(C)CNc1ccccc1CO
Agent: Cl
Product: ClCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In 190 ml of conc. hydrochloric acid was dissolved 19.1 g of 2-(isobutylamino)benzyl alcohol, and the solution was heated in a sealed tube at 100° C. for 40 min. The reaction mixture was stirred for 30 min. under chilling with ice and the precipitated crystals were collected by filtration. The collected crystals were washed successively with hydrochloric acid and acetone and dried to give 16.9 g (yield: 68%) of 2-isobutylamino)benzyl chloride hydrochloride as a white crystalline product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH3:33])=[C:9]([CH3:32])[CH:10]=[C:11]2[C:19]=1[N:18]=[C:17]1[N:12]2[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][C:15]2[N:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=21.B(OC)(OC)[O:35]C>C1COCC1>[OH:35][C:7]1[C:8]([CH3:33])=[C:9]([CH3:32])[CH:10]=[C:11]2[C:19]=1[N:18]=[C:17]1[N:12]2[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][C:15]2[N:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=21
Reactant: COB(OC)OC
Reactant: Cc1cc2c(nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n23)c(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc2c(nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n23)c(O)c1C
Temperature: 25 °C

Procedure:
13.2 ml (33 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise with vigorous stirring to a solution, cooled to −78° C., of 13.2 g (30 mmol) of 10-bromo-3,6-di-tert-butyl-8,9-dimethyl-4,6a,11-triazabenzo[α]fluorene in 300 ml of THF, and the mixture is stirred for a further 30 min. 4.7 ml (42 mmol) of trimethyl borate are added to this solution in one portion, the mixture is stirred for a further 1 h and then allowed to warm to room temperature. The solvent is removed in vacuo, the residue is taken up in 1000 ml of ethyl acetate, the solution is cooled to 5° C., 19 ml of aqueous H2O2 solution (30% by weight) are added with vigorous stirring, and a solution of 825 mg of NaOH in 20 ml of water is then added dropwise. After stirring for 3 h, 300 ml of saturated ammonium chloride solution are added, the organic phase is separated off, washed twice with 200 ml of water each time, dried over magnesium sulfate, and the org. phase is then evaporated to a volume of about 50 ml in vacuo. 200 ml of methanol are added to the crystal slurry, the crystals are filtered off with suction and washed once with 50 ml of methanol and dried in vacuo.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:21][C:22]1[S:26][C:25]([C:27](SC)=[NH:28])=[CH:24][CH:23]=1>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:21][C:22]1[S:26][C:25]([C:27](=[NH:28])[NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH2:12]3)=[CH:24][CH:23]=1
Reactant: CSC(=N)c1ccc(C)s1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)CCCN3CCCN2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a stirred solution of 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in ethanol (6 ml) was added methyl 5-methylthiophene-2-carbimidothioate hydroiodide (265 mg, 0.887 mmol). The resulting suspension was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane. The combined organics were dried, filtered and concentrated, then chromatographed on silica gel with ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane as eluent to give the desired 5-methyl-N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (98 mg, 0.256 mmol, 57.8% yield). 1H NMR (DMSO-d6) δ 7.45 (d, J=3.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.53 (m, 2H), 6.45 (s, 1H), 6.13 (brs, 2H), 3.26-3.16 (m, 4H), 2.68-2.63 (m, 2H), 2.43-2.39 (m, 6H), 2.41 (s, 3H), 1.86-1.82 (m, 2H), 1.68-1.64 (m, 6H). ESI-MS (m/z, %) 383 (MH+, 39), 272 (49), 192 (100). ESI-HRMS calculated for C22H31N4S (MH+), calculated: 383.2264, observed:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1]C1C=CN=CC=1.C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([NH2:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Yield: 122.4 %

Procedure:
To a solution of 4-aminopyridine (3.00 g, 31.9 mmol) in CH2Cl2 (50 mL) at 0° C. was added triethylamine (6.70 mL, 47.9 mmol) and benzoyl chloride (3.70 mL, 31.9 mmol). The ice bath was removed and the resulting mixture was allowed to warm tort over 1.5 h. The reaction was quenched with saturated aqueous NaHCO3, extracted with CH2Cl2, washed with brine, dried (MgSO4) and concentrated. The crude product was recrystallized from EtOAc/hexanes to give 4.73 g (75% yield) of pure benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([F:29])([F:28])[F:27].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:17]2[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]([C:26]([F:27])([F:28])[F:29])=[C:13]([Cl:12])[C:18]=2[N+:19]([O-:21])=[O:20])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: Nc1ncc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
In 20 ml. of dimethylformamide, 1.63 g. of 2-amino-3,5-dichloropyridine was dissolved and 0.73 g. of powdery potassium hydroxide was added with stirring. After the addition, 3.06 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride was added during 10 minutes. The reaction was continued for about 2 hours. After the reaction, the reaction mixture was poured into water and acidified with conc. HCl and the product was extracted with methylene chloride. The extracted layer was washed with water and dehydrated and the solvent was distilled off and the product was separated by a silica gel column with an eluent of toluene and then the solvent was distilled off to obtain 1.38 g. of the object compound having the melting point of 64° to 65° C.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:19])=O>ClCCl>[CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([Cl:19])=[O:6]
Reactant: CN(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Yield: 88.6 %

Procedure:
3-[Methyl-(4-nitro-phenyl)-amino]-propionic acid (1.2 g, 5.35 mmol) in dichloromethane (10 mL) was cooled to 0° C. and thionyl chloride (1.55 mL, 21.4 mmol) was added. The mixture was heated to reflux for 4 h. The solvent was evaporated to give the crude compound which was azeotroped with toluene to remove the traces of thionyl chloride, affording 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (1.15 g, 88%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OC(=O)C)(=O)C.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:8]([C:7]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cccnc1Br
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2ncccc2C#N)cc1

Procedure:
Synthetic Scheme XXV shows the 8-step preparation of the alkylating reagent 2-(4-bromomethylphenyl)-3-cyanopyridine (53) from 2-amino-3-picoline (54) (Aldrich). In step 1, the aminopicoline 54 was converted to the bromopicoline 55 by reaction with bromine, concentrated hydrobromic acid, and sodium nitrite at 0° C. In step 2, the picoline 55 was oxidized with KMNO4 to give the corresponding carboxylic acid 56. In step 3, the acid 56 was reduced to the alcohol 57 with borane/THF. In step 4, the alcohol 57 was oxidized to the aldelyde 58 under Swern conditions or by using MnO2. In step 5, the aldehyde 58 was reacted with hydroxylamine to give the oxime 59. In step 6, the oxime 59 was converted to 2-bromo-3-cyanopyridine (60) with acetic anhydride at reflux. In step 7, the nitrile 60 was coupled with 4-methylphenylboronic acid (52) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-2-(4-methylphenyl)pyridine (61). In step 8, 61 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 53. ##STR79##
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>>[C:1]1([S:7]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[OH:21])[CH2:15][CH2:16]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=S(=O)(NC1CCN(CCCC(O)c2ccccc2)CC1)c1ccccc1

Procedure:
4-Benzenesulphonamido-1-(4-phenyl-4-oxobutyl)piperidine prepared according to Example 2 may be reduced using sodium borohydride to give the title compound.
Reaction SMILES: [OH:1][C:2]1([C:7]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1([C:2]2([OH:1])[CH2:6][CH2:5][O:4][CH2:3]2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C(c1ccccn1)C1(C2(O)CCOC2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccn1)C1(C2(O)CCOC2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a solution of Example 246B (15 mg, 0.06 mmol) in MeOH (5 mL) was added NaBH4 (13 mg, 0.34 mmol) in one portion. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain the title compounds as corloless oils (5.0 mg, yield 30%). MS (M+1) δ 250.2; 1H NMR: (400 MHz, CDCl3): δ 8.60 (d, J=3.6 Hz, 1H), 7.76-7.72 (m, 1H), 7.49-7.46 (m, 1H), 7.31-7.28 (m, 1H), 4.96 (s, 1H), 4.84 (brs, 1H), 4.09-3.83 (m, 3H), 3.76 (d, J=9.6 Hz, 0.66H), 3.56 (d, J=10.0 Hz, 0.44H), 2.27-2.14 (m, 1H), 2.08-1.80 (m, 5H), 1.68-1.50 (m, 1H), 1.16-1.04 (m, 0.67H), 0.95-0.83 (m, 0.48H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1cnc(I)nc1
Product: Clc1ccccc1-c1ncc(Br)cn1
Yield: 69 %

Procedure:
Obtained (0.400 g, yield 69%) following the procedure described in Intermediate 21, starting with 5-bromo-2-iodopyrimidine (2.14 mmol, 0.61 g), 2-chlorophenylboronic acid (2.37 mmol, 0.37 g).
Reaction SMILES: N[C@@H:2]([CH:6](C)C)[C@H:3](O)[CH3:4].[NH2:9][C@@H:10]([CH:19]([CH3:21])[CH3:20])[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CCCCCC>[CH3:20][CH:19]([CH3:21])[C@H:10]([N:9]1[CH2:4][CH2:3][CH2:2][CH2:6]1)[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Reactant: CC(C)[C@H](N)[C@@H](C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]([C@H](O)c1ccccc1)N1CCCC1
Yield: 86 %

Procedure:
Repeat Step (a) of EXAMPLE 1, but replace (2R,3S)-3-amino-4-methylpentan-2-ol with (1R,2S)-2-amino-3-methyl-1-phenylbutan-1-ol, and replace Na2CO3 (1.16 g, 11.0 mmol) with K2CO3 (1.52 g, 11.0 mmol). Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=10:1) is used to purify the coarse product and a slightly-yellow liquid (1.00 g) is obtained. The yield is 86% and the other analysis includes:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:19]([C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)=O.[OH-].[K+]>CCO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])/[CH:17]=[CH:19]/[C:21]3[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-ethanone (prepared following the procedure described in Example 16 STEP A, 533 mg, 2.16 mmol), 4-formylcinnamic acid (381 mg, 2.16 mmol) and 1.7 M KOH (2.54 ml) in EtOH (15 ml) and water (3 ml) was stirred overnight at room temperature. The resulting precipitate was filtered to get 260 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its potassium salt. The mother liquors were acidified with 10% HCl and the resulting green precipitate was filtered to give 240 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride. The mixture of both, the potassium salt and of the hydrochloric salt, was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:27]=[CH:28][CH:29]=2)[N:5]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:6](=[O:21])[C:7]=1[C:8]1[NH:13][C:12]2[CH:14]=[CH:15][C:16](I)=[CH:17][C:11]=2[S:10](=[O:20])(=[O:19])[N:9]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>[Cu]I.CN(C)C=O>[OH:1][C:2]1[C:3]2[N:4]([CH:27]=[CH:28][CH:29]=2)[N:5]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:6](=[O:21])[C:7]=1[C:8]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([NH:60][S:57]([CH:54]3[CH2:56][CH2:55]3)(=[O:59])=[O:58])=[CH:17][C:11]=2[S:10](=[O:20])(=[O:19])[N:9]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Reactant: NS(=O)(=O)C1CC1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C4CC4)ccc3N2)c(O)c2cccn21
Yield: 50.3 %

Procedure:
4-Hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (Example 13a, 0.105 g, 0.199 mmol), potassium triphosphate (0.127 g, 0.598 mmol), sarcosine (0.011 g, 0.119 mmol), and copper (I) iodide (0.015 g, 0.080 mmol) were combined. Anhydrous N,N-dimethylformamide (7 mL) was added followed by cyclopropanesulfonic acid amide (0.12 g, 1 mmol). The solution was degassed while stirring under vacuum and the flask purged with nitrogen. The mixture was stirred at 100° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to a solid. Purification by HPLC (Column Luna 5u C18 (2) 100 Å size 50×21.2 mm, 5 micron, 40%-95% 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, cyclopropanesulfonic acid {3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (0.052 g, 0.10 mmol, 50% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.97 (10H, m), 1.51 (2H, q, J=7.2 Hz), 1.73 (1H, m), 2.71 (1H, m), 4.41 (2H, t, J=7.6 Hz), 6.72 (1H, m), 7.02 (1H, d, J=3.6 Hz), 7.58 (1H, m), 7.63 (2H, m), 7.88 (1H, s), 10.12 (1H, bs). LC-MS (ESI) calcd for C22H25N5O6S2, found 519.12, found 520.3 [M+H+].